Dolichol phosphate mannose synthase (DPM1) mutations define congenital disorder of glycosylation Ie (CDG-Ie)

Congenital disorders of glycosylation (CDGs) are metabolic deficiencies in glycoprotein biosynthesis that usually cause severe mental and psychomotor retardation. Different forms of CDGs can be recognized by altered isoelectr ic focusing (IEF) patterns of serum transferrin (Tf). Two patients with the se symptoms and similar abnormal TfIEF patterns were analyzed by metabolic labeling of fibroblasts with [2-H-3]mannose. The patients produced a trunca ted dolichol-linked precursor oligosaccharide with 5 mannose residues, inst ead of the normal precursor with 9 mannose residues. Addition of 250 mu M m annose to the culture medium corrected the size of the truncated oligosacch aride. Microsomes from fibroblasts of these patients were approximately 95% deficient in dolichol-phosphate-mannose (Dol-P-Man) synthase activity, wit h an apparent K-m for GDP-Man similar to 6-fold higher than normal. DPM1, t he gene coding for the catalytic subunit of Dol-P-Man synthase, was altered in both patients. One patient had a point mutation, C(274)G, causing an R( 92)G change in the coding sequence. The other patient also had the C274G mu tation and a 13-bp deletion that presumably resulted in an unstable transcr ipt. Defects in DPM1 define a new glycosylation disorder, CDG-Ie.