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 isoelectric focusing (IEF) patterns of serum transferrin (Tf). Two patients with these symptoms and similar abnormal Tf IEF patterns were analyzed by metabolic labeling of fibroblasts with ¿2-(3)Hmannose. The patients produced a truncated dolichol-linked precursor oligosaccharide with 5 mannose residues, instead of the normal precursor with 9 mannose residues. Addition of 250 microM mannose to the culture medium corrected the size of the truncated oligosaccharide. Microsomes from fibroblasts of these patients were approximately 95% deficient in dolichol-phosphate-mannose (Dol-P-Man) synthase activity, with an apparent K(m) for GDP-Man approximately 6-fold higher than normal. DPM1, the 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 C(274)G mutation and a 13-bp deletion that presumably resulted in an unstable transcript. Defects in DPM1 define a new glycosylation disorder, CDG-Ie.
Kim
S
S
The Burnham Institute, La Jolla, California 92037, USA.
Westphal
V
V
Srikrishna
G
G
Mehta
D P
DP
Peterson
S
S
Filiano
J
J
Karnes
P S
PS
Patterson
M C
MC
Freeze
H H
HH
D020739:Brain Diseases, Metabolic, Inborn / Q000175:diagnosis / Q000201:enzymology / Q000209:etiology; D002240:Carbohydrate Sequence; D002478:Cells, Cultured; D018981:Congenital Disorders of Glycosylation / Q000150:complications / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics*; D004252:DNA Mutational Analysis; D002658:Developmental Disabilities / Q000175:diagnosis; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D006026:Glycoside Hydrolases / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D007223:Infant; D007525:Isoelectric Focusing; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008297:Male; D008358:Mannose / Q000378:metabolism; D008364:Mannosyltransferases / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D008831:Microcephaly / Q000175:diagnosis; D008969:Molecular Sequence Data; D009154:Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012640:Seizures / Q000175:diagnosis; D017384:Sequence Deletion; D014168:Transferrin / Q000378:metabolism
D007527:Isoenzymes; D014168:Transferrin; D008364:Mannosyltransferases; C022755:dolichyl-phosphate beta-D-mannosyltransferase; D006026:Glycoside Hydrolases; D008358:Mannose