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Lookup NU author(s): Dr Louise VB Anderson, Dr Rumaisa Bashir, Professor Volker StraubORCiD, Emerita Professor Katherine Bushby
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The limb girdle and congenital muscular dystrophies (LGMD and CMD) are characterized by skeletal muscle weakness and dystrophic muscle changes. The onset of symptoms in CMD is within the first few months of life, whereas in LGMD they can occur in late childhood, adolescence or adult life. We have recently demonstrated that the fukutin-related protein gene (FKRP) is mutated in a severe form of CMD (MDC1C), characterized by the inability to walk, leg muscle hypertrophy and a secondary deficiency of laminin alpha2 and alpha -dystroglycan. Both MDC1C and LGMD2I map to an identical region on chromosome 19q13.3. To investigate whether these are allelic disorders, we undertook mutation analysis of FKRPin 25 potential LGMD2I families, including some with a severe and early onset phenotype. Mutations were identified in individuals from 17 families. A variable reduction of alpha -dystroglycan expression was observed in the skeletal muscle biopsy of all individuals studied. In addition, several cases showed a deficiency of laminin alpha2 either by immunocytochemistry or western blotting. Unexpectedly, affected individuals from 15 families had an identical C826A (Leu276Ileu) mutation, including five that were homozygous for this change. Linkage analysis identified at least two possible haplotypes in linkage disequilibrium with this mutation. Patients with the C826A change had the clinically less severe LGMD2I phenotype, suggesting that this is a less disruptive FKRP mutation than those found in MDC1C. The spectrum of LGMD2I phenotypes ranged from infants with an early presentation and a Duchenne-like disease course including cardiomyopathy, to milder phenotypes compatible with a favourable long-term outcome.
Author(s): Bashir R; Straub V; Anderson LVB; Bushby K; Brockington M; Yuva Y; Prandini P; Brown SC; Torelli S; Benson MA; Herrmann R; Burgunder JM; Fallet S; Romero N; Fardeau M; Storey G; Pollitt C; Richard I; Sewry CA; Voit T; Blake DJ; Muntoni F
Publication type: Article
Publication status: Published
Journal: Human Molecular Genetics
Year: 2001
Volume: 10
Issue: 25
Pages: 2851-2859
ISSN (print): 0964-6906
ISSN (electronic): 1460-2083
Publisher: Oxford University Press
URL: http://dx.doi.org/10.1093/hmg/10.25.2851
DOI: 10.1093/hmg/10.25.2851
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