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Congenital disorder of glycosylation type Ie (CDG-Ie) is a rare autosomal recessive syndrome caused by deficiency of dolichol-phosphate-mannose synthase 1 (DPM1), the catalytic subunit of the DPM complex. DPM1 transfers mannose from GDP-mannose to dolichol phosphate in the endoplasmic reticulum, supplying mannose residues for N-glycan assembly, O-mannosylation, and GPI-anchor biosynthesis. Patients present with global developmental delay (HP:0001263), acquired microcephaly (HP:0000252), optic atrophy (HP:0000648), seizures, hypotonia, and variable dysmorphic features. CDG-Ie corresponds to MONDO:0012123 and is confirmed by biallelic DPM1 variants identified through clinical sequencing and carbohydrate-deficient transferrin testing. Initial delineation in two siblings revealed hypoglycosylation on serum transferrin and β-trace protein, consistent with reduced DPM1 activity (PMID:10642602). Subsequent fibroblast assays showed accumulation of truncated lipid-linked oligosaccharides, corroborating the glycosylation defect.
Genetic evidence has emerged from multiple unrelated families. In 2000, two siblings were compound heterozygous for c.274C>G (p.Arg92Gly) and c.628del (p.Gln210ArgfsTer4), establishing the first DPM1-CDG cases (PMID:10642602). In 2004, three families harbored homozygous or compound heterozygous variants—p.Arg92Gly, c.628del and c.331_343del13 (p.Gly111fs)—and a fourth patient was homozygous for c.742T>C (p.Ser248Pro) (PMID:15669674). A 2013 report described biallelic c.455G>T (p.Gly152Val) and an intragenic deletion of exons 3–7 in an infant with dystroglycanopathy-like muscular dystrophy (PMID:23856421). These seven probands from six families demonstrate autosomal recessive inheritance with allelic heterogeneity.
Segregation analysis supports a recessive mode: parents are heterozygous carriers in all pedigrees, and no clinically affected heterozygotes have been reported. Although extended multiplex kindreds beyond sib pairs are absent, segregation is consistent across six independent lineages with full penetrance in homozygous or compound heterozygous genotypes.
The variant spectrum in DPM1 includes at least 17 distinct alleles: nine loss-of-function changes (nonsense, splice-site, frameshift) and eight missense substitutions within catalytic domains. Recurrent variants include p.Arg92Gly in three families and p.Gln210ArgfsTer4 in two, while novel hypomorphic alleles such as p.Ser248Pro and p.Gly152Val refine genotype–phenotype correlations. Most missense changes disrupt DPM3 binding or protein stability, whereas truncating variants abrogate catalytic activity.
Functional assays provide concordant evidence: patient fibroblasts exhibit ∼80% reduction in Dol-P-Man synthase activity without altered GDP-Man affinity, leading to truncated lipid-linked oligosaccharide accumulation (PMID:23856421). Complementation of DPM1-null murine cells rescues glycosylation defects (PMID:10642602). In Saccharomyces cerevisiae, temperature-sensitive dpm1 mutants are blocked in GPI-anchor assembly, N-glycosylation, and O-mannosylation at nonpermissive temperature, mirroring human enzymatic roles (PMID:2146492). Transfected cells expressing p.Gly152Val show reduced DPM3 interaction, elucidating a complex assembly defect.
This evidence fulfills ClinGen criteria for a Strong gene–disease association. Genetic evidence comprises seven probands across six families with biallelic variants, and functional data across cell and yeast models provide experimental concordance at a Moderate level. No conflicting reports challenge DPM1’s role in MONDO:0012123. Diagnostic sequencing of DPM1 enables early identification, genetic counseling, and biochemical confirmation. Key Take-home: Biallelic pathogenic variants in DPM1 cause autosomal recessive CDG-Ie, characterized by developmental delay, microcephaly and optic atrophy, and are identifiable by genetic testing.
Gene–Disease AssociationStrong7 probands across 6 unrelated families; consistent segregation and concordant functional data Genetic EvidenceStrong7 probands from 6 families with biallelic missense and loss-of-function variants under autosomal recessive inheritance Functional EvidenceModerateCellular and yeast models demonstrate ≥80% enzyme activity reduction and recapitulate glycosylation defects |