A mutation in the human MPDU1 gene causes congenital disorder of glycosylation type If (CDG-If)

We describe a new congenital disorder of glycosylation, CDG-If. The patient has severe psychomotor retardation, seizures, failure to thrive, dry skin and scaling with erythroderma, and impaired vision. CDG-If is caused by a d efect in the gene MPDU1, the human homologue of hamster Lec35, and is the f irst disorder to affect the use, rather than the biosynthesis, of donor sub strates for lipid-linked oligosaccharides. This leads to the synthesis of i ncomplete and poorly transferred precursor oligosaccharides lacking both ma nnose and glucose residues. The patient has a homozygous point mutation (22 1T -->C, L74S) in a semiconserved amino acid of MPDU1. Chinese hamster ovar y Lec35 cells lack a functional Lec35 gene and synthesize truncated lipid-l inked oligosaccharides similar to the patient's. They lack glucose and mann ose residues donated by Glc-P-Dol and Man-P-Dol. Transfection with the norm al human MPDU1 allele nearly completely restores normal glycosylation, wher eas transfection with the patient's MPDU1 allele only weakly restores norma l glycosylation. This work provides a new clinical picture for another CDG that may involve synthesis of multiple types of glycoconjugates.