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Congenital disorders of glycosylation (CDGs) are autosomal recessive multisystem diseases caused by defects in N-linked glycosylation. DPAGT1 encodes UDP-GlcNAc:dolichol phosphate N-acetylglucosamine‐1‐phosphotransferase (GPT), the enzyme catalyzing the first step of the dolichol-linked oligosaccharide pathway. Loss-of-function variants in DPAGT1 result in the CDG-Ij subtype (MONDO:0011964), characterized by severe hypotonia, intractable seizures, microcephaly, global developmental delay, and early mortality.
Homozygosity mapping in a large consanguineous family identified 18 affected infants harboring a novel homozygous missense variant, c.902G>A (p.Arg301His) (PMID:23430862), confirming DPAGT1‐CDG in an autosomal recessive pedigree. Subsequent exome sequencing in non-consanguineous families revealed compound heterozygous missense variants such as c.85A>T (p.Ile29Phe) and c.503T>C (p.Leu168Pro), associated with milder phenotypes including moderate intellectual disability and hypotonia (PMID:23249953). An expanded cohort of 11 patients from eight families further delineated severe early-onset epileptic encephalopathy and muscular hypotonia (PMID:30117111).
The variant spectrum encompasses missense (n>20), splice site, start‐loss, and frameshift mutations. Recurrent alleles include c.509A>G (p.Tyr170Cys) and c.902G>A (p.Arg301His), each confirmed in independent families. Segregation is consistent with autosomal recessive inheritance in multiple pedigrees, without evidence of dominant‐negative effects. The overall genetic evidence includes 31 probands across five reports (n=18 consanguineous, n=2 compound heterozygous, n=11 encephalopathy cohort), reaching the ClinGen genetic cap.
Functional assays in patient-derived fibroblasts demonstrate reduced GPT activity (~10% of normal) and impaired glycoprotein synthesis (PMID:12872255). Transient expression in CHO or COS-7 cells shows misfolding and mislocalization of mutant proteins. Fibroblasts exhibit heightened sensitivity to ER stressors, and in vitro studies confirm aberrant splicing for intronic variants. The unfolded protein response is not overtly activated but cells show reduced glycosylation capacity (PMID:28662078).
A chemically induced Dpagt1 mouse model (p.Gly166Arg) recapitulates photoreceptor degeneration and ER stress without neuromuscular involvement, underscoring tissue-specific vulnerability and confirming loss-of-function pathogenesis (PMID:36233305).
Collectively, definitive genetic and functional evidence establishes DPAGT1 as the causal gene for CDG-Ij. The broad variant spectrum and concordant biochemical assays support clinical testing and variant interpretation. Early molecular diagnosis enables genetic counseling, carrier screening, and potential therapeutic avenues targeting splicing or protein folding. Key Take-home: Biallelic DPAGT1 variants cause a recessive CDG-Ij with a consistent loss-of-function mechanism amenable to diagnostic and prenatal testing.
Gene–Disease AssociationDefinitive31 probands in five independent reports over >10 y with consistent autosomal recessive segregation and concordant functional data Genetic EvidenceStrong31 probands with bi-allelic DPAGT1 variants including a consanguineous kindred (n=18), compound heterozygous cases (n=2), and additional series (n=11); variant spectrum includes missense, splice, start-loss, and frameshift mutations Functional EvidenceStrongMultiple in vitro assays show ~10% residual GPT activity, mislocalization of mutant proteins, impaired glycosylation in patient fibroblasts, and a mouse model recapitulates key features |