A comparative study of alpha-dystroglycan glycosylation in dystroglycanopathies suggests that the hypoglycosylation of alpha-dystroglycan does not consistently correlate with clinical severity.
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.
Jimenez-Mallebrera
Cecilia
C
Dubowitz Neuromuscular Centre, Institute of Child Health and Great Ormond Street Hospital for Children, UCL, London, UK. c.jimenez@imperial.ac.uk
Torelli
Silvia
S
Feng
Lucy
L
Kim
Jihee
J
Godfrey
Caroline
C
Clement
Emma
E
Mein
Rachael
R
Abbs
Stephen
S
Brown
Susan C
SC
Campbell
Kevin P
KP
Kröger
Stephan
S
Talim
Beril
B
Topaloglu
Haluk
H
Quinlivan
Ros
R
Roper
Helen
H
Childs
Anne M
AM
Kinali
Maria
M
Sewry
Caroline A
CA
Muntoni
Francesco
F
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
D049030:Dystroglycans