title: A comparative study of alpha-dystroglycan glycosylation in dystroglycanopathies suggests that the hypoglycosylation of alpha-dystroglycan does not consistently correlate with clinical severity.
abstract: 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.
authors.affiliation: Dubowitz Neuromuscular Centre, Institute of Child Health and Great Ormond Street Hospital for Children, UCL, London, UK. c.jimenez@imperial.ac.uk
authors.forename: Cecilia
authors.initials: C
authors.lastname: Jimenez-Mallebrera
authors.forename: Silvia
authors.initials: S
authors.lastname: Torelli
authors.forename: Lucy
authors.initials: L
authors.lastname: Feng
authors.forename: Jihee
authors.initials: J
authors.lastname: Kim
authors.forename: Caroline
authors.initials: C
authors.lastname: Godfrey
authors.forename: Emma
authors.initials: E
authors.lastname: Clement
authors.forename: Rachael
authors.initials: R
authors.lastname: Mein
authors.forename: Stephen
authors.initials: S
authors.lastname: Abbs
authors.forename: Susan C
authors.initials: SC
authors.lastname: Brown
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Campbell
authors.forename: Stephan
authors.initials: S
authors.lastname: Kröger
authors.forename: Beril
authors.initials: B
authors.lastname: Talim
authors.forename: Haluk
authors.initials: H
authors.lastname: Topaloglu
authors.forename: Ros
authors.initials: R
authors.lastname: Quinlivan
authors.forename: Helen
authors.initials: H
authors.lastname: Roper
authors.forename: Anne M
authors.initials: AM
authors.lastname: Childs
authors.forename: Maria
authors.initials: M
authors.lastname: Kinali
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Sewry
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
mesh_terms: D000293:Adolescent; D001706:Biopsy; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D049030:Dystroglycans / Q000378:metabolism*; D005838:Genotype; D006031:Glycosylation; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D009136:Muscular Dystrophies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D010641:Phenotype; D012720:Severity of Illness Index; D013194:Staining and Labeling
chemical_list: D049030:Dystroglycans