Submission Details

MPDU1 was first reported in relation to MPDU1-congenital disorder of glycosylation (synonym: congenital disorder of glycosylation, type If) in 2001 (Kranz et al, PMID: 11733556; Schenk et al, PMID: 11733564). This condition is characterized by developmental delay, intellectual disability, seizures, brain atrophy, skin disorder, cardiac defects, and a CDG type I pattern of serum transferrin glycosylation (increase in asialo- and disialotransferrin). In addition, a specific pattern of lipid-linked oligosaccharides has been observed in patient fibroblasts and Lec35 CHO cells, which have a defect in the hamster orthologue of MPDU1. This includes accumulation of Man9GlcNAc2 and Man5GlcNAc2 and presence of the complete Glc3Man9GlcNAc2 oligosaccharide (Kranz et al, PMID: 11733556; Schenk et al, PMID: 11733564).

MPDU1-congenital disorder of glycosylation is currently the only disorder known to result from variants in MPDU1. 12 variants (7 missense, 2 small in-frame deletions, 1 nonsense, 1 frameshift, 1 initiation codon) that have been reported in 13 probands in 9 publications (Kranz et al, 2001 PMID: 11733556; Schenk et al, 2001, PMID: 11733564; Al Teneiji et al, 2017, PMID: 28122681; Bastaki et al, 2018, PMID: 28940310; Thiel et al, 2018, PMID: 29721919; van Tol et al, 2019, PMID: 31741824; Abu Bakar et al, 2022, PMID: 35279850; Darouich et al, 2023, PMID: 36755425; Wei et al, 2025, PMID: 38831602) are included in this curation. One variant, c.218G>A (p.Gly73Glu) (ClinVar Variation ID: 5867) has been identified in 4 independent probands. Additional evidence is available in the literature (e.g. PMID: 31677975, 35810431) but the maximum score for genetic evidence (12 points) has been reached.

This gene-disease relationship is also supported by experimental evidence. The function of MPDU1 in glycosylation, as a chaperone that facilitates the transport of dolichol-linked sugars - mannose-P-dolichol and glucose-P-dolichol - across the ER membrane, is consistent with the results of analysis of transferrin glycosylation and lipid linked oligosaccharides from patients. Lec35 (hamster orthologue of MPDU1, has been shown to be involved in all four classes of sugar-P-dolichol–dependent reactions known in mammalian cells; GPD-dependent reactions in LLO synthesis, and MPD-dependent reactions in LLO, GPI, and C-mannosyl tryptophan synthesis (Anand et al, 2001, PMID: 11179430). Glycosylation patterns in Lec35 cells are similar to those observed in patients. Human MPDU1 cDNA rescues the glycosylation phenotype in Lec35 CHO cells (Anand et al, 2001, PMID: 11179430).

In summary, there is definitive evidence supporting the relationship between MPDU1 and MPDU1-congenital disorder of glycosylation (also known as congenital disorder of glycosylation, type If). This classification was approved by the ClinGen Congenital Disorders of Glycosylation GCEP on July 16, 2025 (SOP Version 11).