HGNC Approved Gene Symbol: PMM2
SNOMEDCT: 277893002, 459063003;
Cytogenetic location: 16p13.2 Genomic coordinates (GRCh38) : 16:8,797,839-8,849,325 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p13.2 | Congenital disorder of glycosylation, type Ia | 212065 | Autosomal recessive | 3 |
The PMM2 gene encodes phosphomannomutase (EC 5.4.2.8), an enzyme necessary for the synthesis of GDP-mannose.
Matthijs et al. (1997) identified phosphomannomutase-1 (PMM1; 601786) by database searching for human cDNAs with similarity to Candida or yeast phosphomannomutase. Biochemical studies of PMM1 and phosphomannomutases from rat and human liver provided evidence for the existence in mammals of a second phosphomannomutase with different kinetic and antigenic properties. By database searching for sequences similar to that of PMM1, Matthijs et al. (1997) identified identified and subsequently cloned a PMM2 cDNA. The deduced 246-amino acid PMM2 protein shares 66% and 57% sequence identity with PMM1 and yeast phosphomannomutase, respectively.
Matthijs et al. (1997) mapped the PMM2 gene to 16p13 by Southern blot analysis of a genomic mapping panel and by hybridization to DNA from YACs previously assigned to that chromosomal region (D16S406 to D16S404). Bjursell et al. (1998) achieved refined mapping of the PMM2 gene by analysis of radiation hybrids.
Schollen et al. (1998) determined the PMM2 intron/exon structure and identified 8 exons.
Van Schaftingen and Jaeken (1995) identified a deficiency of phosphomannomutase activity in patients with carbohydrate-deficient glycoprotein syndrome type Ia (CDG1A; 212065).
In 16 patients with CDG1A from different geographic origins and with a documented phosphomannomutase deficiency, Matthijs et al. (1997) identified 11 different missense mutations in PMM2 (see, e.g., 601785.0001-601785.0004).
Matthijs et al. (1998) described the results of an exhaustive mutation analysis of the PMM2 gene in 56 patients with documented PMM deficiency from different geographic origins. By SSCP analysis and by sequencing, they identified 23 different missense mutations and a single-basepair deletion in 99% of the disease chromosomes. The R141H mutation (601785.0001) was found in 43 of 112 disease alleles. However, this mutation was never observed in the homozygous state, suggesting that homozygosity is incompatible with live birth. Homozygous mutations were found in other patients (D65Y, 601785.0005 and F119L, 601785.0006). One particular genotype, R141H/D188G (601785.0007), which was prevalent in Belgium and the Netherlands, was associated with a severe phenotype and a high mortality. Apart from this, there was only a limited relation between the genotype and the clinical phenotype.
Kjaergaard et al. (1998) identified 34 mutations on 36 disease chromosomes in 18 unrelated Danish patients with CDG1. All patients had less than 15% residual activity of phosphomannomutase. Two mutations accounted for 88% of all mutations: F119L (601785.0006) and R141H (601785.0001) were each found in 16 of 36 CDG1 alleles. These 2 new mutations were found to be in linkage disequilibrium with 2 different alleles of the marker D16S3020, suggesting that there is 1 ancestral origin for each mutation. Two new mutations, G117R and D223E, were identified also. As reported by others, no patient was homozygous for either of the 2 common mutations. This could be interpreted as indicating that homozygosity for these mutations is lethal or, on the other hand, so benign that such patients are not detected.
Kondo et al. (1999) identified 3 missense mutations in the PMM2 gene in 2 unrelated Japanese families with CDG1. The mutations occurred in exons 5 and 8, as have most of the mutations identified in the Caucasian population.
Kjaergaard et al. (1999) determined the PMM2 genotypes of 22 unrelated Danish patients with CDG Ia. The largest proportion (18) had the genotype R141H/F119L. R141H was present in heterozygous state in 1 patient, while F119L was homozygous in 1 patient and heterozygous with G117R in another. The lack of patients homozygous for R141H was statistically highly significant. To investigate the effect of PMM2 mutations on phosphomannomutase activity, Kjaergaard et al. (1999) cloned the cDNA into a vector. Following the introduction of mutations into the PMM2 cDNA by site-specific mutagenesis, wildtype and mutant PMM2 cDNAs were expressed in E. coli, and the activity of PMM2 was determined by an enzymatic assay. Recombinant R141H, G117R, and T237R (601785.0011) PMM2 had no detectable catalytic activity. F119L PMM2 had 25% of the activity of wildtype. Each of the 22 patients had at least 1 mutation that retained residual PMM2 activity. The results supported the hypotheses that a genotype conveying residual PMM2 catalytic activity is required for survival, and that homozygosity for R141H impairs PMM2 to a degree incompatible with life.
Matthijs et al. (1999) reviewed the molecular basis of CDG Ia. Matthijs et al. (2000) collated data from 6 research and diagnostic laboratories involved in searching for PMM2 mutations. In total, they listed 58 different mutations found in 249 patients from 23 countries. Bjursell et al. (2000) performed a mutation screen on 61 CDG Ia patients, 37 of whom were from Scandinavian countries. They succeeded in detecting more than 95% of the mutations, all of them missense mutations. Seven were found only in Scandinavian families. Of the 20 mutations found, 10 had not previously been reported. The R141H (601785.0001) and F119L (601785.0006) mutations accounted for 58% of the mutations detected. The most common genotype was compound heterozygosity for these 2 mutations (36%). Although 2 patients were homozygous for F119L, no patient was homozygous for the most common mutation, R141H. Most mutations were located in exon 5 or exon 8, while no mutation was detected in exon 2. When the frequency of each mutation was considered, exon 5 comprised 61% of the mutations. Thus, analysis of exon 5 in these patients enabled reliable and time-saving first screening in prenatal diagnostic cases.
Grunewald et al. (2001) reported that 9 of 54 patients with CDG Ia had a rather high residual PMM activity in fibroblasts included in the normal range (means of controls +/- 2 SD), amounting to 35 to 70% of the mean control value. The clinical diagnosis of CDG Ia was difficult because 6 of the 9 patients belonged to a subgroup characterized by a phenotype that is milder than classic CDG Ia. These patients lacked some of the symptoms that are suggestive for the diagnosis, such as inverted nipples and abnormal fat deposition, and, as a mean, had higher residual PMM activity in fibroblasts compared with patients with moderate or severe manifestations. However, they all showed mild mental retardation, hypotonia, cerebellar hypoplasia, and strabismus. All of them had an abnormal serum transferrin pattern and a significantly reduced PMM activity in leukocytes. Of the 9 patients with mild presentation, 6 were compound heterozygotes for the C241S mutation (601785.0012), which is known to reduce PMM activity by only approximately 2-fold. Grunewald et al. (2001) suggested that intermediate PMM values in fibroblasts may mask the diagnosis of CDG Ia, which is better accomplished by measurement of PMM activity in leukocytes and mutation search in the PMM2 gene.
Vuillaumier-Barrot et al. (2000) studied the activity of mutant proteins encoded by arg141 to his (R141H; 601785.0001), cys241 to ser (C241S; 601785.0012), cys9 to tyr (C9Y; 601785.0015), leu32 to arg (L32R; 601785.0016), and thr226 to ser (T226S; 601785.0017). They found that the protein encoded by R141H had no detectable activity, while the others had increased specific activity (23 to 41% of normal levels). The authors speculated that this is the reason R141H is not seen in homozygous state since, in this form, it would most likely be lethal.
Among a total of 55 patients with CDG1A, Westphal et al. (2002) found that a 911T-C (F304S) polymorphism in the ALG6 gene (604566) was almost twice as frequent in severely affected patients (0.41) compared to moderate or mildly affected patients (0.21). Functional expression studies showed that the F304S allele had a reduced ability to rescue defective glycosylation of an alg6-deficient strain of S. cerevisiae during rapid growth. The authors concluded that the presence of the F304S allele may act as a genetic modifier to exacerbate the clinical outcome in severely affected CDG1A patients.
Briones et al. (2002) presented their experience with a diagnosis of 26 Spanish patients from 19 families with CDG Ia due to PMM deficiency. Patients in all but 1 of the families were compound heterozygous for PMM2 mutations. Eighteen different mutations were detected. In contrast to other series in which the R141H mutation represents 43 to 53% of the alleles, only 9 of 36 (25%) of the alleles had this mutation. The common European F119L mutation was not identified in any of the Spanish patients but the V44A (601785.0020) and D65Y (601785.0005) mutations probably originated in the Iberian peninsula, as they have only been reported in Portuguese and Latin-American patients. Probably because of this genetic heterogeneity, Spanish patients showed very diverse phenotypes that are, in general, milder than in other series.
Schollen et al. (2007) described 2 unusual truncating mutations in 2 CDG Ia patients. One was a deep intronic point mutation (601785.0019), and the other was an Alu retrotransposition-mediated complex deletion (601785.0021). Schollen et al. (2007) cautioned that detection of these mutations stresses the importance of combining PMM2 mutation screening on genomic DNA with analysis of the transcripts and/or with the enzymatic analysis of the phosphomannomutase activity, as these types of mutations would not be easily identified by PCR-based mutation analysis at the genomic level. Vega et al. (2009) found that the deep intronic mutation identified by Schollen et al. (2007) activated a pseudoexon sequence in intron 7. Antisense morpholino oligonucleotides targeted to the 3- and 5-prime cryptic splice sites rescued the defect and allowed correctly spliced mRNA to be translated into a functional protein.
Najmabadi et al. (2011) performed homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arab) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability. In family 8307998, they identified a homozygous missense mutation in the PMM2 gene (601785.0023) in 3 sibs with mild intellectual disability, thin upper lip, flat nasal bridge, and strabismus, who were diagnosed with glycosylation disorder CDG Ia. The parents, who were first cousins, were carriers, and they had 5 healthy children.
Martinez-Monseny et al. (2019) identified mutations in the PMM2 gene in 31 patients with CDG Ia. The severity of the homozygous mutations, which were found in 3 patients, was categorized based on potential protein alteration effects and prior published in vitro studies of residual enzymatic activity. The severity of the potential protein alteration impact of the compound heterozygous mutations was classified as mild, moderate, or severe based on the combined protein alteration effects and residual enzymatic activity of each mutation. The distribution of patients based on potential protein alterations of their molecular findings included 1 severe, 17 moderate, 1 mild, and 11 unknown (due to lack of information about the pathogenicity of at least one pathogenic variant). Statistical analysis of dysmorphology, clinical, and neuroradiologic characteristics did not reveal any significant associations with the molecular severity classification.
Quelhas et al. (2021) used computational chemistry to study the dimerization and substrate binding effects of 5 mutations in PMM2 including: L32R (601785.0016), D65Y (601785.0005), F119L (601785.0006), R141H (601785.0001) and D197A. Each mutation was studied as both single and double mutant. The analysis predicted that the F119L mutation impaired protein dimerization, the R141H mutation impacted substrate binding, and the L32R, F65Y, and D197A mutations affected PMM2 structure and dynamic behavior. Analysis of the effects of a double D197A mutation showed only a mild effect on the dynamics of the PMM2 protein, which may explain why this mutation has been associated with disease only when in compound heterozygous state with a highly deleterious mutation.
Schneider et al. (2012) generated transgenic mice with homozygous or compound heterozygous hypomorphic Pmm2 alleles: R137H, which is analogous to human R141H (601785.0001), and F118L, which is predicted to lead to mild loss of enzyme activity. Homozygous R137H and compound heterozygous R137H/F118L mice were embryonic lethal. Homozygosity for R137H was associated with no residual enzymatic activity, whereas R137H/F118L mice had about 11% residual activity. Homozygous F118L mice were clinically similar to wildtype, with 38 to 42% residual PMM2 activity, which was sufficient to prevent pathologic consequences. Compound heterozygous R137H/F118L embryos showed very poor intrauterine growth with extensive degradation of multiple organs and evidence of hypoglycosylation of glycoproteins. Treatment of heterozygous F118L females with oral mannose in water beginning 1 week prior to mating resulted in a 2-fold increase of serum mannose concentrations and rescued the embryonic lethality of compound heterozygous R137H/F118L offspring, who survived beyond weaning. Compound heterozygous offspring under treatment showed organ development and glycosylation comparable to wildtype mice, indicating mannose-mediated normalization of glycosylation. The phenotypic rescue remained apparent even after 4-month maintenance of the offspring on normal water. The results revealed an essential role for proper glycosylation during embryogenesis and suggested that mannose administration to at-risk mothers may reduce the phenotype of offspring.
In a family in Sicily in which linkage studies indicated mapping of congenital disorder of glycosylation type I (CDG1A; 212065) to 16p13, Matthijs et al. (1997) found that affected individuals were compound heterozygous for a 425G-A transition (R141H) and a 647A-T transversion (N216I; 601785.0002) in the PMM2 gene. Among 18 unrelated Danish patients with CDG Ia, Kjaergaard et al. (1998) found that this and the F119L mutation (601785.0006) accounted for 88% of all mutations. Each was found in 16 of 36 PMM2 alleles.
Matthijs et al. (1999) commented on the intriguing observation of the total lack of patients homozygous for the common R141H mutation. The residual activity of the in vitro expressed R141H recombinant protein is almost zero, supporting the inference that homozygosity for this mutation is lethal early in development. Patients homozygous for the relatively frequent F119L mutation have been found, and 1 patient homozygous for the D65Y mutation (601785.0005) has been identified. In these patients, the residual activity of the deficient enzyme was, in the words of Matthijs et al. (1999), 'relatively pronounced.'
Schollen et al. (2000) determined the frequency of the R141H mutation in 2 normal populations: in neonates of Dutch origin, 1 in 79 were carriers, whereas in the Danish population, a carrier frequency of 1 in 60 was found. These figures were clearly in disequilibrium with the frequency of CDG Ia that had been estimated at 1 in 80,000 and 1 in 40,000 in these populations. Haplotype analysis of 43 patients with the R141H mutation of different geographic origins indicated that it is an old mutation in the Caucasian population. Based on the new data, the disease frequency was calculated at 1 in 20,000 in these populations. The authors concluded that the disease was probably underdiagnosed.
Vuillaumier-Barrot et al. (2000) identified the R141H mutation in 9 (41%) of 22 chromosomes in French patients with CDG Ia.
In a male infant diagnosed with CDG Ia, Bohles et al. (2001) showed a pro113-to-leu (P113L) mutation in compound heterozygosity with the arg141-to-his mutation.
Quelhas et al. (2006) found that the R141H substitution was the most common mutation among 15 Portuguese patients with CDG1A, accounting for 7 of 26 mutations (26%). The second most common mutation was D65Y (601785.0005), which accounted for 6 of 26 mutations (23%). Haplotype analysis indicated a founder effect for the R141H substitution.
For discussion of the asn216-to-ile (N216I) mutation in the PMM2 gene that was found in compound heterozygous state in patients with congenital disorder of glycosylation type Ia (CDG1A; 212065) by Matthijs et al. (1997), see 601785.0001.
Neumann et al. (2003) identified homozygosity for the N216I mutation in a 16-month-old boy with CDG Ia. In contrast to previously reported patients, he had postnatal macrosomia and did not have inverted nipples or abnormal fat pads. His parents, who were consanguineous, were heterozygous for the mutation. The authors suggested that homozygosity for this mutation could have a specific phenotype correlation.
In a family from Sicily in which congenital disorder of glycosylation type I (CDG1A; 212065) showed linkage to 16p13, Matthijs et al. (1997) found that members with CDG Ia were compound heterozygous for a 385G-A transition (V129M) and a 484C-T transition (R162W; 601785.0004) in the PMM2 gene.
For discussion of the arg162-to-trp (R162W) mutation in the PMM2 gene that was found in compound heterozygous state in patients with congenital disorder of glycosylation type Ia (CDG1A; 212065) by Matthijs et al. (1997), see 601785.0003.
In a mutation screening of 56 patients with congenital disorder of glycosylation type I (see CDG1A; 212065), Matthijs et al. (1998) identified 3 alleles (one homozygous and one compound heterozygous patient) with a G-to-T transversion at nucleotide 193, resulting in an asp65-to-tyr (D65Y) mutation. The compound heterozygous patient, who died at the age of 4 months due to hepatic insufficiency, had the R141H mutation (601785.0001) on the other allele.
Quelhas et al. (2006) found that the R141H substitution was the most common mutation among 15 Portuguese patients with CDG1A, accounting for 7 of 26 mutations (26%). The second most common mutation was D65Y, which accounted for 6 of 26 mutations (23%). Haplotype analysis indicated a founder effect of Iberian origin for the D65Y substitution.
In a mutation screening of 56 patients with congenital disorder of glycosylation type I (see CDG1A, 212065), Matthijs et al. (1998) identified 18 occurrences of a phe119-to-leu (F119L) mutation, which resulted from a C-to-A transversion at nucleotide 357. Among 18 unrelated Danish patients with CDG1, Kjaergaard et al. (1998) found that this and the R141H mutation (601785.0001) accounted for 88% of all mutations. Each was found in 16 of 36 CDG1 alleles.
In a mutation screening of 56 patients with congenital disorder of glycosylation type I (see CDG1A, 212065), Matthijs et al. (1998) identified 5 occurrences of an asp188-to-gly (D188G) mutation, all of which were in compound heterozygous state with the R141H mutation (601785.0001). An A-to-G transition at nucleotide 563 resulted in the D188G substitution.
In Danish cases of congenital disorder of glycosylation type I (see CDG1A, 212065), Kjaergaard et al. (1998) identified a G-to-C transversion at nucleotide 349, resulting in a gly117-to-arg (G117R) substitution. The mutation was present in compound heterozygous state with the common F119L mutation (601785.0006).
In Danish cases of congenital disorder of glycosylation type I (see CDG1A, 212065), Kjaergaard et al. (1998) identified a C-to-G transversion at nucleotide 669, resulting in an asp223-to-glu (D223E) substitution. The patient was a compound heterozygote, but the second mutation was not identified.
Bjursell et al. (1998) identified a 357C-A transversion in exon 5 of the PMM2 gene as the change associated with the frequent 'haplotype A' found in patients with congenital disorder of glycosylation type Ia (CDG1A; 212065) from western Scandinavia. The mutation created a restriction site not present in the normal allele, which could be recognized by the restriction enzyme Tru9I.
In a patient with congenital disorder of glycosylation type I (CDG1A; 212065), Kjaergaard et al. (1999) identified a thr237-to-arg substitution (T237R) in the PMM2 gene. The patient was a compound heterozygote for the asp223-to-glu substitution (601785.0009).
In a review of PMM2 mutations causing congenital disorder of glycosylation type Ia (CDG1A; 212065), Matthijs et al. (1999) noted that 4 patients had a 722G-C change in exon 8, resulting in a cys241-to-ser (C241S) mutation in a nonconserved region in the C-terminal part of the PMM2 protein. Vuillaumier-Barrot et al. (2000) determined that this mutation decreases the activity of PMM2 by only 50%. Grunewald et al. (2001) found that the C241S mutation was present in compound heterozygous state in 6 of 9 patients with a mild form of CDG Ia.
Vuillaumier-Barrot et al. (2000) identified the C241S mutation in compound heterozygosity with R141H (601785.0001) in a French patient with CDG Ia.
In 3 of 22 chromosomes in French patients with congenital disorder of glycosylation type I (CDG1A; 212065), Vuillaumier-Barrot et al. (2000) identified a 395T-C transition in exon 5 of the PMM2 gene, resulting in an ile132-to-thr (I132T) substitution. Two of the patients were compound heterozygous for I132T and R141H (601785.0001), and the other was compound heterozygous for I132T and another pathogenic PMM2 mutation.
In 3 of 22 chromosomes in French patients with congenital disorder of glycosylation type I (CDG1A; 212065), Vuillaumier-Barrot et al. (2000) identified a 691G-A transition in exon 8 in the PMM2 gene, resulting in a val231-to-met (V231M) substitution. All patients were compound heterozygous for V231M and R141H (601785.0001).
In a French patient with congenital disorder of glycosylation type Ia (CDG1A; 212065), Vuillaumier-Barrot et al. (2000) identified compound heterozygosity for 2 mutations in the PMM2 gene: a 26G-A transition in exon 1 resulting in a cys9-to-tyr (C9Y) substitution and R141H (601785.0001).
In a French patient with congenital disorder of glycosylation type Ia (CDG1A; 212065), Vuillaumier-Barrot et al. (2000) identified a 95TA-GC change in exon 2 of the PMM2 gene, resulting in a leu32-to-arg (L32R) substitution. The second mutant allele was not identified.
In a French patient with congenital disorder of glycosylation type Ia (CDG1A; 212065), Vuillaumier-Barrot et al. (2000) identified compound heterozygosity for 2 mutations in the PMM2 gene: a 677C-G transversion in exon 8 resulting in a thr226-to-ser (T226S) substitution, and R141H (601785.0001).
In a male infant diagnosed with congenital disorder of glycosylation type Ia (CDG1A; 212065), Bohles et al. (2001) identified compound heterozygosity for mutations in the PMM2 gene: a pro113-to-leu (P113L) substitution and an arg141-to-his (R141H; 601785.0001) substitution.
In a patient with congenital disorder of glycosylation type Ia (CDG1A; 212065), Schollen et al. (2007) detected compound heterozygosity for a V231M mutation in PMM2 (601785.0014) and a deep intronic point mutation, notated as 639-15479C-T in the cDNA. The latter variant activated a cryptic splice site which resulted in in-frame insertion of a pseudoexon of 123 bp between exons 7 and 8.
Vega et al. (2009) referred to this mutation as 640-15479C-T or IVS7-15479C-T. In vitro functional expression assays showed that the mutation activated a pseudoexon sequence in intron 7. Antisense morpholino oligonucleotides targeted to the 3- and 5-prime cryptic splice sites rescued the defect and allowed correctly spliced mRNA to be translated into a functional protein.
In a patient with congenital disorder of glycosylation type Ia (CDG1A; 212065), Schollen et al. (2007) detected compound heterozygosity for a val44-to-ala (V44A) mutation in PMM2 arising from a 131T-C transition in exon 2, and a large deletion (601785.0021).
In a patient with congenital disorder of glycosylation type Ia (CDG1A; 212065), Schollen et al. (2007) found compound heterozygosity for a missense mutation in the PMM2 gene (601785.0020) and an Alu retrotransposition-mediated complex deletion of approximately 28 kb encompassing exon 8.
In a patient with congenital disorder of glycosylation type Ia (CDG1A; 212065), Vega et al. (2009) identified compound heterozygosity for 2 mutations in the PMM2 gene: a G-to-C transversion in intron 3 (IVS3-1G-C), resulting in the skipping of exons 3 and 4, and the L32R (601785.0016) mutation. Western blot analysis showed 28% residual protein.
In family 8307998, Najmabadi et al. (2011) identified a homozygous A-to-T transversion in the PMM2 gene at genomic coordinate Chr:16:8807735 (NCBI36), resulting in a tyr106-to-phe (Y106F) substitution, in 3 sibs with mild intellectual disability, thin upper lip, flat nasal bridge, and strabismus, who were diagnosed with glycosylation disorder congenital disorder of glycosylation type Ia (CDG1A; 212065). The parents, who were first cousins, were carriers, and they had 5 healthy children.
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