Jimenez-Mallebrera, C and Torelli, S and Feng, L and Kim, J and Godfrey, C and Clement, E and Mein, R and Abbs, S and Brown, SC and Campbell, KP and Kroger, S and Talim, B and Topaloglu, H and Quinlivan, R and Roper, H and Childs, AM and Kinali, M and Sewry, CA and Muntoni, F (2009) A Comparative Study of alpha-Dystroglycan Glycosylation in Dystroglycanopathies Suggests that the Hypoglycosylation of alpha-Dystroglycan Does Not Consistently Correlate with Clinical Severity. BRAIN PATHOL , 19 (4) 596 - 611. 10.1111/j.1750-3639.2008.00198.x.
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Hypoglycosylation of alpha-dystroglycan underpins a subgroup of muscular dystrophies ranging from congenital onset of weakness, severe brain malformations and death in the perinatal period to mild weakness in adulthood without brain involvement. Mutations in six genes have been identified in a proportion of patients. POMT1, POMT2 and POMGnT1 encode for glycosyltransferases involved in the mannosylation of alpha-dystroglycan but the function of fukutin, FKRP and LARGE is less clear. The pathological hallmark is reduced immunolabeling of skeletal muscle with antibodies recognizing glycosylated epitopes on alpha-dystroglycan. If the common pathway of these conditions is the hypoglycosyation of alpha-dystroglycan, one would expect a correlation between clinical severity and the extent of hypoglycosylation. By studying 24 patients with mutations in these genes, we found a good correlation between reduced alpha-dystroglycan staining and clinical course in patients with mutations in POMT1, POMT2 and POMGnT1. However, this was not always the case in patients with defects in fukutin and FKRP, as we identified patients with mild limb-girdle phenotypes without brain involvement with profound depletion of alpha-dystroglycan. These data indicate that it is not always possible to correlate clinical course and alpha-dystroglycan labeling and suggest that there might be differences in alpha-dystroglycan processing in these disorders.
|Title:||A Comparative Study of alpha-Dystroglycan Glycosylation in Dystroglycanopathies Suggests that the Hypoglycosylation of alpha-Dystroglycan Does Not Consistently Correlate with Clinical Severity|
|Keywords:||alpha-dystroglycan, congenital muscular dystrophy, glycosylation, immunohistochemistry, limb-girdle muscular dystrophy, CONGENITAL MUSCULAR-DYSTROPHY, WALKER-WARBURG-SYNDROME, FUKUTIN GENE-MUTATIONS, MENTAL-RETARDATION, DEFECTIVE GLYCOSYLATION, ABNORMAL GLYCOSYLATION, BETA-DYSTROGLYCAN, CEREBELLAR CYSTS, LAMININ, PHENOTYPE|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Child Health > Department of Neurosciences and Mental Health > ICH - Dubowitz Neuromuscular Centre|
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