MPDU1 and Congenital Disorder of Glycosylation

MPDU1 has been independently implicated in congenital disorder of glycosylation (CDG), a multisystem disease characterized by defects in protein N‑glycosylation. Multiple case reports, including an infant with severe ichthyosis (PMID:29721919) and another presenting with a ciliopathy‑like phenotype (PMID:36755425), provide clinical evidence supporting the association of MPDU1 variants with the CDG phenotype. These studies consistently report autosomal recessive inheritance with segregation of rare deleterious variants in affected families.

Several multi‐patient studies have integrated MPDU1 within diagnostic panels for CDG. In a DHPLC‐based screening study, MPDU1 was evaluated alongside other glycosylation genes in a cohort of novel cases suspected of CDG (PMID:12357336), while a comprehensive review further underscored the role of MPDU1 as one of the 15 genes implicated in dolichol-linked oligosaccharide biosynthesis defects (PMID:19862844). Additional evidence from a single‑center study in Arab patients (PMID:28940310) reinforces the importance of MPDU1 in familial segregation analyses.

Genetic evidence for the MPDU1–CDG association is further supported by the identification of pathogenic variants, such as the homozygous missense change c.503G>A (p.Gly168Glu) found in unrelated probands. This variant has been shown to co‑segregate with the disease phenotype and is complemented by a diverse variant spectrum observed in these studies. The consistency across multiple independent reports confirms a strong genetic contribution to the disorder.

Functional studies provide additional, though moderate, evidence that loss of MPDU1 function disrupts the glycosylation pathway. Cellular models, including expression cloning in Chinese hamster ovary cells, have demonstrated that restoring MPDU1 function rescues abnormal glycosylation (PMID:8663248) and that a critical role for MPDU1 exists in mannose‑P‑dolichol utilization (PMID:11179430). These experimental observations are concordant with the clinical phenotypes observed in CDG patients.

Integrating both genetic and functional data, the evidence robustly supports the association of MPDU1 with congenital disorder of glycosylation. The documented inheritance pattern, confirmed segregation in affected families, and validated functional deficits together underscore that MPDU1 mutations result in a perturbation of glycosylation essential for normal development. While additional data exist that exceed the maximum ClinGen scoring cap, the current body of evidence is sufficient to guide both diagnostic decision‑making and commercial test development.

Key Take‑home: Comprehensive evaluation of both clinical and experimental findings confirms MPDU1 variants as an essential contributor to congenital disorder of glycosylation, underscoring its clinical utility as a diagnostic marker for the condition.

References

• Journal of inherited metabolic disease • 2018 • Severe ichthyosis in MPDU1‑CDG PMID:29721919
• Pediatric and developmental pathology • 2023 • Severe Ciliopathy‑Like Phenotype in an Infant With a Novel MPDU1 Missense Variant PMID:36755425
• European journal of human genetics • 2002 • DHPLC analysis as a platform for molecular diagnosis of congenital disorders of glycosylation (CDG) PMID:12357336
• Human mutation • 2009 • Congenital disorders of glycosylation: an update on defects affecting the biosynthesis of dolichol‑linked oligosaccharides PMID:19862844
• Annals of human genetics • 2018 • Single‑center experience of N‑linked Congenital Disorders of Glycosylation with a Summary of Molecularly Characterized Cases in Arabs PMID:28940310
• The Journal of biological chemistry • 1996 • Expression cloning of a novel suppressor of the Lec15 and Lec35 glycosylation mutations of Chinese hamster ovary cells PMID:8663248
• Molecular biology of the cell • 2001 • Requirement of the Lec35 gene for all known classes of monosaccharide‑P‑dolichol‑dependent glycosyltransferase reactions in mammals PMID:11179430

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