Limb-girdle muscular dystrophy: diagnostic evaluation, frequency and clues to pathogenesis.
We characterized the frequency of limb-girdle muscular dystrophy (LGMD) subtypes in a cohort of 76 Australian muscular dystrophy patients using protein and DNA sequence analysis. Calpainopathies (8%) and dysferlinopathies (5%) are the most common causes of LGMD in Australia. In contrast to European populations, cases of LGMD2I (due to mutations in FKRP) are rare in Australasia (3%). We have identified a cohort of patients in whom all common disease candidates have been excluded, providing a valuable resource for identification of new disease genes. Cytoplasmic localization of dysferlin correlates with fiber regeneration in a subset of muscular dystrophy patients. In addition, we have identified a group of patients with unidentified forms of LGMD and with markedly abnormal dysferlin localization that does not correlate with fiber regeneration. This pattern is mimicked in primary caveolinopathy, suggesting a subset of these patients may also possess mutations within proteins required for membrane targeting of dysferlin.
Lo
Harriet P
HP
Institute for Neuromuscular Research, The Children's Hospital at Westmead, Sydney, Australia.
Cooper
Sandra T
ST
Evesson
Frances J
FJ
Seto
Jane T
JT
Chiotis
Maria
M
Tay
Valerie
V
Compton
Alison G
AG
Cairns
Anita G
AG
Corbett
Alistair
A
MacArthur
Daniel G
DG
Yang
Nan
N
Reardon
Katrina
K
North
Kathryn N
KN
D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism; D015331:Cohort Studies; D003593:Cytoplasm / Q000378:metabolism / Q000473:pathology; D004252:DNA Mutational Analysis; D000073939:Dysferlin; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D049288:Muscular Dystrophies, Limb-Girdle / Q000145:classification / Q000175:diagnosis* / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D021381:Protein Transport / Q000235:genetics; D012038:Regeneration / Q000235:genetics; D012189:Retrospective Studies; D012508:Sarcolemma / Q000378:metabolism / Q000473:pathology
D051242:Caveolin 1; C114839:DYSF protein, human; D000073939:Dysferlin; D008565:Membrane Proteins; D009124:Muscle Proteins