Other entities represented in this entry:
HGNC Approved Gene Symbol: GALT
SNOMEDCT: 124354006, 398664009;
Cytogenetic location: 9p13.3 Genomic coordinates (GRCh38) : 9:34,646,675-34,651,035 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9p13.3 | Galactosemia | 230400 | Autosomal recessive | 3 |
Galactose-1-phosphate uridylyltransferase (GALT; EC 2.7.7.12) is the second enzyme in the evolutionarily conserved galactose metabolic pathway. It facilitates the simultaneous conversion of uridine diphosphoglucose and galactose-1-phosphate to uridine diphosphogalactose and glucose-1-phosphate, respectively (summary by Tang et al., 2014).
Reichardt and Berg (1988) used short peptide sequences conserved between E. coli and yeast to isolate a human GALT cDNA clone. The deduced 379-amino acid protein has a molecular mass of approximately 43 kD.
GALT/IL11RA Spliced Read-Through Transcript
Magrangeas et al. (1998) established the existence of poly(A) site choice and fusion splicing of 2 adjacent genes, encoding galactose-1-phosphate uridylyltransferase and interleukin-11 receptor alpha-chain (IL11RA; 600939), in normal human cells. This 16-kb transcription unit contains 2 promoters (the first one constitutive, and the second, 8 kb downstream, highly regulated) and 2 cleavage/polyadenylation signals separated by 12 kb. The promoter from the GALT gene yields 2 mRNAs, a 1.4-kb mRNA encoding GALT and a 3-kb fusion mRNA when the first poly(A) site is spliced out and the second poly(A) site is used. The 3-kb mRNA codes for a fusion protein containing part of the GALT protein and the entire IL11RA protein. The GALT promoter/IL11RA poly(A) transcript results from leaky termination and alternative splicing.
By gene dosage studies, Aitken and Ferguson-Smith (1979) assigned the structural gene for GALT to the short arm of chromosome 9. Shih et al. (1982, 1984) assigned the GALT locus to 9p13 by gene dosage. By deletion mapping, Kondo and Nakamura (1984) corroborated the 9p13 localization.
In a patient with classic galactosemia, or galactosemia I (GALAC1; 230400), Reichardt and Woo (1990, 1991) found a methionine-to-lysine change at codon 142 of the GALT gene, which resulted in reduction of the specific activity of the mutated protein to about 4% of normal (606999.0001).
The Duarte polymorphism was identified by Reichardt and Woo (1991), who pointed out that the galactosemia mutations tend to occur in regions of the gene that are highly conserved throughout evolution whereas the polymorphisms change variable residues. Elsas et al. (1994) presented evidence that the N314D substitution, a 940A-G transition in exon 10 (rs2070074; 606999.0005), is a common allele that causes the Duarte GALT biochemical phenotype of reduced enzyme activity, known as the 'D2' variant. Elsas et al. (1994) found that the N314D substitution occurs in a predominantly Caucasian, nongalactosemic population, with a prevalence of 5.9%. When found in cis with a silent mutation, L218L (rs2070075; 606999.0012), the Duarte allele N314D causes increased enzyme activity, known as the 'Los Angeles' or 'D1' variant. Subsequently, Kozak et al. (1999) showed that a 4-bp deletion (-119delGTCA; 606999.0017) in the 5-prime region of the GALT gene was linked with the Duarte allele and conferred reduced enzymatic activity. Carney et al. (2009) showed that the 5-prime 4-bp deletion is the causal mutation in Duarte galactosemia and suggested that direct tests for this deletion could enhance or supplant current tests.
In Japan, where classic galactosemia is thought to be only one-twentieth as frequent as it is in Caucasian populations of the United States, Ashino et al. (1995) reported 2 novel GALT mutations in 2 Japanese patients with GALT deficiency and found also the N314D substitution responsible for the Duarte variant and the arg333-to-trp mutation (R333W; 606999.0002) previously found in Caucasians.
Greber-Platzer et al. (1997) found from studies in 30 unrelated families (24 Austrian, 2 Croatian, and 4 German) with classic galactosemia that DGGE detected 59 of the 60 alleles. The Q188R mutation accounted for 60% of these alleles; K285N (606999.0013) accounted for 28%. In addition, they found 8 novel candidate galactosemia mutations. In all D2 variants, N314D occurred in cis with 2 intronic sequence changes; in 3 patients with the D1 variant, N314D was in cis with a neutral mutation in exon 7 (L218L).
Elsas and Lai (1998) stated that more than 130 mutations in the GALT gene (606999) had been associated with GALT deficiency. Two common mutations, Q188R (606999.0006) and K285N (606999.0013), accounted for more than 70% of galactosemia-producing alleles in the white population and were associated with classic galactosemia and impaired GALT function. In the black population, S135L (606999.0010) accounted for 62% of the alleles causing galactosemia and was associated with good outcomes. A large 5-kb deletion in the GALT gene was identified in Ashkenazi Jews. A comprehensive review of the 120 or more mutations was provided.
Elsas et al. (1995) described a strategy for identifying new mutations in the GALT gene. A total of 12 new and 21 previously reported rare mutations were found. Among the novel group of 12 new mutations, an unusual biochemical phenotype was found in a family in which the newborn proband had classic galactosemia. From the father, he had inherited 2 mutations in cis: asn314 to asp (N314D; 606999.0005) and glu203 to lys (E203K; 606999.0014). From the mother, he had inherited a mutation in the splice acceptor site of intron C of the GALT gene. The GALT activity in erythrocytes of the father, who was heterozygous for the double mutation, was near normal. An asymptomatic sister showed compound heterozygosity for 3 mutations: E203K-N314D/N314D. Surprisingly, her erythrocytes had normal GALT activity. Elsas et al. (1995) speculated that E203K and N314D codon changes produce intraallelic complementation when in cis. The E203K mutation was located in codon 7 and was the result of a GAG-to-AAG transition; the N314D mutation was in exon 10 and resulted from an AAC-to-GAC transition. The latter mutation is a frequent basis of the Duarte variant; the former was a new mutation found in this study. The chromosome with only one mutation, N314D, came from the proband's mother.
Galactosemia I
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988). Tyfield et al. (1999) stated that by the end of 1998 more than 150 different base changes in the GALT gene were recorded in 24 different populations and ethnic groups of 15 countries worldwide.
Suzuki et al. (2001) estimated that the birth incidence of classic galactosemia is 1 per 47,000 in the white population. Among whites, Suzuki et al. (2001) found the frequency of the Q188R mutation (606999.0006) to be 0.29%, and that of the K285N mutation (606999.0013) to be 0.062%.
Murphy et al. (1999) estimated the incidence of classic transferase-deficient galactosemia in Ireland and determined the underlying GALT mutation spectrum in the Irish population and in the Traveller group (an endogamous group of commercial/industrial nomads within the Irish population). Based on a survey of newborn screening records, the incidence of classic transferase-deficient galactosemia was estimated to be 1 in 480 and 1 in 30,000 among Traveller and non-Traveller communities, respectively. Fifty-six classic galactosemic patients were screened for mutations in the GALT gene. Q188R was the sole mutant allele among the Travellers, as well as being the most frequent mutant allele among the non-Travellers (89.1%). Of the 5 non-Q188R mutant alleles in the non-Traveller group, one was R333G (606999.0015) and one was F194L (606999.0016), with 3 remaining uncharacterized. Anonymous population screening had shown the Q188R carrier frequency to be 0.092 or 1 in 11 among the Travellers, as compared with 0.009 or 1 in 107 among the non-Travellers. The Q188R mutation was shown to be in linkage disequilibrium with a SacI RFLP flanking exon 6 of the GALT gene. Lin and Reichardt (1995) demonstrated that the Q188R mutation is in linkage disequilibrium with the SacI RFLP in African American, Asian, Caucasian, and Latino galactosemic patients. This was interpreted to indicate that the Q188R mutation arose once in the history of the modern human population and was spread worldwide by demic diffusion. The same disequilibrium in the Irish population suggested that the Q188R mutation was present in the indigenous population before the Travellers separated and was carried into the Traveller population by its founders. The findings suggested, furthermore, that the modern Traveller subpopulation in Ireland had an endogenous origin. The high frequency of the Q188R allele appears to be due to founder effect coupled with rapid expansion of this population.
Duarte-1 and Duarte-2 Alleles
Vaccaro et al. (1984) studied the frequency of the Duarte and Los Angeles variants of red cell gal-1-P uridylyltransferase in Italy; the 2 have similar electrophoretic patterns but the enzyme activity in heterozygotes is about half normal in the former and about 1.5 times normal in the latter. No apparent clinical abnormality accompanies either. The allele frequencies were: N = 0.9192; G (for galactosemia) = 0.0036; D (for Duarte) = 0.0372 and LA (for Los Angeles) = 0.0400.
By cross-species comparison, Carney et al. (2009) found that all non-human species, including chimpanzee, macaque, and mouse, encoded D rather than N at codon 314, strongly implicating D314 as the ancestral allele and suggesting the variant predominant in human is most appropriately termed D314N. In primates, the CTA(Leu) codon predominates, indicating CTA as the ancestral allele in humans. The proximal 5-prime GALT sequence contains a repeated tetranucleotide sequence of GTCA and predominates as a 3-repeat sequence (GTCA)3 in humans and primates, whereas mice carry only 1 repeat (GTCA)1. Carney et al. (2009) suggested that the repeat sequence appears to have expanded through the course of evolution and the 4-bp deletion (606999.0017) represents a contraction of 1 repeat. The authors reported that the frequency of the D314 allele (606999.0005) in the CEPH HapMap sample is 11.3%, which is unusually high compared with Yoruba, Chinese, and Japanese populations, which each exhibit frequencies of D314 well under 3%. The frequency of the TTA(Leu) codon (606999.0012) accounted for 4.5% of alleles in the CEPH sample, whereas the frequency is even rarer in non-European populations, with an observed frequency of about 1% in the Chinese sample and a complete absence in the Yoruba and Japanese samples.
Using a gene-trap strategy, Tang et al. (2014) created Galt -/- mice. Compared with wildtype, Galt -/- mice showed elevated red blood cell galactose-1-phosphate, both in the absence and presence of dietary galactose challenge. Galt -/- females had smaller litter sizes and fewer lifetime pregnancies, as well as fewer numbers of follicles and more corpora lutea of larger size per ovary, compared with controls. Feeding a high-galactose diet to lactating Galt -/- females resulted in lethality in over 70% of Galt -/- pups before weaning. Galactose-challenged Galt -/- pups showed cerebral edema and inflammatory response, abnormal changes in Purkinje and outer granular cell layers of cerebellum, and lower ratio of reduced glutathione to oxidized glutathione in blood.
Early studies on the mapping of the galactose-1-phosphate uridylyltransferase locus yielded conflicting results, placing it on chromosome 2 (Sun et al. (1973, 1974, 1977); Chu et al., 1975), and on chromosome 3 (Tedesco et al., 1974; Allerdice and Tedesco, 1975).
In a patient with classic galactosemia (GALAC1; 230400), Reichardt and Woo (1990, 1991) found a methionine-to-lysine change at a position that is conserved in all eukaryotes sequenced to date but in none of the prokaryotes. The mutation reduced the specific activity of the mutated protein to about 4% of normal.
In a patient with severe galactosemia I (GALAC1; 230400) and undetectable GALT enzymatic activity, Reichardt and Woo (1990) and Reichardt et al. (1991) found substitution of arginine-333 by tryptophan caused by a transition at nucleotide 1025. The region surrounding this missense mutation is the most highly conserved domain in the homologous enzymes of E. coli, yeast, and humans. This mutation appears to be rare. See also 606999.0006 and Elsevier and Fridovich-Keil (1996).
Reichardt and Woo (1991) identified a substitution of valine-44 by methionine in a patient with galactosemia I (GALAC1; 230400).
This polymorphism was identified by Reichardt and Woo (1991).
This polymorphism was identified by Reichardt and Woo (1991). The asn314-to-asp (N314D; rs2070074) substitution results from a 940A-G transition in exon 10 of the GALT gene. In 111 biochemically unphenotyped controls with no history of galactosemia, Elsas et al. (1994) identified 13 N314D alleles. Using G for the allele causing classic galactosemia and D for the Duarte allele, Elsas et al. (1994) proposed that the D/N, D/D, and D/G genotypes show approximately 75%, 50%, and 25% of normal GALT activity, respectively. In addition, the Duarte allele is associated with an isoform of the enzyme that has more acidic pI than normal. This variant is known as Duarte, Duarte-2, or D2 (Holton et al., 2001).
Ashino et al. (1995) identified the N314D substitution in Japanese patients with GALT deficiency and speculated that the mutation arose before Asian and Caucasian peoples diverged. Carney et al. (2009) reported that the frequency of the D314 allele in the CEPH HapMap sample is 11.3%, which is unusually high compared with Yoruba, Chinese, and Japanese populations, which each exhibit frequencies of D314 well under 3%.
The characteristic Duarte isoform is also associated with a variant allele (652C-T; L218L; 606999.0012), yielding the 'Los Angeles (LA) phenotype,' which has nearly normal or increased GALT enzyme activity. Podskarbi et al. (1996) referred to the 'Los Angeles variant' as Duarte-1 (D1), and noted that the N314D substitution was associated with a silent L218L substitution. They found the same substitution, N314D, in conjunction with 2 regulatory intronic mutations, 1105G-C and 1391G-A, in the D2 variant. Although D1 and D2 have identical electrophoretic mobility and isoelectric focusing points, their GALT activities differ: D1 variants show 110% to 130% of normal RBC activity, but D2 variants show only 40% to 50%. The N314D polymorphism occurs in both variants. Podskarbi et al. (1996) suggested that the decrease in GALT activity in D2 may be due to regulation of GALT gene expression by the intronic mutations. They suggested that the 1105G-C site may be critical to the function of erythroid transcription factor NFE1 (305371), since it flanks the core consensus sequence for 1 of its binding sites. Alternatively, both intronic mutations may be involved in aberrant splice processing, possibly resulting in a low level of correctly spliced mRNA.
Langley et al. (1997) evaluated GALT enzyme activity and screened the GALT genes of 145 patients with 1 or more N314D-containing alleles. They found 7 with the 'LA' biochemical phenotype, and all had the The 652C-T transition in exon 7 in cis with the N314D substitution. In pedigree analyses, this 652C-T transition segregated with the LA phenotype of increased GALT activity in 3 different biochemical phenotypes: LA/N, LA/G, and LA/D. From other studies, Langley et al. (1997) concluded that the 652C-T transition increases GALT activity by increasing GALT protein abundance without increasing transcription or decreasing thermolability. They postulated a favorable codon bias for the mutated codon with consequently increased translation rates.
Kozak et al. (1999) found that the Duarte allele is linked to a 4-bp deletion 5-prime to the translation start site (-119_-116delGTCA; 606999.0016) of GALT. Elsas et al. (2001) found that this 4-bp deletion conferred reduced luciferase activity when transfected into cell lines. Additionally, human lymphoblasts derived from patients with the Duarte allele had reduced GALT mRNA. In the Los Angeles variant, the promoter is intact. Trbusek et al. (2001) presented evidence that the 4-bp promoter deletion is a crucial factor in reduction of Duarte allele enzyme activity.
Carney et al. (2009) reported that the N314D protein was functionally neutral in mammalian cell and yeast expression studies. In contrast, the 5-prime 4-bp deletion characteristic of D2 alleles appeared to be functionally impaired in reporter gene transfection studies. Allele-specific quantitative RT-PCR revealed that D2 alleles expressed less mRNA in vivo than their wildtype counterparts. The 4-bp deletion appeared to be exclusive to D2 alleles amongst GG, NN, and DG populations. Carney et al. (2009) concluded that the 4-bp 5-prime deletion is the causal mutation in Duarte galactosemia and suggested that direct tests for this deletion could enhance or supplant current tests.
Reichardt et al. (1991) demonstrated a transition at nucleotide 591 that substituted arginine for glutamine-188 (Q188R) in patients with galactosemia I (GALAC1; 230400). The mutated glutamine is not only highly conserved in evolution, but is also 2 amino acid residues downstream from the active site histidine-proline-histidine triad and results in about 10% of normal enzymatic activity. The Q188R mutation was the most frequent galactosemia mutation characterized to 1991; it accounted for one-fourth of the galactosemia alleles studied. Elsas et al. (1994) stated that the Q188R mutation accounts for approximately 70% of Caucasian patients with galactosemia in the state of Georgia (USA), where classic galactosemia has an incidence of 1/38,886 (as determined in 1,396,766 liveborn infants).
Although the Q188R mutation is prevalent in the United States, Ashino et al. (1995) found no example in Japanese patients.
Elsevier and Fridovich-Keil (1996) applied a yeast coexpression system for GALT to investigate the impact of naturally occurring mutations on subunit association of this dimeric enzyme and holoenzyme function. They described the purification and characterization of 2 heterodimers, R333W/wildtype (see 606999.0002) and Q188R/wildtype, revealing that although the first exhibits approximately 50% wildtype activity, the second exhibits only approximately 15% wildtype activity. Neither heterodimer varied significantly from the wildtype with regard to apparent Km for either substrate used, although Q188R/WT but not R333W/WT heterodimers demonstrated significantly increased thermal sensitivity relative to the wildtype enzyme. Elsevier and Fridovich-Keil (1996) commented that their results demonstrated for the first time a partial dominant-negative effect caused by a naturally occurring mutation in human GALT.
Reichardt et al. (1992) characterized 2 galactosemia I (GALAC1; 230400) mutations, L74P and F171S (606999.0008), and 1 polymorphism, S135L, in the GALT gene. Both mutations resulted in reduced enzymatic activity on expression studies, whereas the polymorphism resulted in near normal activity. Both mutations involved evolutionarily conserved residues, while the polymorphism occurred in a nonconserved domain.
See 606999.0007 and Reichardt et al. (1992).
Flach et al. (1990) identified a his319-to-gln (H319Q) mutation in the GALT gene by sequencing PCR-amplified DNA from an Italian patient with galactosemia I (GALAC1; 230400). The mutation was a C-to-A transversion at basepair 985. Reichardt et al. (1993) demonstrated that the H319Q allele encodes an unstable polypeptide. This is a CRM-negative mutation that affects a domain conserved in E. coli and yeast. Therefore, histidine-319 presumably encodes a structurally important residue.
Baker et al. (1966) described black patients with classic galactosemia (GALAC1; 230400) who lacked GALT activity in their erythrocytes and yet were able to oxidize a substantial amount of labeled galactose to CO2 in vivo (Segal and Cuatrecasas, 1968). Liver and intestinal mucosa biopsy specimens from these patients expressed about 10% of normal GALT activity. This apparent tissue specificity of GALT enzyme expression was labeled the 'Negro variant' of galactosemia. Lai et al. (1996) demonstrated that the underlying mutation is a C-to-T transition at bp1158 of the GALT gene that results in a serine-to-leucine substitution at codon 135 (S135L). Population screening was performed using a restriction enzyme assay; the mutation abolishes a TaqI recognition site. The S135L mutation was not found in 84 white patients with homozygous galactosemia or in 87 white control subjects without galactosemia. One S135L allele was found out of the 100 GALT alleles in 50 black subjects; 16 out of 32 alleles in 16 galactosemic patients were of the S135L type. In 1 patient with galactosemia, the S135L mutation was maternal in origin; the patient had a black mother and a white father.
Ninfali et al. (1996) described an 8-year-old boy with galactosemia I (GALAC1; 230400) as well as necrotic muscle fibers and muscle hypotrophy. This child was a compound heterozygote. One allele was a previously described glu188-to-arg change (606999.0006). The other allele was a novel A-to-C substitution at nucleotide position 1454 in exon 6, predicting a proline to threonine change at position 183.
Langley et al. (1997) noted that the homozygous Duarte phenotype (230400) (N314D; 606999.0005) is usually associated with approximately 50% of normal GALT enzyme activity, but sometimes the Duarte biochemical phenotype, as defined by a shift in its isozyme-banding pattern toward the anode on isoelectric focusing, is associated with increased GALT enzyme activity; this biochemical variant has been called the 'Los Angeles (LA) variant' by Ng et al. (1973) and others and is also know as Duarte-1 or D1.
Langley et al. (1997) evaluated GALT enzyme activity and screened the GALT gene of 145 patients with 1 or more N314D-containing alleles. They found 7 with the LA biochemical phenotype, and all had a 652C-T transition in exon 7 in cis with the N314D substitution. The 652C-T transition is a rare neutral polymorphism for leucine at amino acid 218 (L218L; rs2070075). In pedigree analyses, the 652C-T transition segregated with the LA phenotype of increased GALT activity. From other studies, Langley et al. (1997) concluded that the codon change in 314D in cis with the 652C-T transition produces the LA variant galactosemia and that this nucleotide change increases GALT activity by increasing GALT protein abundance without increasing transcription or decreasing thermolability. They postulated a favorable codon bias for the mutated codon with subsequently increased translation rates as the mechanism.
Carney et al. (2009) reported that the frequency of the TTA(Leu) codon accounted for 4.5% of alleles in the CEPH HapMap sample, whereas the frequency is even rarer in non-European populations, with an observed frequency of about 1% in the Chinese sample and a complete absence in the Yoruba and Japanese samples.
In a study of 30 families with classic galactosemia (GALAC1; 230400) in Denmark, Greber-Platzer et al. (1997) found that the second common galactosemia mutation was lys285 to gln (K285N), accounting for 28% of GALT gene alleles.
See Elsas et al. (1995).
In Ireland, classic galactosemia (GALAC1; 230400) is very frequent among the Travellers, an endogamous nomadic group in which all cases are due to homozygosity for the Q188R mutation (606999.0006). The same allele accounts for most of the disease alleles among non-Travellers (89.1%). Murphy et al. (1999) found that of the 5 non-Q188R mutant alleles in the non-Traveller group, one was R333G and one was F194L (606999.0016), with 3 remaining uncharacterized.
See 606999.0015 and Murphy et al. (1999).
Kozak et al. (1999) found that the Duarte allele (N314D; 606999.0005) is linked to a 4-bp deletion, 5-prime to the translation start site (-119_-116delGTCA) of GALT, resulting in disruption of predicted binding sites of 2 transcriptional activators (AP1Q2 and AP1Q4). Elsas et al. (2001) found that this 4-bp deletion conferred reduced luciferase activity when transfected into cell lines. Additionally, human lymphoblasts derived from patients with the Duarte allele had reduced GALT mRNA. In the Los Angeles variant (606999.0012), the promoter is intact. Trbusek et al. (2001) presented evidence that the 4-bp promoter deletion is a crucial factor in reduction of Duarte allele enzyme activity.
Carney et al. (2009) reported that the N314D substitution was functionally neutral in mammalian cell and yeast expression studies. In contrast, the 5-prime 4-bp deletion characteristic of D2 alleles appeared to be functionally impaired in reporter gene transfection studies. Allele-specific quantitative RT-PCR revealed that D2 alleles expressed less mRNA in vivo than their wildtype counterparts, suggesting that underexpression at the mRNA level contributes to the compromised function of the D2 GALT allele. The 4-bp deletion appeared to be exclusive to D2 alleles amongst GG, NN, and DG populations. Carney et al. (2009) concluded that the 4-bp 5-prime deletion is the causal mutation in Duarte galactosemia and suggested that direct tests for this deletion could enhance or supplant current tests.
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