Alternative titles; symbols
HGNC Approved Gene Symbol: PGM3
SNOMEDCT: 1187623009;
Cytogenetic location: 6q14.1 Genomic coordinates (GRCh38): 6:83,148,705-83,193,900 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q14.1 | Immunodeficiency 23 | 615816 | Autosomal recessive | 3 |
For background information on the PGMs, see PGM1 (171900).
Nadeau et al. (1981) identified Pgm3 in the mouse and showed by substrate specificities and cofactor requirements that mouse Pgm1 is homologous to human PGM2 (172000), mouse Pgm2 to human PGM1, and mouse Pgm3 to human PGM3.
The interaction of erythropoietin (EPO; 133170) with the EPO receptor (EPOR; 133171) activates multiple signaling cascades. Using differential display to identify genes expressed in response to EPO, Li et al. (2000) isolated a partial human endothelial cell cDNA encoding AGM1. They obtained a full-length AGM1 coding sequence by screening a human endothelial cell cDNA library. The deduced 542-amino acid AGM1 protein is identical to human N-acetylglucosamine-phosphate mutase (GenBank AF102265). It contains a 10-amino acid segment showing high similarity with the putative active site motif of several hexose phosphate mutases. Northern blot analysis and RT-PCR confirmed that AGM1 mRNA is upregulated in endothelial cells after stimulation with EPO. Northern blot analysis detected a major, approximately 2.4-kb AGM1 transcript in all human tissues tested except lung, with relatively high expression in pancreas, heart, liver, and placenta, and relatively low expression in brain, skeletal muscle, and kidney. Two minor transcripts of approximately 5 and 8 kb were also found in all tissues except lung.
Pang et al. (2002) presented evidence that AGM1 is identical to PGM3. They identified 2 AGM1 alleles containing a G or an A at nucleotide 1396, which can encode aspartic acid or asparagine at codon 466, respectively. Cell extracts of COS-7 cells after transfection with a plasmid containing an AGM1 allele with 1396G or 1396A showed similar electrophoretic patterns to the PGM3*1 or PGM3*2 protein, respectively, with the isozyme detection method used for PGM3 phenotyping. The genotypes determined by the 2 alleles of AGM1 coincided exactly with the PGM3 phenotypes in 20 individuals. Furthermore, the allele frequency of the AGM1 nucleotide polymorphism in a Japanese population was similar to that previously reported for PGM3*1 and PGM3*2.
Sassi et al. (2014) reported that the PGM3 gene contains 14 exons and spans 29 kb.
PGM1 and PGM3 are not closely linked (Hopkinson and Harris, 1968). By study of human-hamster somatic cell hybrids, Jongsma et al. (1973) showed that chromosome 6 carries PGM3. Since PGM3 is linked to HLA (Lamm et al., 1970), the major histocompatibility locus must be on chromosome 6. The order is centromere--HLA-D--HLA-B--HLA-C--HLA-A. PGM3 is not located between HLA and the centromere and is probably on the long arm of 6. Kompf et al. (1978) and Schunter et al. (1978) presented evidence suggesting that PGM3 is on the HLA-A side of MHC. Baur and Rittner (1978) applied a computer program to family data to arrive at the conclusion that PGM3 is on the HLA-B side of the MHC.
From study of a 3-generation family segregating for variation of the centromeric heterochromatic region of chromosome 6p11, Bakker et al. (1979) concluded that the HLA cluster and 6ph are about 6 cM apart (with peak lod score of 3.466), that GLO is on the centromeric side of HLA, and that HLA-B is closer to the centromere than HLA-A. Parrington et al. (1979) found no PGM3 heterozygotes among 13 informative tumors (10 heterozygous patients), suggesting that the locus may be very close to the centromere.
Lamm et al. (1981) gave further information on the relationship of PGM3 and HLA. They concluded that PGM3 is probably located at about the level of 6q16. They studied a family in which the father had a crossover in HLA and was heterozygous for PGM3.
By somatic cell hybrid analysis, Li et al. (2000) mapped the AGM1 gene to chromosome 6.
Nadeau et al. (1981) mapped the mouse Pgm3 gene to chromosome 9.
Whereas PGM1 and PGM2 polymorphism is determined in red cells, PGM3 is detected in white cells (Hopkinson and Harris, 1968).
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
Immunodeficiency 23
In affected members of the family with immunodeficiency with hyper-IgE and cognitive impairment (IMD23; 615816) reported by Hay et al. (2004), Zhang et al. (2014) identified compound heterozygous mutations in the PGM3 gene (172100.0001 and 172100.0002). Three Egyptian males with the disorder were homozygous for another pathogenic mutation (172100.0003). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families.
In 9 affected members of 4 consanguineous families of North African origin with IMD23, Sassi et al. (2014) identified 3 different homozygous mutations in the PGM3 gene (172100.0004-172100.0006). The mutations in the first 2 families were found by homozygosity mapping and candidate gene sequencing. The second 2 probands were found by direct sequencing of the PGM3 gene in 32 unrelated patients with a similar phenotype. Patient neutrophils showed decreased levels of complex tri- and tetra-antennary N-glycans and an accumulation of bi-antennary N-glycans compared with controls, indicating decreased PGM3 function and impaired glycosylation.
In 3 unrelated patients with IMD23, Stray-Pedersen et al. (2014) identified biallelic mutations in the PGM3 gene (172100.0007-172100.0010). In vitro functional expression assays in E. coli showed that all of the mutations resulted in reduced phosphate-group transfer from GlcNAc-6-P to GlcNAc-1-P, consistent with a loss of PGM3 enzyme function. None of the patients had glycosylation defects of serum transferrin (TF; 190000) or APOC3 (107720). The patients showed unexplained clinical variability: in addition to immunodeficiency, 2 patients had skeletal anomalies resembling Desbuquois dysplasia (DBQD1; 251450), including short stature, brachydactyly, dysmorphic facial features, and impaired intellectual development.
In 5 sibs with immunodeficiency-23 (IMD23; 615816) originally reported by Hay et al. (2004), Zhang et al. (2014) identified compound heterozygous mutations in the PGM3 gene: a c.1585G-C transversion (c.1585G-C, NM_001199917.1) resulting in a glu529-to-gln (E529Q) substitution at a highly conserved residue in the substrate-binding loop, and a 5-bp deletion (c.1438_1442del; 172100.0002), resulting in a frameshift and premature termination (Leu480SerfsTer10). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and were filtered against the dbSNP (build 134), Exome Variant Server, and 1000 Genomes Project databases. The truncating mutation was predicted to result in nonsense-mediated mRNA decay. PGM3 activity was substantially decreased in patient fibroblasts, and there was an accumulation of GlcNAc-6-P and a decrease in UDP-GlcNAc. These changes were associated with glycosylation defects: there was hyposialylation of O-linked serum glycans and undergalactosylation of N-linked oligosaccharides, although serum transferrin (TF; 190000) glycosylation was normal.
For discussion of the 5-bp deletion (c.1438_1442del, NM_001199917.1) in the PGM3 gene that was found in compound heterozygous state in patients with immunodeficiency-23 (IMD23; 615816) by Zhang et al. (2014), see 172100.0001.
In 3 affected members of a consanguineous Egyptian family with immunodeficiency-23 (IMD23; 615816), Zhang et al. (2014) identified a homozygous c.975T-G transversion (c.975T-G, NM_001199917.1) in the PGM3 gene, resulting in an asp325-to-glu (D325E) substitution at a highly conserved residue at the interface between the metal-binding and sugar-binding domains. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was filtered against the dbSNP (build 134), Exome Variant Server, and 1000 Genomes Project databases. PGM3 mRNA levels were normal in patient cells, but protein levels were significantly decreased, suggesting that the mutation resulted in an unstable protein. PGM3 activity was substantially decreased in patient fibroblasts, and there was an accumulation of GlcNAc-6-P and a decrease in UDP-GlcNAc. These changes were associated with glycosylation defects: there was hyposialylation of O-linked serum glycans and undergalactosylation of N-linked oligosaccharides, although serum transferrin glycosylation was normal.
In 4 affected members of a consanguineous Tunisian family with immunodeficiency-23 (IMD23; 615816), Sassi et al. (2014) identified a homozygous 3-bp deletion (c.1018_1020del, ENST00000513973) in exon 9 of the PGM3 gene, resulting in deletion of a highly conserved residue (Glu340del) in the central sugar-binding domain. The mutation, which segregated with the disorder in the family, was not found in 170 control individuals or in the 1000 Genomes Project database. Western blot analysis of patient cells showed decreased PGM3 levels, suggesting increased degradation of the mutant protein. Catalytic activity of the mutant protein was reduced to 20 to 30% residual activity compared with wildtype. Patient neutrophils showed decreased levels of bi-, tri-, and tetra-antennary N-glycans and accumulation of hybrid glycans compared with controls, indicating decreased PGM3 function and impaired glycosylation.
In 2 brothers, born of consanguineous Tunisian parents, with immunodeficiency-23 (IMD23; 615816) previously reported by Ayed et al. (1987), Sassi et al. (2014) identified a homozygous c.248T-C transition (c.248T-C, ENST00000513973) in exon 4 of the PGM3 gene, resulting in a leu83-to-ser (L83S) substitution at a highly conserved residue in the N-terminal catalytic domain. Two similarly affected Moroccan sibs, born of consanguineous parents, were also found to carry the homozygous L83S mutation, but genotype data were not available to investigate a founder effect. The mutation, which segregated with the disorder in both families, was not found in 170 control individuals or in the 1000 Genomes Project database. Catalytic activity of the mutant protein was reduced to 20 to 30% residual activity compared with wildtype. Patient neutrophils showed decreased levels of complex tri- and tetra-antennary N-glycans and accumulation of bi-antennary N-glycans compared with controls, indicating decreased PGM3 function and impaired glycosylation.
In a boy, born of consanguineous Turkish parents, with immunodeficiency-23 (IMD23; 615816), Sassi et al. (2014) identified a homozygous c.1504G-T transversion (c.1504G-T, ENST00000513973) in exon 13 of the PGM3 gene, resulting in an asp502-to-tyr (D502Y) substitution at a highly conserved residue in the C-terminal phosphate-binding domain. The mutation, which segregated with the disorder in the family, was not found in 170 control individuals or in the 1000 Genomes Project database. Patient neutrophils showed decreased levels of complex tri- and tetra-antennary N-glycans and accumulation of bi-antennary N-glycans compared with controls, indicating decreased PGM3 function and impaired glycosylation.
In an Afghan girl with immunodeficiency-23 (IMD23; 615816), Stray-Pedersen et al. (2014) identified a homozygous c.737A-G transition (c.737A-G, NM_015599.2) in exon 6 of the PGM3 gene, resulting in an asn246-to-ser (N246S) substitution at a highly conserved residue close to the active site. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not present in the Exome Variant Server, 1000 Genomes Project, or dbSNP databases, or in 2 large in-house exome databases. The patient also had a skeletal dysplasia resembling Desbuquois dysplasia (DBQD1; 251450). In vitro functional expression studies in E. coli showed that the N246S mutant protein was inactive.
In a Mexican boy, born of unrelated parents, with immunodeficiency-23 (IMD23; 615816), Stray-Pedersen et al. (2014) identified a heterozygous c.715G-C transversion (c.715G-C, NM_015599.2) in exon 6 of the PGM3 gene, resulting in an asp239-to-his (D239H) substitution at a highly conserved residue close to the active site. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not present in the Exome Variant Server, 1000 Genomes Project, or dbSNP databases, or in 2 large in-house exome databases. The D239H mutation was inherited from the patient's unaffected mother. The unaffected father transmitted a 1.2-Mb deletion of chromosome 6q14.1-q14.2 that encompassed the entire PGM3 gene as well as 3 neighboring genes. Two older sibs of the patient died from infection in infancy; DNA from these patients was not available.
In a German boy with immunodeficiency-23 (IMD23; 615816), Stray-Pedersen et al. (2014) identified compound heterozygous mutations in the PGM3 gene: a 1-bp duplication (c.737dupA, NM_015599.2) resulting in a frameshift and premature termination (Asn246LysfsTer7), and a c.1352A-G transition in exon 11, resulting in a gln451-to-arg (Q451R; 172100.0010) substitution at a moderately conserved residue in domain 4 close to the substrate-binding site. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and were not present in the Exome Variant Server, 1000 Genomes Project, or dbSNP databases, or in 2 large in-house exome databases. The patient also had a skeletal dysplasia resembling Desbuquois dysplasia (DBQD1; 251450).
For discussion of the gln451-to-arg (Q451R) mutation in the PGM3 gene (c.1352A-G, NM_015599.2) that was found in compound heterozygous state in a patient with immunodeficiency-23 (IMD23; 615816) by Stray-Pedersen et al. (2014), see 172100.0009.
In 2 Swedish sibs with immunodeficiency-23 (IMD23; 615816), Lundin et al. (2015) identified a homozygous G-to-A transition in the PGM3 gene, resulting in an ile322-to-thr (I322T) substitution. The mutation, which was found by targeted sequencing in a cohort of patients, segregated with the disorder in the family. In vitro functional expression studies showed that the mutant protein had 47.8% activity of the wildtype protein, likely due to decreased protein stability. The patients were 2 of 4 sibs originally reported by Bjorksten and Lundmark (1976) as having recurrent infections, lymphopenia, mild neutropenia, eosinophilia, and increased IgA; IgE levels were normal. Three of the 4 sibs died between 10 and 16 years of age. Lundin et al. (2015) noted that this family may be the first reported with this disorder.
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Zhang, Y., Yu, X., Ichikawa, M., Lyons, J. J., Datta, S., Lamborn, I. T., Jing, H., Kim, E. S., Biancalana, M., Wolfe, L. A., DiMaggio, T., Matthews, H. F., and 11 others. Autosomal recessive phosphoglucomutase 3 (PGM3) mutations link glycosylation defects to atopy, immune deficiency, autoimmunity, and neurocognitive impairment. J. Allergy Clin. Immun. 133: 1400-1409, 2014. [PubMed: 24589341] [Full Text: https://doi.org/10.1016/j.jaci.2014.02.013]