TY - JOUR
T1 - A combined defect in the biosynthesis of N- and O-glycans in patients with cutis laxa and neurological involvement
T2 - The biochemical characteristics
AU - Wopereis, Suzan
AU - Morava, Éva
AU - Grünewald, Stephanie
AU - Mills, Philippa B.
AU - Winchester, Bryan G.
AU - Clayton, Peter
AU - Coucke, Paul
AU - Huijben, Karin M.L.C.
AU - Wevers, Ron A.
N1 - Funding Information:
This work was supported by the European Commission, contract number QLG-CT2000-0047 (Euroglycan and Euroglycanet) and the Wellcome Trust, UK.
PY - 2005/6/30
Y1 - 2005/6/30
N2 - Based on our preliminary observation of abnormal glycosylation in a cutis laxa patient, nine cutis laxa patients were analyzed for congenital defects of glycosylation (CDG). Isoelectric focusing of plasma transferrin and apolipoproteinC-III showed that three out of nine patients had a defect in the biosynthesis of N-glycans and core 1 mucin type O-glycans, respectively. Mass spectrometric N-glycan analyses revealed a relative increase of glycans lacking sialic acid and glycans lacking sialic acid and galactose residues. Mutation analysis of the fibulin-5 gene (FBLN5), which has been reported in cases of autosomal recessive cutis laxa, revealed no mutations in the patients' DNA. Evidence is presented that extracellular matrix (ECM) proteins of skin are likely to be highly glycosylated with N- and/or mucin type O-glycans by using algorithms for predicting glycosylation. The conclusions in this study were that the clinical phenotype of autosomal recessive cutis laxa seen in three patients is not caused by mutations in the FBLN5 gene. Our findings define a novel form of CDG with cutis laxa and neurological involvement due to a defect in the sialylation and/or galactosylation of N- and O-glycans. Improper glycosylation of ECM proteins of skin may form the pathophysiological basis for the cutis laxa phenotype.
AB - Based on our preliminary observation of abnormal glycosylation in a cutis laxa patient, nine cutis laxa patients were analyzed for congenital defects of glycosylation (CDG). Isoelectric focusing of plasma transferrin and apolipoproteinC-III showed that three out of nine patients had a defect in the biosynthesis of N-glycans and core 1 mucin type O-glycans, respectively. Mass spectrometric N-glycan analyses revealed a relative increase of glycans lacking sialic acid and glycans lacking sialic acid and galactose residues. Mutation analysis of the fibulin-5 gene (FBLN5), which has been reported in cases of autosomal recessive cutis laxa, revealed no mutations in the patients' DNA. Evidence is presented that extracellular matrix (ECM) proteins of skin are likely to be highly glycosylated with N- and/or mucin type O-glycans by using algorithms for predicting glycosylation. The conclusions in this study were that the clinical phenotype of autosomal recessive cutis laxa seen in three patients is not caused by mutations in the FBLN5 gene. Our findings define a novel form of CDG with cutis laxa and neurological involvement due to a defect in the sialylation and/or galactosylation of N- and O-glycans. Improper glycosylation of ECM proteins of skin may form the pathophysiological basis for the cutis laxa phenotype.
KW - Congenital disorder of glycosylation
KW - Cutis laxa
KW - Glycan biosynthesis defect
KW - N-glycosylation
KW - O-glycosylation
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U2 - 10.1016/j.bbadis.2004.11.009
DO - 10.1016/j.bbadis.2004.11.009
M3 - Article
C2 - 15955459
AN - SCOPUS:20444442445
SN - 0925-4439
VL - 1741
SP - 156
EP - 164
JO - Biochimica et Biophysica Acta - Molecular Basis of Disease
JF - Biochimica et Biophysica Acta - Molecular Basis of Disease
IS - 1-2
ER -