HGNC Approved Gene Symbol: PAH
SNOMEDCT: 7573000; ICD10CM: E70.0;
Cytogenetic location: 12q23.2 Genomic coordinates (GRCh38) : 12:102,836,889-102,958,441 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q23.2 | [Hyperphenylalaninemia, non-PKU mild] | 261600 | Autosomal recessive | 3 |
| Phenylketonuria | 261600 | Autosomal recessive | 3 |
Phenylalanine hydroxylase (PAH; EC 1.14.16.1) catalyzes the hydroxylation of phenylalanine to tyrosine, the rate-limiting step in phenylalanine catabolism. The reaction is dependent on tetrahydrobiopterin (BH4), as a cofactor, molecular oxygen, and iron. Phenylketonuria (PKU; 261600) is an autosomal recessive inborn error of metabolism resulting from a deficiency of PAH (Zurfluh et al., 2008).
Two isozymes of phenylalanine hydroxylase were reported to exist in human fetal liver (Barranger et al., 1972). Isozymes have also been reported in rat liver Pah (Kaufman et al., 1975). Most of this variation is explainable by (1) purified enzyme contains different polymeric structures of a single subunit, i.e., trimers or tetramers; (2) animals heterozygous for polymorphic variants in the PAH gene produce protein subunits with slightly different charge and electrophoretic migration; and (3) posttranslational modification. There is no evidence to support the involvement of more than 1 locus encoding the apoenzyme for PAH.
Kwok et al. (1985) isolated a full-length cDNA encoding PAH from a human liver cDNA library. The predicted protein contains 452 amino acids and shares 96% homology with rat Pah.
Scriver (2007) stated that the PAH protein contains regulatory, catalytic, and tetramerization domains. They noted that the 452-amino acid monomer assembles to form functional dimeric and tetrameric forms of the enzyme.
By Northern blot analysis, Lichter-Konecki et al. (1999) detected highest expression of a 2.5-kb PAH transcript in human liver, followed by kidney, pancreas, and brain. A 4.6-kb transcript was also detected in liver, kidney, and pancreas. RNase protection assays confirmed PAH expression in liver and kidney. RNA in situ hybridization revealed PAH expression in proximal convoluted tubules of adult and fetal kidney cortex and in the cerebral cortex of fetal brain. Immunohistochemical analysis confirmed expression of PAH protein in proximal convoluted kidney tubules.
The PAH gene spans 90 kb (Guttler and Woo, 1986) and contains 13 exons (Konecki et al., 1991).
Scriver (2007) stated that the PAH genomic sequence and its flanking regions span about 171 kb. The 5-prime UTR covers about 27 kb, and the 3-prime sequence downstream of the poly(A) site in exon 13 covers about 65 kb.
Using a cDNA probe for human PAH to analyze human-mouse hybrid cells by Southern hybridization, Lidsky et al. (1984) showed that the PAH gene is on chromosome 12 and presumably on the distal part of 12q because in hybrids containing translocated chromosome 12, it segregated with PEPB (169900) (12q21) and not with TPI (190450) (12p13). Woo et al. (1984) assigned the PAH gene to chromosome 12q21-qter by restriction analysis of DNA from human-hamster somatic cell hybrids. By in situ hybridization, the assignment of the PAH gene was narrowed to chromosome 12q22-q24.1 (Woo et al., 1984). By means of RFLPs, O'Connell et al. (1985) confirmed assignment of the PAH gene to terminal 12q.
Ledbetter et al. (1987) localized the Pah gene to mouse chromosome 10 by in situ hybridization. Justice et al. (1990) also mapped the Pah gene to mouse chromosome 10. Shimizu et al. (1992) mapped the location of Pah in relation to other loci on that chromosome by means of RFLPs in multipoint backcrosses.
Ledley et al. (1985) found that expression of human PAH in mouse fibroblasts, which do not normally express Pah, resulted in enzymatic activity characteristic of human liver PAH.
Wang et al. (1992) generated multiple mouse lines expressing a 9-kb DNA fragment from the 5-prime end of the human PAH gene fused to the bacterial chloramphenicol acetyltransferase (CAT) reporter gene. In all expressing lines, CAT activity was detected predominantly in liver, with much lower levels in kidney. Immunohistochemical analysis localized CAT expression to hepatocytes and renal epithelial cells, both of which also express endogenous mouse Pah. Both the transgene and endogenous mouse Pah were activated at about the same stage of embryonic development in mouse liver. Wang et al. (1992) concluded that the 9-kb DNA fragment flanking the 5-prime end of the human PAH gene contains all the necessary cis-acting elements to direct tissue- and development-specific expression in vivo.
Using PAH enzyme assays, Lichter-Konecki et al. (1999) demonstrated enzymatic hydroxylation of phenylalanine to tyrosine in human liver and kidney lysates, with increasing tyrosine formation over time. The results indicated 40 to 45% as much enzymatic activity in kidney lysates as in liver lysates.
Kaufman (1999) described the derivation of a quantitative model of phenylalanine metabolism in humans. The model was based on the kinetic properties of pure recombinant human PAH and on estimates of the in vivo rates of phenylalanine transamination and protein degradation. Calculated values for the steady-state concentration of blood phenylalanine, rate of clearance of phenylalanine from the blood after an oral load of the amino acid, and dietary tolerance of phenylalanine all agreed with data from normal as well as from phenylketonuric patients and obligate heterozygotes. Kaufman (1999) suggested that these calculated values may help in the decision about the degree of restriction of phenylalanine intake that is necessary to achieve a satisfactory clinical outcome in patients with classic PKU and in those with milder forms of the disease.
Li et al. (2021) identified long noncoding RNAs (lncRNAs) in both mice and humans that interacted with PAH. The mouse lncRNA, Pair (PAH-activating long intergenic noncoding RNA), was among the most upregulated lncRNAs in adult livers compared with embryonic livers. Pair -/- mice showed hypopigmentation, growth retardation, and elevated serum phenylalanine, but normal levels of Pah and its cofactor BH4. Mutant mice also developed seizures at about 8 to 10 months of age, reduced brain size, and lower tyrosine hydroxylase (TH; 191290) and, concomitantly, reduced tyrosine. Pull-down experiments showed that Pair formed complexes with Pah. The authors found that PAH also associated with the human lncRNA HULC (612210). Crystal structure analysis revealed that a region from nucleotides 184 to 216 of HULC formed hydrogen bonds with amino acids thr63 and his64 of PAH. They proposed that the lncRNA stabilizes the interaction of PAH and phe. Introduction of HULC mimics into PAH mutant cells from PKU patients increased PAH activity in converting phe to tyr in 11 of 17 PAH mutants, including the most common PAH mutation, suggesting that HULC mimics may provide a possible therapeutic role. Li et al. (2021) noted that low conservation between mouse and human lncRNAs has hindered the discovery of lncRNAs involved in human diseases. They pointed out that human HULC and mouse Pair both associate with PAH at its N-terminal regulatory domain, and that HULC could rescue Pah activity in Pair-deficient cells, and vice versa.
PAH Mutations
The first PKU mutation identified in the PAH gene was a single base change (GT to AT) in the canonical 5-prime splice donor site of intron 12 (612349.0001). Gene transfer and expression experiments demonstrated that the splice donor site mutation resulted in abnormal PAH mRNA processing and loss of PAH activity (DiLella et al., 1986).
Ledley et al. (1986) studied 2 families in which 1 member had classic PKU and other members had non-PKU mild HPA. They identified RFLPs that differentiated the 4 phenylalanine hydroxylase alleles in each family. PKU and non-PKU mild hyperphenylalaninemia were found to be allelic. Certain pairs of alleles induced the more severe PKU phenotype, whereas others induced the less severe hyperphenylalaninemia phenotype. Several of the alleles contributed to either one or the other.
Guttler and Woo (1986) reviewed the molecular genetics of PKU.
Scriver et al. (1989) summarized the intragenic lesions identified in PAH to date. Cotton (1990) listed 18 PAH mutations found to date and noted the ethnic extraction and the dominant haplotype. He pointed out that one-third of the mutations are located in exon 7.
John et al. (1990) presented a tabulation of 20 PAH mutations showing 3 instances of putative recurrent mutation.
Konecki and Lichter-Konecki (1991) reviewed 31 PAH mutations reported in cases of PKU up to December 1990. They also attempted a correlation between the clinical phenotypes and the nature of the mutations. To explain the high frequency of mutant PAH alleles they dismissed a high mutation rate and random genetic drift as well as founder effect (except in some populations such as the Yemenite Jews and French Canadians). Compensating heterozygote advantage seemed most likely. They quoted the hypothesis of Woo (1989) concerning increased viability of the fetus, afforded by modest hyperphenylalaninemia in the pregnant heterozygote, in the face of exposure to ochratoxin A. This compound is a known ubiquitous mycotoxin abortifacient.
Eisensmith and Woo (1992) reviewed mutations and polymorphisms in the human PAH gene. About 50 of the mutations were single-base substitutions, including 6 nonsense mutations and 8 splicing mutations, with the remainder being missense mutations. Of the missense mutations, 12 apparently resulted from the methylation and subsequent deamination of highly mutagenic CpG dinucleotides. Recurrent mutations had been observed at several sites, producing associations with different haplotypes in different populations. Studies of in vitro expression showed significant correlations between residual PAH activity and severity of the disease phenotype.
Dworniczak et al. (1992) concluded that although a large number of mutations have been identified in exon 7 of PAH, this is probably a reflection of the functional importance of this highly conserved sequence rather than a consequence of its being a mutation hotspot.
By means of a DGGE analysis, Eiken et al. (1996) identified 8 of 9 Norwegian PKU mutations that had escaped detection by SSCP analysis.
Okano et al. (1998) characterized the PAH mutations in 41 Japanese patients with PKU. Of 21 mutations identified, the most frequent was arg413 to pro (R413P; 612349.0016), which was found in 30.5% of the patients.
Hillert et al. (2020) evaluated genotypes and metabolic phenotypes of patients with PKU from several databases, including PAHvdb, ClinVar, HGMD, and LOVD. Of 16,092 patients, 61.7% had classic PKU, 21.9% had mild PKU, and 16.4% had mild hyperphenylalaninemia. Of 16,196 patients, 72.9% were compound heterozygous and 27.1% were homozygous for PAH mutations. Of the mutations, 58.3% were missense, 13.9% were frameshift, and 13.1% were splicing. Most mutations (59.2%) were located in the central catalytic domain. The 3 most prevalent genotypes were homozygosity for R408W (612349.0002), found in 4.8% of patients; homozygosity for c.1066-11G-A, found in 2.6% of patients; and compound heterozygosity for R408W and IVS12+1G-A (612349.0001), found in 1.6% of patients.
Characterization of PAH Mutations
Waters et al. (2000) characterized 4 PKU-associated PAH mutations that change an amino acid distant from the enzyme active site. Using 3 complementary in vitro protein expression systems and 3D structural localization, Waters et al. (2000) demonstrated a common mechanism, i.e., PAH protein folding is affected, causing altered oligomerization and accelerated proteolytic degradation, leading to reduced cellular levels of this cytosolic protein. Enzyme-specific activity and kinetic properties are not adversely affected, implying that the only way these mutations reduce enzyme activity within cells in vivo is by producing structural changes which provoke the cell to destroy the aberrant protein. The mutations were chosen because of their associations with a spectrum of in vivo hyperphenylalaninemia among patients. Waters et al. (2000) concluded that their in vitro data suggests that interindividual differences in cellular handling of the mutant but active PAH proteins contributes to the observed variability of phenotypic severity.
Most PAH missense mutations impair enzyme activity by causing increased protein instability and aggregation. Gjetting et al. (2001) described an alternative mechanism by which some PAH mutations may render phenylalanine hydroxylase defective. They used database searches to identify regions in the N-terminal domain of PAH with homology to the regulatory domain of prephenate dehydratase (PDH), the rate-limiting enzyme in the bacterial phenylalanine biosynthesis pathway. Naturally occurring N-terminal PAH mutations are distributed in a nonrandom pattern and cluster within residues 46-48 (amino acids GAL) and 65-69 (amino acids IESRP), 2 motifs highly conserved in PDH. To examine whether N-terminal PAH mutations affect the ability of PAH to bind phenylalanine at the regulatory domain, wildtype and 5 mutant forms (including G46S, 612349.0055; A47V, 612349.0056; and I65T, 612349.0063) of the N-terminal domain (residues 2-120) of 612349 human PAH were expressed as fusion proteins in E. coli. Binding studies showed that the wildtype form of this domain specifically binds phenylalanine, whereas all mutations abolished or significantly reduced this phenylalanine-binding capacity. The data suggested that impairment of phenylalanine-mediated activation of PAH may be an important disease-causing mechanism of some N-terminal PAH mutations.
Most missense mutations found in PKU result in misfolding of the phenylalanine hydroxylase protein, increased protein turnover, and loss of enzymatic function. Pey et al. (2007) studied the prediction of the energetic impact on PAH native-state stability of 318 PKU-associated missense mutations, using the protein-design algorithm FoldX. For the 80 mutations for which expression analyses had been performed in eukaryotes, in most cases they found substantial overall correlation between the mutational energetic impact and both in vitro residual activities and patient metabolic phenotype. This finding confirmed that the decrease in protein stability is the main molecular pathogenic mechanism in PKU and the determinant for phenotypic outcome. Metabolic phenotypes had been shown to be better predicted than in vitro residual activities, probably because of greater stringency in the phenotyping process. All the remaining 238 PKU missense mutations compiled in the PAH locus knowledgebase (PAHvdb) were analyzed, and their phenotypic outcomes were predicted on the basis of the energetic impact provided by FoldX. Residues in exons 7-9 and in interdomain regions within the subunit appeared to play an important structural role and constitute hotspots for destabilization.
Using recombinant proteins expressed in E. coli, Gersting et al. (2008) characterized 10 BH4-responsive PAH mutations, including arg408 to trp (R408W; 612349.0002) and tyr414 to cys (Y414C; 612349.0017). Residual activity was generally high, but allostery was disturbed in almost all variants, suggesting altered protein conformation. This hypothesis was confirmed by reduced proteolytic stability, impaired tetramer assembly or aggregation, increased hydrophobicity, and accelerated thermal unfolding, which primarily affected the regulatory domain, in most variants. Three-dimensional modeling revealed that the misfolding was communicated throughout the protein. Gersting et al. (2008) concluded that global conformational changes in PAH hinder the molecular motions essential for enzyme function.
Jung-KC et al. (2019) found that expression of different HPA-associated human PAH mutants in COS-7 cells correlated with expression of endogenous Dnajc12 (606060). Analysis of liver samples from HPA mice homozygous for the Pah val106-to-ala (V106A) mutation showed that expression of mutant Pah was not changed at the transcriptional level. Instead, the mutant Pah protein showed increased aggregation and degradation compared with wildtype. Further analysis demonstrated that mutant Pah interacted with Dnajc12, likely leading to its degradation through a ubiquitin-dependent pathway.
Martinez-Pizarro et al. (2018) investigated the mechanism of pathogenicity of 2 intron 11 mutations in the PAH gene, c.1199+17G-A and c.1199+20G-C. Minigene assays with each PAH mutation showed increased exon 11 skipping compared to wildtype. RNA affinity studies were then performed to determine which splicing factors bind to the intronic region where each mutation was located. These studies demonstrated that U1 snRNP70 had strong binding to an oligonucleotide containing wildtype PAH intron 11 sequence but abolished binding to oligonucleotides containing the c.1199+17G-A and c.1199+20G-C mutations. Further mutagenesis studies demonstrated that a U1 binding site at the IVS11+18 position was important for exon 11 recognition. Overexpression of an adapted U1 snRNA that bound to the IVS11+18 position and the mutant IVS11+17 or IVS11+20 sites resulted in increased intron 11 inclusion. Martinez-Pizarro et al. (2018) concluded that the c.1199+17G-A and c.1199+20G-C PAH mutations were pathogenic due to modification of a U1 snRNA regulatory element binding site.
Jin et al. (2022) performed whole-genome sequencing in 10 patients with PKU from Northwest China in whom only 1 heterozygous mutation had been identified in the PAH gene. Three deep intronic mutations were identified, including c.706+368T-C, c.1065+241C-A, and c.1199+502A-T. The c.1199+502A-T mutation was identified in heterozygous state in 6 of the 10 patients and may therefore be a recurrent mutation in Northwest China. A minigene assay and RNA sequencing in patient blood demonstrated that the c.1199+502A-T mutation leads to inclusion of a 25-bp pseudoexon. In silico analysis suggested that both the c.706+368T-C and c.1065+241C-A mutations strengthen exon splice enhancer binding sites. Minigene assays showed that both the c.706+368T-C and c.1065+241C-A mutations may also result in the inclusion of pseudoexons.
PAH Mutation Database
Hoang et al. (1996) described the PAH Mutation Analysis Consortium Database contributed to by 81 investigators in 26 countries. The relational database records both disease-producing and polymorphic allelic variation at the locus. The authors stated that as of 27 September 1995 the database recorded 248 alleles in 798 different associations (with polymorphic haplotype, geographic region, and population), along with additional information. Ascertainment of probands is largely through newborn screening for hyperphenylalaninemia. The authors included information on accessing the database via the Internet. Nowacki et al. (1997) gave further details on the PAH database.
PAH Genotype and Disease Severity
Guldberg et al. (1998) extended previous studies suggesting that the highly variable metabolic phenotypes of PAH deficiency correlate with PAH genotypes. They identified both causative mutations in 686 patients from 7 European centers. They used the phenotypic characteristics of 297 functionally hemizygous patients (i.e., patients with 1 null allele rendering the other allele functionally hemizygous) to assign 105 of the mutations to 1 of 4 arbitrary phenotype categories. The findings suggested that allelic variation at the PAH locus is the major determinant of the metabolic phenotype of PAH deficiency. The disease severity in most cases is determined by the least severe of 2 PAH mutations, i.e., mild PKU is 'dominant.' Furthermore, 2 mutations with similar severity may confer a milder phenotype than either of the mutations would do if it acted alone. The classification of the 105 PAH mutations may allow the prediction of the biochemical phenotype in more than 10,000 genotypic combinations, which may be useful for the management of hyperphenylalaninemia in newborns.
Guttler et al. (1999) reported findings from the maternal PKU collaborative study concerning genotype, biochemical phenotype, and cognitive performance in females with phenylalanine hydroxylase deficiency. PAH gene mutations were examined in 222 hyperphenylalaninemic females, with the discovery of a total of 84 different mutations, and complete genotype was obtained in 199 individuals. Based on previous knowledge about mutation-phenotype associations, 78 of the mutations could be assigned to 1 of 4 classes of severity: severe PKU, moderate PKU, mild PKU, and non-PKU mild hyperphenylalaninemia.
Benit et al. (1999) tested the activity of the mutant gene products from 11 PAH-deficient patients in a eukaryotic expression system. Two mutations, ala259 to val (612349.0028) and leu333 to phe (612349.0050), markedly reduced PAH activity; 1 mutation, glu390 to gly (612349.0051), mildly altered the enzyme activity, and most of the mutant genotypes reduced the in vitro expression of PAH activity to 15 to 30% of controls. Comparing the predicted residual activity derived from expression studies to the clinical phenotypes of the PAH-deficient patients, Benit et al. (1999) found that homozygosity for the L333F/E390G mutations resulted in severe and mild PAH deficiencies, respectively, both in vivo and in vitro, while compound heterozygosity (L333F/E390G) resulted in an intermediate dietary tolerance. Similarly, in vitro expression studies largely predicted dietary tolerance in compound heterozygotes for other mutations. Taken together, these results supported the view that expression studies are useful in predicting residual enzyme activity and that the mutant genotype at the PAH locus is the major determinant of metabolic phenotype in hyperphenylalaninemias.
PAH Genotype and Tetrahydrobiopterin-Responsive PKU
At least half of patients with phenylketonuria have a mild clinical phenotype. Muntau et al. (2002) explored the therapeutic efficacy of tetrahydrobiopterin for the treatment of mild phenylketonuria. Tetrahydrobiopterin significantly lowered blood phenylalanine levels in 27 of 31 patients with mild hyperphenylalaninemia (10 patients) or mild phenylketonuria (21 patients). Phenylalanine oxidation was significantly enhanced in 23 of these 31 patients. Conversely, none of the 7 patients with classic phenylketonuria had a response to tetrahydrobiopterin. Long-term treatment with tetrahydrobiopterin in 5 children increased daily phenylalanine tolerance, allowing them to discontinue their restricted diets. Seven mutations were classified as probably associated with responsiveness to tetrahydrobiopterin, including V245A (612349.0059) and E390G (612349.0051). Six mutations were classified as potentially associated with responsiveness, including F39L (612349.0031), D415N (612349.0043), R158Q (612349.0006), and I65T (612349.0063). Four mutations were inconsistently associated with responsiveness, including Y414C (612349.0017), L48S (612349.0034), and R261Q (612349.0006). Mutations connected to tetrahydrobiopterin responsiveness were predominantly in the catalytic domain of the protein and were not directly involved in cofactor binding. Muntau et al. (2002) concluded that responsiveness could not consistently be predicted on the basis of genotype, particularly in compound heterozygotes.
Lassker et al. (2002) reported 2 new patients with tetrahydrobiopterin-responsive PKU and compared their PAH genotypes to those of previous cases from the literature. These patients carried missense mutations in the PAH gene, confirming the suggestion of Erlandsen and Stevens (2001) that tetrahydrobiopterin-responsive patients are frequently carriers of missense mutations within the DNA region coding for the catalytic domain of the enzyme. Both patients showed no effect of tetrahydrobiopterin at 7.5 mg/kg/day on plasma phenylalanine levels in the newborn period, and the authors suggested that a normal neonatal tetrahydrobiopterin test does not necessarily exclude tetrahydrobiopterin responsiveness in all such patients.
Pey et al. (2004) analyzed the kinetics and cofactor binding properties of 7 mild PKU mutations, including I65T (612349.0063), P244L (612349.0047), R261Q (612349.0006), V388M (612349.0045), and Y414C (612349.0017). BH4 prevented degradation of the V388M and Y414C protein variants by acting as a chemical chaperone. In addition, in all the mutants, BH4 increased PAH activity and protected the protein from rapid inactivation. Pey et al. (2004) concluded that the response to BH4 substitution therapy by PKU mutations may have a multifactorial basis, involving chemical chaperone and protective effects.
Zurfluh et al. (2008) analyzed data on 315 patients with BH4-responsive PKU from a large PKU database. The average residual activity for 57 BH4-responsive mutations was 46.8%, and the most common variants included R261Q (612349.0006), Y414C (612349.0017), and V245A (612349.0059). Combined genotype data additional from other genetic databases and published reports yielded population-specific figures for the percentage of PKU patients predicted to be BH4 responders: 58% in Germany, 76% in Northern Ireland, 55% in South Korea, and 57% in northern China. The genotype-predicted prevalence figures were generally higher than data generated from BH4-loading test data.
Toncheva et al. (2023) analyzed genomewide sequencing data from the Allen Ancient DNA Resource including data from 8 Neanderthals, 1 Denisovan, and 1 individual with a Neanderthal mother and Denisovan father. Five different mutations in the PAH gene were identified including A111X (in 6 alleles) R261X (in 4 alleles), P281L (in 4 alleles), A300S (in 8 alleles), and R243X (in 2 alleles). Interestingly, Toncheva et al. (2023) identified 4 homozygous mutations in a 120,000-year-old Neanderthal. Based on these samples, they concluded that each of the mutations had a higher minor allele frequency in these archaic populations than what was present in the gnomAD database. Toncheva et al. (2023) hypothesized that these PAH mutations in present-day humans may be due to introgression from other archaic human species.
McDonald et al. (1990) isolated mutant mice exhibiting hereditary hyperphenylalaninemia after ethylnitrosourea mutagenesis of the germ line. By linkage mapping, they demonstrated that the disorder, which had other characteristics close to those of phenylketonuria, mapped to mouse chromosome 10 at or near the Pah locus.
McDonald and Charlton (1997) identified a mutation within the protein coding sequence of the Pah gene in each of 2 genetic mouse models for human phenylketonuria. A genotype/phenotype relationship that was strikingly similar to the human disease emerged, underscoring the similarity of PKU in mouse and man. The enu1 mutation, induced by the chemical mutagen N-ethyl-N-nitrosourea (ENU), predicts a conservative valine-to-alanine amino acid substitution and is located in exon 3, a gene region where serious mutations are rare in humans. The phenotype in mice is mild. The second ENU-induced mutation, enu2, predicts a radical phenylalanine-serine substitution and is located in exon 7, a gene region where serious mutations are common in humans. The phenotype of the second mutation is severe.
Smith and Kang (2000) used the ENU-induced mouse model of PKU to study cerebral protein synthesis. They suggested that ultimately a more thorough understanding of the role of protein synthesis in the ability of the brain to grow and develop normally and to undergo plasticity will help in the understanding of the etiology of mental retardation in PKU and the formulation of new treatments.
Gersting et al. (2010) found that loss of function in Pah-enu1 mice was a consequence of misfolding, aggregation, and accelerated degradation of the enzyme. Tetrahydrobiopterin (BH4) attenuated this triad by conformational stabilization augmenting the effective PAH concentration, which led to rescue of the biochemical phenotype and enzyme function in vivo. Combined in vitro and in vivo analyses revealed a selective pharmaceutical action of BH4 confined to the pathologic metabolic state.
Brooks et al. (2023) generated a humanized mouse model with a c.1222C-T mutation in exon 12 of the PAH gene. Prime editing delivered by an adeno-associated viral vector (AAV) was then used to correct the mutation. Targeted prime editing in 6- and 10-week old mutant mice resulted in partial correction of PAH liver enzyme activity and improvement of the blood phenylalanine levels well below the 360 micromol/L goal threshold.
The first phenylketonuria (PKU; 261600) mutation identified in the PAH gene was a single base change (GT to AT) in the canonical 5-prime splice donor site of intron 12 (DiLella et al., 1986). Direct hybridization analysis using specific oligonucleotide probes demonstrated tight association with a specific RFLP haplotype called haplotype 3. The splicing mutation was the most prevalent PKU allele among Caucasians. Marvit et al. (1987) found that the GT-to-AT substitution at the 5-prime splice donor site of intron 12 resulted in the skipping of the preceding exon during RNA splicing. cDNA clones had shown an internal 116-basepair deletion corresponding precisely to exon 12 and leading to the synthesis of the truncated protein lacking the C-terminal 52 amino acids. Gene transfer and expression studies using the mutant PAH cDNA indicated that the deletion abolished PAH activity in the cell as a result of protein instability. The studies of Marvit et al. (1987) indicated that in fact a single nucleotide substitution rather than a deletion was the basis of the abnormal gene product.
DiLella et al. (1987) reported the molecular lesion associated with the RFLP haplotype-2 mutant allele in phenylketonuria (PKU; 261600). This defect is caused by a CGG-to-TGG transition in exon 12, resulting in an amino acid substitution (arg-to-trp) at residue 408 (R408W) of PAH. Direct hybridization analysis of the point mutation using a specific oligonucleotide probe demonstrated that this mutation is in linkage disequilibrium with RFLP haplotype-2 alleles that make up about 20% of mutant PAH genes. This is presumably another example of CpG mutation.
In French Canadians, John et al. (1990) found that the R408W mutation in exon 12 is associated with haplotype 1; in other populations, it occurs on haplotype 2. A CpG dinucleotide is involved in this mutation, compatible with a recurrent mutation, although gene conversion or a single recombination between haplotypes 2 and 1 is possible.
Kalaydjieva et al. (1991) found this mutation in high frequency in Bulgaria, Lithuania, and eastern Germany, where it occurred on haplotype 2. Pooling of data on European populations suggested a Balto-Slavic origin of the R408W defect, with an east-west cline in its frequency.
Tsai et al. (1990) found this mutation in Chinese patients on a different haplotype, namely, no. 44.
Jaruzelska et al. (1991) found that haplotype 2 was most frequently (62%) associated with PKU alleles in Poland where, in the western part of the country, the frequency of PKU is 1 in 5,000 live births. Furthermore, the R408W mutation was in complete linkage disequilibrium with this haplotype. Similar observations have been made in other Eastern European countries such as the former German Democratic Republic, Czechoslovakia, and Hungary. Zygulska et al. (1991) found similar results in southern Poland. Zygulska et al. (1991) found the R408W mutation in 25 of 44 chromosomes from 22 unrelated Polish families with at least 1 PKU child. In 24 of these, mutation was on haplotype 2. A different mutation in the same codon, arg408-to-gln (R408Q; 612349.0038), has been described. Recurrent mutations in the 408 codon appear to occur; at least 2 different mutations (at least mutations on different RFLP haplotype background) have been identified in Chinese patients (Lin et al., 1992). Codon 408 (CGG) contains a CpG hotspot (Ramus et al., 1992). The R408W mutation is a CGG-to-TGG change in the coding strand; the R408Q mutation (612349.0038) is a GCC-to-GTC change in the noncoding strand. Ivaschenko and Baranov (1993) described a rapid and efficient PCR/StyI test for identification of this mutation. Tighe et al. (2003) stated that the R408W mutation in Europe arose by recurrent mutation and is associated with 2 major PAH haplotypes. R408W associated with the 2.3 haplotype exhibits a west-east cline of relative frequency reaching its maximum in the Balto-Slavic region, whereas R408W associated with the 1.8 haplotype exhibits an east-west cline peaking in Connacht, the most westerly province of Ireland. Spatial autocorrelation analysis demonstrated that the 2 clines are consistent with a pattern likely to have been established by human dispersal. Stojiljkovic et al. (2006) identified the R408W mutation in 18% of mutant alleles among 34 unrelated patients with PKU from Serbia and Montenegro. Gersting et al. (2008) stated that the R408W mutation occurs within the catalytic domain of PAH. Unlike wildtype recombinant PAH, which formed tetramers when expressed in E. coli, PAH with the R408W mutation formed high-molecular-mass aggregates, indicative of severe distortion of the protein's oligomeric state.
In a German patient with phenylketonuria (PKU; 261600), Lichter-Konecki et al. (1988) found a novel restriction fragment pattern with the restriction endonuclease MspI, and showed by molecular cloning and DNA sequencing that the variation was created by a T-to-C transition in exon 9, resulting in a leu311-to-pro (L311P) substitution.
Lyonnet et al. (1989) found a change of glu280-to-lys (E280K) in a child with a variant form of phenylketonuria (PKU; 261600). The enzyme showed partial residual activity. The mutation was linked to a rare RFLP haplotype at the PAH locus found in South Europe and North Africa. In studies to the time of publication, the genotype-haplotype association was both inclusive and exclusive. Okano et al. (1990) demonstrated the E280K mutation in association with haplotype 1 in a patient in Denmark. Lyonnet et al. (1989) found this mutation in association with haplotype 38, representing about 10% of all PKU alleles in North Africa. Okano et al. (1990) suggested that this was a recurrent mutation. The site of the mutation involves a CpG dinucleotide.
From analysis of the PAH mutation database, Byck et al. (1997) demonstrated that the E280K allele accounts for 1.5% of PKU chromosomes worldwide. It occurs on 4 different haplotypes in Europeans and on haplotypes 1 and 2 in Quebec. Whereas a single recombination event could explain the 2 haplotype associations in Quebec, the mutation involves a CpG dinucleotide, a recognized mutation hotspot. By analyzing multiallelic markers 5-prime and 3-prime to the E280K allele on 12 mutant and 30 normal chromosomes, Byck et al. (1997) concluded that recurrent mutation is the likely origin of E280K in Quebec. Byck et al. (1997) found 48 CpG sites (sense and antisense strands) in the PAH gene. Of these, 7 were devoid of known mutations, 16 harbored 'PKU' alleles involving CpG doublets, and the remainder contained mutations that did not involve a C-to-T or G-to-A substitution in the doublet. These hypermutable CpG sites were found to harbor 32 different mutations in association with at least 66 different haplotypes and resulting hyperphenylalaninemia.
Wang et al. (1989) reported that phenylketonuria (PKU; 261600) occurs with a prevalence of about 1 in 16,500 births among Chinese individuals, a frequency similar to that among Caucasians. They identified a mutation in codon 111 in exon 3 converting arginine to a stop codon (R111X) and resulting in PKU. The mutation was in linkage disequilibrium with the mutant haplotype 4 which is the most prevalent form among Asians. The mutation accounted for about 10% of Chinese PKU alleles and has not been found among Caucasians. Huang et al. (1990) made the prenatal diagnosis of the R111X mutation by use of DNA amplification with PCR and oligonucleotide hybridization.
Abadie et al. (1989) presented evidence that CpG dinucleotides represent mutation hotspots in phenylketonuria (PKU; 261600). Starting with the observation that the PAH gene contains 22 CpG dinucleotides including 5 doublets in exon 7, they carried out sequence analysis of exon 7 in 20 unrelated PAH-deficient kindreds of Mediterranean ancestry. This procedure resulted in the detection of 2 novel missense mutations whose location and nature (CG-to-CA and CG-to-TG) were consistent with the accidental deamination of a 5-methylcytosine in a CpG doublet: codon 261 (arg to gln, or R261Q) and codon 252 (arg to trp, or R252W; 612349.0007).
In the Swiss population, Okano et al. (1990) found an arg158-to-gln mutation (R158Q; 612349.0010) as the basis of phenylketonuria. The substitution was in exon 5; an arg261-to-gln mutation in exon 7 was apparently an accompanying silent change. Expression analysis in heterozygous mammalian cells after site-directed mutagenesis demonstrated that indeed the arg158-to-gln mutation was the cause of PKU, and that the other mutation was silent.
In Zurich, Superti-Furga et al. (1991) observed intrauterine growth retardation, microcephaly, and developmental delay in 2 first cousins whose mothers, 24- and 23-year-old sisters, had blood phenylalanine concentrations of approximately 1.2 mmol/l but had never been treated and had no overt mental retardation. Both mothers were shown to be homozygous for the arg261-to-gln mutation. This experience indicates that the homozygous state of this mutation is accompanied by only mild clinical manifestations but sufficient elevation of blood phenylalanine to cause maternal PKU syndrome in offspring.
Kleiman et al. (1993) studied a family in which of 2 of 3 sibs had classic PKU and were compound heterozygotes for the R261Q mutation. Both PKU children, as well as their non-PKU brother, had microcephaly with head circumference below the second percentile; the IQ of the non-PKU boy was 89, while that of his parents was 100. The findings suggested maternal PKU, and further study demonstrated that the mother was homozygous for the R261Q mutation. She was found, however, to be well adjusted socially and worked as a school teacher.
In patients with PKU from the Old Order Amish in Lancaster County, Pennsylvania, Wang et al. (2007) identified compound heterozygosity for 2 PAH mutations: R261Q and a 3-bp deletion at codon 94 (612349.0030). The incidence of PKU in the Lancaster County Amish was 1 in 10,000, similar to that in other populations.
The phenylketonuria (PKU; 261600)-associated arg252-to-trp (R252W) missense mutation was discovered by Abadie et al. (1989). Okano et al. (1991) described a C-to-T transition at the first base of codon 252, which resulted in the substitution of tryptophan for arginine. Analysis of expression vectors containing the mutant cDNA and transfected into mammalian cells revealed negligible enzyme activity and undetectable levels of immunoreactive PAH protein. Population genetic studies among Italians showed marked linkage disequilibrium between the R252W mutation and RFLP haplotype 1. The R252W mutation was found on 10% of haplotype 1 mutant chromosomes.
Kalanin et al. (1994) found the R252W mutation in 10 homozygotes with classic PKU among Gypsies of Eastern Slovakia.
Levy (1989) reviewed the then-known mutations in the PAH gene causing phenylketonuria (PKU; 261600), including a deletion of exon 3 described by Avigad et al. (1987) in Yemenite Jews.
Avigad et al. (1990) reported that a deletion spanning the third exon of the PAH gene is responsible for all PKU cases among Yemenite Jews. Using a molecular probe that detects carriers of the deletion, they identified 5 carriers among 200 randomly selected volunteers from this community who were not related to the known PKU families. Although the deleted gene was traced to 25 different locations throughout Yemen, family histories and official documents of the Yemenite Jewish community showed that the common ancestor of all the carriers of this defect lived in San'a, the capital of Yemen, before the 18th century.
In 9 French Canadian patients with hyperphenylalaninemia (see PKU, 261600), John et al. (1989) demonstrated a novel mutation on 5 of the 18 mutant chromosomes: an A-to-G transition (met to val) in codon 1 (M1V), the translation-initiation codon. In all cases the mutation was associated with haplotype 2. A homozygote for this mutation had the PKU phenotype. In 1 proband it was inherited with the splice junction mutation in exon 12 (612349.0001) (on haplotype 3), conferring PKU. In 2 probands it was inherited with a mutation on haplotype 1, conferring PKU in 1 and non-PKU hyperphenylalaninemia in the other.
In contemporary families in France with classic PKU, Lyonnet et al. (1992) found the M1V mutation on 4 of 152 independent chromosomes. All of the French and Quebec M1V mutations occurred on RFLP haplotype 2. The contemporary mutant French chromosomes clustered in southern Brittany (Finistere Sud). Genealogic reconstruction of the Quebec families identified 53 shared ancestors and a center of diffusion in the Perche region in 17th century France. The 2 clusters in France, one historical and the other contemporary, are not incompatible if one assumes the possibility that settlers returned from Nouvelle France or moved from Perche to southern Brittany.
By expression analysis of the M1V mutation, John et al. (1992) demonstrated nondetectable levels of PAH protein and activity.
In 7 out of 94 phenylketonuria (PKU; 261600) alleles, Dworniczak et al. (1989) identified a G-to-A transition in nucleotide 695 in exon 5 of PAH. Twenty-four percent of the PKU alleles were in a background of haplotype 4; all 7 of the G-to-A transitions were on the haplotype 4 background. The base substitution predicted an arg158-to-gln (R158Q) change.
In exon 7 of the PAH gene in a Hungarian patient with phenylketonuria (PKU; 261600), Wang et al. (1990) found, by direct sequencing of PCR-amplified DNA, a C-to-T transition causing a change of arg243 to a stop codon (R243X). The mutant allele was associated with haplotype 4. The mutation was present in 2 of 9 mutant haplotype 4 alleles among Eastern Europeans but was not found among Western Europeans and Asians.
The pro281-to-leu (P281L) mutation in exon 7 was found on haplotype 1 in an Italian patient with phenylketonuria (PKU; 261600) (Okano et al., 1991). cDNA carrying the mutation was constructed and transfected into cultured mammalian cells. Expression analysis revealed negligible enzyme activity and undetectable levels of immunoreactive PAH protein. This mutation, like the arg252-to-trp mutation (R252W; 612349.0007), is in marked linkage disequilibrium with RFLP haplotype 1. The P281L mutation was found on 20% of haplotype 1 mutant chromosomes in the Italian population (Okano et al., 1991).
Dworniczak et al. (1991) found this mutation on 25% of all mutant haplotype 1 alleles in the German population. In addition, they identified this mutation on 1 mutant haplotype 4 allele. Expression analysis of the mutant allele in cultured mammalian cells demonstrated absence of immunoreactive PAH in cells transfected with this missense mutation, identical steady-state levels of mRNA in cells carrying both normal and mutant constructs, and absence of PAH activity in cells transfected with the mutant allele.
Baric et al. (1994) pointed to data indicating that the highest frequency of the P281L mutation is in Croatia where it was detected in 55% of haplotype 1 alleles, corresponding to 12% of all PKU alleles. They interpreted this finding as indicating that the mutation originated in southeastern Europe.
The tyr204-to-cys (Y204C) mutation, which occurs in exon 6 of PAH, was found on haplotype 4 in 12 (13%) of 81 alleles from Chinese patients with phenylketonuria (PKU; 261600) and 1 (5%) of 22 alleles from Japanese patients with PKU (Wang et al., 1991).
The arg243-to-gln (R243Q) mutation in exon 7 of PAH was found on haplotype 4 in 19 (18%) of 81 alleles from Chinese patients with phenylketonuria (PKU; 261600) (Wang et al., 1991).
The trp326-to-ter (W326X) mutation in exon 10 of PAH was found on haplotype 4 in a Chinese patient with phenylketonuria (PKU; 261600) (Wang and Woo, 1990). Also see Wang et al. (1992).
The arg413-to-pro (R413P) mutation in exon 12 of PAH was found on haplotype 4 in a Chinese patient with phenylketonuria (PKU; 261600) (Wang and Woo, 1990). A change of CGC to CCC was responsible for the substitution. Haplotype 4 is the predominant PAH haplotype in the East Asian population, accounting for 13.8% of northern Chinese and 27% of Japanese PKU alleles, but it is rare in southern Chinese (2.2%) and is absent in Caucasian populations. Wang et al. (1991) presented data demonstrating unambiguously that the mutation occurred after racial divergence of East Asians and Caucasians and suggested that the R413P allele spread throughout the East Asia by a founder effect. Previous studies of protein polymorphisms in eastern Asia suggested that 'northern Mongoloids' represented a founding population in Asia. The PKU data are consistent.
The tyr414-to-cys (Y414C) mutation in exon 12 of PAH was found on haplotype 4 in a Caucasian patient with non-phenylketonuria hyperphenylalaninemia (see PKU, 261600) (Okano et al., 1991). An A-to-G transition at the second base of codon 414 was responsible. In vitro expression studies showed that the Y414C mutation produced a protein with a significant amount of PAH enzyme activity, i.e., approximately 50% of normal steady-state levels.
Gersting et al. (2008) stated that the Y414C mutation occurs within the dimerization motif of the PAH oligomerization domain, which interacts with the catalytic domain of the same PAH subunit. They found that tetramerization of recombinant PAH with the Y414C mutation resembled that of the wildtype protein. The reduction in activity resulting from the Y414C mutation appeared to be due to a global conformational change in the protein that reduced allostery.
An AG-to-AA change in the splice acceptor site of intron 4 (IVS4) of PAH was found on haplotype 4 in a Chinese patient with phenylketonuria (PKU; 261600) (Wang and Woo, 1990).
In a Chinese patient with classic PKU, Wang et al. (1991) found a G-to-A transition at the last base in intron 4 of the PAH gene, which abolished the 3-prime-acceptor site. The mutation was found to represent 8% of all PKU chromosomes in Chinese but was not found in Japanese and Caucasian PKU patients. It was prevalent in southern China but rare in northern China, providing additional evidence that there were multiple founding populations of PKU in east Asia. The prevalence of PKU was found to be 1 in 16,500 Chinese by Liu and Zuo (1986).
The tyr356-to-ter (Y356X) mutation in exon 11 of PAH was found on haplotypes 4, 7, and 9 in Chinese patients with phenylketonuria (PKU; 261600) (Wang and Woo, 1990). Also see Wang et al. (1992). This Y356X mutation is associated with multiple haplotypes, possibly due to crossover, gene conversion, or recurrent mutation.
In a patient with classic phenylketonuria (PKU; 261600), Svensson et al. (1990) identified compound heterozygosity for a G-to-T transversion in the PAH gene, resulting in a gly272-to-ter (G272X) substitution, and a deletion of CTT leucine codon 364 (612349.0021).
In 47 Norwegian nuclear families with at least 1 child with PKU, Apold et al. (1990) found haplotype 7, which is relatively rare in other populations, in 20% of all mutant haplotypes. In 14 of the 17 mutant haplotypes 7, a deletion of the BamHI restriction site in exon 7 of the PAH gene was found. The abrogation of the site was shown to be due to a G-to-T transversion, changing glycine-272 to a stop codon in exon 7. The families with this mutation were clustered along the southeastern coast of Norway, suggesting a founder effect. Melle et al. (1991) found the same mutation on the background of RFLP haplotype 7 in patients from northeastern France or Belgium.
Apold et al. (1993) compiled data on the frequency of the G272X mutation in European populations. The mutation occurs north of the Alps and has a particularly high frequency in the Oslo Fjord region of Norway with the adjacent Bohuslan region of Sweden. An intermediate frequency was noted in the eastern part of Germany with the adjacent western part of Czechoslovakia. Genealogic studies revealed no common source for this mutation, but there was some geographic convergence to the Bohuslan region. The findings suggested a single origin for this mutation, with at least one founding population in southeastern Norway/adjacent Sweden.
For discussion of the 3-bp deletion of CTT leucine codon 364 in the PAH gene that was found in compound heterozygous state in a patient with classic phenylketonuria (PKU; 261600) by Svensson et al. (1990), see 612349.0020.
In a patient with phenylketonuria (PKU; 261600), Melle et al. (1991) found a C-to-T transition at codon 273 of PAH, which led to substitution of serine for phenylalanine (S273F). This mutation and the neighboring gly272-to-ter mutation (G272X; 612349.0020) alter the BamHI site. Both mutations were identified in patients from northeastern France or Belgium and both occurred on the background of RFLP haplotype 7. These mutations are located in exon 7, in which the largest number of mutant genotypes (7) have been identified in PKU.
Using the chemical cleavage method (CCM) on amplified DNA encompassing exons 7 and 8 of the PAH gene, Dianzani et al. (1991) found a novel mutation in an Italian patient with phenylketonuria (PKU; 261600): a G-to-A substitution at the 5-prime donor junction splice site of intron 7.
In a study of phenylketonuria (PKU; 261600) in U.S. blacks living in Maryland, Hofman et al. (1991) found that 40% of mutant PAH alleles had 1 of 2 previously undescribed haplotypes. Both of these could be derived from known haplotypes by a single event. One of these haplotypes was characterized by a new MspI restriction site, located in intron 8, which was present in 5 of 16 black mutant alleles but was not found in 60 U.S. black controls, 20 U.S. Caucasian controls, or 20 Caucasian mutant PAH alleles. Sequence analysis of DNA from a single individual, homozygous for the MspI-associated haplotype, showed homozygosity for a C-to-T transition at nucleotide 896 in exon 7, resulting in the conversion of leucine-255 to serine (L255S).
Huang et al. (1991) identified a GTA(val)-to-GTT(val) synonymous mutation in codon 399 of the PAH gene in Chinese. They found no linkage disequilibrium between this polymorphism and phenylketonuria (PKU; 261600) mutations.
An A-to-T substitution at cDNA nucleotide 1197 of the PAH gene had been regarded as a silent mutation because both the wildtype (GUA) and the mutant (GUU) alleles encode a valine residue at codon 399. The nucleotide is located at the 3-prime end of exon 11 at position -3 of the exon-intron junction. Chao et al. (2001) demonstrated that skipping of exon 11 occurred with the allele containing the 1197A-T substitution. Thus, this mutation is not a neutral polymorphism but a mutation that induces posttranscriptional skipping of exon 11 leading to a PKU phenotype.
By the method of single-strand conformation polymorphism (SSCP), Labrune et al. (1991) demonstrated a GCC-to-GTC change in codon 259, resulting in replacement of alanine by valine (A259V) and suppression of a PalI restriction site (GGCC) in the PAH gene. The mutation was carried by a haplotype-42 mutant allele and was found in 2 first-cousin patients of northern French ancestry with phenylketonuria (PKU; 261600).
Using the SSCP technique, Labrune et al. (1991) demonstrated a T-to-G transversion at the first nucleotide of codon 277 (TAT to GAT) changing a tyrosine to aspartic acid (Y277D). The mutation was found in a patient of eastern French ancestry with phenylketonuria (PKU; 261600).
In a patient with mild phenylketonuria (PKU; 261600), Caillaud et al. (1991) reported a 3-bp in-frame deletion resulting in loss of isoleucine-94. The mutant enzyme showed markedly reduced affinity for phenylalanine. Since the deletion was located in the third exon of the gene, which shows no homology with other hydroxylases, Caillaud et al. (1991) suggested that exon 3 is involved in the specificity of PAH for phenylalanine. It appeared that this mutation may have occurred recently on the background of a haplotype II gene in Portugal.
In patients with PKU from the Old Order Amish in Lancaster County, Pennsylvania, Wang et al. (2007) identified compound heterozygosity for 2 PAH mutations: R261Q (612349.0006) and the 3-bp deletion at codon 94. The incidence of PKU in the Lancaster County Amish was 1 in 10,000, similar to that in other populations.
See Forrest et al. (1991).
See Forrest et al. (1991).
Dworniczak et al. (1991) identified a G-to-A transition at position 546 in intron 10 of the PAH gene, 11 bp upstream from the intron 10/exon 11 boundary. The mutation activated a cryptic splice site and resulted in an in-frame insertion of 9 nucleotides between exons 10 and 11 of the processed mRNA. Normal amounts of liver PAH protein were present in homozygous phenylketonuria (PKU; 261600) patients, but no catalytic activity could be detected. This loss of enzyme activity was probably caused by conformational changes resulting from the insertion of 3 additional amino acids (gly-leu-gln) between the normal sequences encoded by exons 10 and 11. The mutation was in tight association with chromosomal haplotypes 6, 10, and 36. Because of the high frequency of these particular haplotypes in Bulgaria, Italy, and Turkey, Dworniczak et al. (1991) suspected that this mutation may be one of the more frequent defects in the PAH gene causing classic PKU in southern Europe. Perez et al. (1992) also found this mutation in Spain. Furthermore, Perez et al. (1993) found that this mutation is the predominant molecular lesion causing PKU in Chile, Argentina, and Mexico.
This mutation, which is also referred to as IVS10nt546, is the major Mediterranean PKU mutation. It was found by Desviat et al. (1997) in 87.5% of PAH mutant alleles in Spanish Gypsies, but was on a different RFLP and STR haplotype background then the same mutation in Spanish non-Gypsies. It was found in 14 of 16 gypsy PKUs; 1 allele carried the R252W mutation, which had been found in all gypsy PKU families from Slovakia by Kalanin et al. (1994); the nature of the mutation on 1 of 16 alleles was not determined.
In PKU patients from the Old Order Amish in Geauga County, Ohio, Wang et al. (2007) found homozygosity for the splice site mutation in intron 10. The incidence of PKU in this group was estimated to be 1 in 1,000, much higher than in other populations.
Esfahani and Vallian (2019) found that this splice site mutation was the most common among 140 Iranian patients with PKU, with a frequency of 26.07%.
By DNA sequence analysis of the 13 exons and the intron/exon boundaries of the PAH gene, Konecki et al. (1991) detected 2 base transitions resulting in missense mutations in a Turkish patient with phenylketonuria (PKU; 261600). A leu48-to-ser (L48S) mutation was associated with the mutant haplotype 3 allele and a glu221-to-gly (E221G; 612349.0035) substitution with the mutant haplotype 4 allele. By allele-specific oligonucleotide (ASO) dot-blot analysis, Konecki et al. (1991) subsequently detected the leu48-to-ser mutation in haplotype 4 PKU alleles of 9 of 48 (18.8%) unrelated Caucasian PKU families. In the homozygous state this mutation resulted in mild PKU. The glu221-to-gly mutation was detected only in the proband and his father.
Stojiljkovic et al. (2006) found that the L48S mutation was the most common among 34 unrelated patients with PKU from Serbia and Montenegro, occurring in 21% of mutant alleles. This mutation was exclusively associated with the classical severe PKU phenotype, defined as having pretreatment plasma phenylalanine levels above 1200 micromol/liter.
For discussion of the glu221-to-gly (E221G) mutation in the PAH gene that was found in compound heterozygous state in a patient with phenylketonuria (PKU; 261600) by Konecki et al. (1991), see 612349.0034.
In 2 unrelated phenylketonuria (PKU; 261600) patients of German and Turkish origin, Dworniczak et al. (1991) demonstrated a CGA-to-TGA mutation in codon 261 of exon 7, transforming arg261 to a stop codon (R261X). The different ethnic backgrounds and the different polymorphic characteristics of the 2 mutant alleles suggested independent origins. Since another mutation (R261Q; 612349.0006) has been described in the same codon of the PAH gene, codon 261 appears to be a mutation hotspot.
Eigel et al. (1991) identified deletion of a single base in codon 55 (exon 2) of the PAH gene in a patient with phenylketonuria (PKU; 261600). The mutation altered the reading frame so that a stop signal (TAA) was generated in codon 60 of the PAH gene. All PKU alleles showing the codon 55 frameshift mutation exhibited haplotype 1; furthermore, 13% of all mutant haplotype 1 alleles carried this particular mutation.
In a Norwegian patient with phenylketonuria (PKU; 261600), Eiken et al. (1992) identified a novel mutation in exon 12 in association with haplotype 12 alleles, by use of SSCP analyses. A patient who was homozygous for the arg408-to-gln (R408Q) mutation exhibited a mild PKU variant. Eiken et al. (1992) mapped the district of origin of the R408Q and phe299-to-cys (F299C; 612349.0039) mutations by determining the birthplaces of the relevant grandparents. In contrast to both the overall distribution of PKU mutations and the general population density in Norway, the ancestors of these 2 mutations appeared to be restricted to the western and northern coastal districts. See 612349.0042.
In Chinese, Lin et al. (1992) found a G-to-A transition in codon 408 as the basis of phenylketonuria. The missense mutation resulted in the substitution of arginine for glutamine and accounted for about 5% of PKU chromosomes among Chinese. The mutation was in linkage disequilibrium with RFLP haplotype 4. The arg408-to-trp mutation (R408W; 612349.0002) is in the same codon.
The mutant haplotype 8 occurs relatively frequently in Norwegian phenylketonuria (PKU; 261600) patients (comprising 6% of mutant genes), whereas it is rare among other European PKU patients. Normal haplotype 8 genes have not been observed in any European population. Eiken et al. (1992) found that all mutant haplotype 8 chromosomes carried the phe299-to-cys (F299C) mutation described briefly by Okano et al. (1989). A patient homozygous for the F299C mutation manifested severe PKU.
In a single chromosome of a Chinese patient with phenylketonuria (PKU; 261600) out of a total of 104 Chinese PKU chromosomes, Wang et al. (1992) identified a T-to-A transversion at the second base of intron 7, altering the invariant dinucleotide of the splice donor signal from GT-to-GA. The mutation occurred on the background of haplotype 7.
John et al. (1992) identified a ser349-to-pro (S349P) mutation on haplotype 1 in French Canadians from eastern Quebec with phenylketonuria (PKU; 261600). Other mutations in this population include met1-to-val (M1V; 612349.0009) on haplotype 2 and arg408-to-trp (R408W; 612349.0002) on haplotype 1.
Weinstein et al. (1993) identified the S349P mutation on haplotype 4 in North African Jews with PKU. The mutation was caused by a T-to-C change in exon 10 of the PAH gene. In vitro expression of the mutation showed normal levels of mRNA with virtually no enzymatic activity or protein immunoreactivity, pointing to a highly unstable protein.
Knappskog et al. (1995) found the S349P mutation in 1 Norwegian and 1 Polish PKU allele on a haplotype 1.7 background. The mutation had been reported on a total of 3 different haplotypes, suggesting recurrent mutation. In 2 different E. coli expression systems, it was shown that the S349P mutation, introduced by site-directed mutagenesis, resulted in complete loss of enzymatic activity. Thus, protein instability alone did not seem to be the direct cause of the lack of activity of this PKU mutation, as previously reported.
Svensson et al. (1992) hypothesized that there is at least 1 mild hyperphenylalaninemia (261600) mutation linked to haplotype 12 in the Swedish population, since 7 of 8 patients carrying haplotype 12 were found to have mild HPA. Sequence analysis revealed a C-to-G transversion at the second base of codon 322, resulting in a substitution of glycine for alanine (A322G), in 4 mutant haplotype 12 genes, and a G-to-A transition at the second base of codon 408, resulting in a substitution of glutamine for arginine (R408E; 612349.0038), in another 3 mutant haplotype 12 genes. These mutations were not found on normal alleles or other mutant alleles. Testing in a eukaryotic expression system in which the enzyme activities of different mutant PAH enzymes reflect the relative severities showed that the A322G mutant had about 75% and the R408Q mutant about 55% of the wildtype PAH enzyme activity.
Economou-Petersen et al. (1992) found compound heterozygosity at the PAH locus in all 17 Danish families with non-phenylketonuria hyperphenylalaninemia (see PKU, 261600). By ASO probing for common PKU mutations, they found that 12 of 17 non-PKU HPA children had a PKU allele on 1 chromosome. To identify molecular lesions in the second allele, individual exons were amplified by PCR and screened for mutations by single-strand conformation polymorphism. Two new missense mutations were identified. Three children had inherited a G-to-A transition at codon 415 in exon 12, converting GAC (asp) to AAC (asn) (D415N).
In the study in which they demonstrated that all 17 Danish families with non-phenylketonuria hyperphenylalaninemia (see PKU, 261600) had compound heterozygosity for a PKU mutation, Economou-Petersen et al. (1992) demonstrated that the other allele in 1 child possessed an A-to-G transition at codon 306 in exon 9, causing the replacement of an isoleucine by a valine (I306V). They demonstrated that the hyperphenylalaninemia mutations had less impact on the heterozygote's ability to hydroxylate phenylalanine to tyrosine than did the PKU mutation in the other heterozygous parent.
In a Japanese patient with phenylketonuria (PKU; 261600), Takahashi et al. (1992) identified compound heterozygosity for the arg413-to-pro mutation (R413P; 612349.0016) and a previously unidentified mutation, a G-to-A transition at base 1384 of their cDNA clone that altered valine at codon 388 in exon 11 to methionine (V388M). The mutations were identified through the study of 'ectopic' or 'illegitimate' transcription of the PAH gene in lymphoblast mRNA by use of PCR.
Desviat et al. (1995) stated that the V388M mutant enzyme has similar levels of immunoreactive protein and PAH mRNA and 43% residual activity, which correlates well with the mild phenotype exhibited by homozygous patients. In Spain, this mutation is present in 5.7% of mutant alleles and is always associated with haplotype 1.7. In Brazil, where it accounts for 9% of alleles, it is also found only on haplotype 1.7. However, Desviat et al. (1995) found that in Chile, where V388M accounts for 13% of alleles, it is carried by haplotype 4.3. The authors found that recurrent mutation was the most plausible explanation and was supported by the fact that the mutation involves a CpG dinucleotide.
Leandro et al. (1995) reported on a mutation analysis of PKU in South and Central Portugal. A National Screening Program for PKU was started in Portugal in 1979. The incidence of the disorder was found to be approximately 1:15,000 in the Portuguese population, a value within the limits of the frequency found in other Caucasian populations. The V388M mutation was found in a frequency of 18.8% in a study of 16 patients. This mutation was found in no patients in Spain, Italy, or Turkey. The fact that V388M was found in a Japanese PKU patient prompted the study of haplotype association since, to that time, only 2 PAH mutations had been found in both Caucasian and populations; these were associated with different haplotypes in the 2 populations. Because of the historic connections between Portugal and Japan, the V388M mutation in Japan may have originated from Portugal. Leandro et al. (1995) stated that 2 cases of V388M mutation in PKU reported from the area of Boston, Massachusetts, had Portuguese ancestry.
In a Polish patient with typical phenylketonuria (PKU; 261600), Jaruzelska et al. (1992) found a 15-bp in-frame deletion in exon 11 of the PAH gene. The deletion was on the background of haplotype 4. The resulting protein was expected to lack 5 amino acids in the catalytic domain of the enzyme.
In a Spanish patient with phenylketonuria (PKU; 261600), Desviat et al. (1992) found a C-to-T transition at the second base of codon 244, causing a substitution of a proline (CCT) for a leucine (CTT) (P244L). The mutation was on haplotype 12 and was inherited from the father.
In a Norwegian patient with phenylketonuria (PKU; 261600) who was compound heterozygous for the IVS12 mutation (612349.0001), Eiken et al. (1992) demonstrated that the other allele carried a G-to-A transition converting the start codon of the PAH gene from ATG (met) to ATT (ile) (M1I). It would be predicted that the mRNA transcribed from this mutated gene would not be translated. Since the IVS12 mutation also abolishes PAH enzymatic activity, the patient in this case would be expected to have no biologically active gene product, leading to a severe PKU phenotype. Observations supported the prediction. The IVS12 mutation, which is the most frequent PKU allele in Norway, occurring in 19% of Norwegian PKU chromosomes, was inherited from the mother. The other mutation was not found in any relatives including the father in whom fingerprint patterns were fully compatible with paternity. Eiken et al. (1992) suggested that this represents a de novo mutation occurring in the father, who in this case had the highest age of any father in the series of Norwegian PKU patients, 45 years.
In a French patient with a mild form of phenylketonuria (PKU; 261600), Abadie et al. (1993) found deletion of exon 11 due to a C-to-T transition at the first nucleotide of the splice acceptor triplet of intron 10. The mother was heterozygous for the mutation. The other allele was the R261Q mutation (612349.0006), which has also been associated with mild phenylketonuria and in this case was inherited from the father.
In a patient with non-phenylketonuria hyperphenylalaninemia (see PKU, 261600) born of North African parents, Abadie et al. (1993) demonstrated compound heterozygosity for 2 missense mutations in exons 10 and 11, namely, leu333 to phe (L333F) and glu390 to gly (E390G; 612349.0051), respectively.
For discussion of the glu390-to-gly (E390G) mutation in the PAH gene that was found in compound heterozygous state in a patient with non-phenylketonuria hyperphenylalaninemia (see PKU, 261600) by Abadie et al. (1993), see 612349.0050.
Zschocke et al. (1999) described a child in whom PKU was apparently caused by homozygosity for the E390G mutation in exon 11 of the PAH gene. However, the clinical severity of the disease was not as mild as expected, the mutation was not identified in the father despite confirmed paternity, and the paternal allele showed a highly unusual pattern of polymorphic markers in the PAH gene. The patient was found to have a large deletion involving exons 9, 10, and 11 (612349.0064) of the PAH gene, and was thus a compound heterozygote, accounting for the more severe phenotype.
Using a modified application of the chemical cleavage of mismatch (CCM) method to screen exons 9, 10, and 11 of the PAH gene in 17 Italian patients with phenylketonuria (PKU; 261600), Dianzani et al. (1993) found a nonsense heterozygous C-to-G transversion in exon 11 in 1 patient. The change caused a ser-to-ter substitution at amino acid 359 (S359X).
In a Pakistani girl with mild hyperphenylalaninemia (see PKU, 261600), Guldberg et al. (1993) used PCR in combination with denaturing gradient gel electrophoresis (DGGE) to demonstrate homozygosity for a T-to-C transition at position 515 in the PAH cDNA. This mutation changed codon 98 from TTG to TCG, resulting in a substitution of leucine with serine (L98S).
Up to 10% of newborn children with a positive Guthrie test have non-phenylketonuria hyperphenylalaninemia (see PKU, 261600), i.e., mild elevation of serum phenylalanine that does not require dietary treatment. Depending on the relative frequencies of different PAH mutations in a particular population, non-PKU hyperphenylalaninemia is usually caused by the combined effect of a mild hyperphenylalaninemia mutation and a severe PKU mutation. In a comprehensive analysis of non-PKU HPA in Northern Ireland, Zschocke et al. (1994) found that the thr380-to-met (T380M) mutation was present in over 70% of such cases. Screening for this mutation is easy and inexpensive and can help confirm the diagnosis of non-PKU HPA in most cases at an early stage. This should be clinically useful and reassuring for parents.
Eiken et al. (1996) demonstrated a gly46-to-ser (G46S) mutation in the PAH gene in phenylketonuria (PKU; 261600) patients and studied its phenotypic consequences in 3 homozygotes and 13 compound heterozygotes. DNA sequencing following fluorescence-based SSCP revealed a G-to-A transition at their cDNA position 136. The G46S mutation was present in 17 of 236 Norwegian PKU alleles (7.2%) and in 8 of 176 Swedish PKU alleles (4.5%). Three patients were homozygous for the G46S mutation; 2 were untreated and had mild and severe mental retardation, respectively. Studies with an in vitro transcription-transition system revealed an abnormal susceptibility of the mutant enzyme to form catalytically inactive high-molecular-mass aggregates. This aggregation of the mutant protein, followed by increased cellular degradation, was compatible with the clinical/metabolic phenotype of the affected patients.
In a study of 30 Danish children with non-phenylketonuria hyperphenylalaninemia (see PKU, 261600), Guldberg et al. (1994) identified a C-to-T change in exon 2 of the PAH gene, resulting in an ala-to-val substitution at position 47 (A47V).
In a study of 30 Danish children with non-phenylketonuria hyperphenylalaninemia (see PKU, 261600), Guldberg et al. (1994) identified a C-to-A change in exon 3 of the PAH gene, resulting in a ser-to-arg substitution at position 87 (S87R).
In a study of 30 Danish children with non-phenylketonuria hyperphenylalaninemia (see PKU, 261600), Guldberg et al. (1994) identified a G-to-T change in exon 6 of the PAH gene, resulting in an arg-to-leu substitution at position 176 (R176L).
In a study of 30 Danish children with non-phenylketonuria hyperphenylalaninemia (see PKU, 261600), Guldberg et al. (1994) identified a T-to-C change in exon 7 of the PAH gene, resulting in a val-to-ala substitution at position 245 (V245A).
In a study of 30 Danish children with non-phenylketonuria hyperphenylalaninemia (see PKU, 261600), Guldberg et al. (1994) identified an A-to-G substitution at position 3 of the donor splice site of intron 10 of the PAH gene. The same mutation was identified in phenotypically similar sibs. The other allele contained a tyr414-to-cys mutation (Y414C; 612349.0017).
Studying 17 Icelandic patients with phenylketonuria (PKU; 261600), Guldberg et al. (1997) found that 42% of mutant alleles were represented by a 1-bp deletion mutation (1129delT). The deletion changed codons 376 (AAT, asn) and 377 (TAC, tyr) with frameshift. Thus, codon 377 was changed from TAC (tyr) to ACA (thr) and a premature termination codon was created at residue 399. The authors referred to the mutation as Y377fsdelT. The mutation was found on 13 apparently independent alleles in 4 homozygous patients and 5 genetic compounds.
Corsello et al. (1999) determined the plasma amino acids in 48 Sicilian women with 1 or more microcephalic children. As a result, 2 families came to their attention. Unexpectedly, maternal phenylketonuria (PKU; 261600) in these 2 families was responsible for the microcephaly and was caused by untreated classic PKU rather than mild hyperphenylalaninemia. The mothers were mentally retarded, with blood phenylalanine levels more than 1,200 micromol/l. DNA studies demonstrated a pro407-to-leu (P407L) mutation due to a C-to-T transition at the second base of codon 407. The second family had a previously known mutation, R111X (612349.0005). The parents of this mother (the grandparents of the microcephalic child) were related as first cousins once removed; both were heterozygous for the R111X mutation.
In a French Canadian patient with phenylketonuria (PKU; 261600), John et al. (1992) identified a T-to-C transition at codon 65 of the PAH gene, resulting in an ile65-to-thr (I65T) substitution. The mutation was not found on 116 normal chromosomes. Expression analysis of the I65T mutation in COS cells demonstrated a 75% loss of both immunoreactive protein and enzyme activity.
For discussion of the deletion involving exons 9, 10, and 11 of the PAH gene that was found in compound heterozygous state in a patient with phenylketonuria (PKU; 261600) by Zschocke et al. (1999), see 612349.0051.
Chen et al. (2002) studied a case of non-phenylketonuria hyperphenylalaninemia (see PKU, 261600) detected by a national newborn screening program in Taiwan. The paternally inherited allele harbored a de novo E76G mutation (612349.0067). The basal promoter and the mRNA processing were normal in the PAH allele inherited from the mother. However, a 3.7-kb deletion was identified in the 5-prime flanking region of the maternally inherited PAH allele. Characterization of the deleted sequence led to the identification of a novel liver-specific DNaseI hypersensitive site located 3.3 kb upstream of the RNA initiation site of the PAH gene. They showed that this site comprises a liver-specific enhancer with cAMP responsiveness. They further showed by mutation analysis that the enhancer carries a major hepatocyte nuclear factor-1 (HNF4A; 142410)-binding site important for the enhancer function but not for cAMP responsiveness. In transient transfection assays with a reporter gene, they demonstrated that a PAH plasmid construct carrying the deletion, designated as -4173_-407del, was severely impaired in phenylalanine hydroxylase transcriptional activity.
In a case of non-phenylketonuria hyperphenylalaninemia (see PKU, 261600), Chen et al. (2002) found a de novo glu76-to-gly (E76G) substitution in the PAH protein. They detected an A-to-G transition at position 227 of the patient's PAH cDNA. This mutation was found in compound heterozygosity with a 3.7-kb deletion (612349.0066).
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