Journal Article

Mutations in the fukutin-related protein gene (<i>FKRP</i>) identify limb girdle muscular dystrophy 2I as a milder allelic variant of congenital muscular dystrophy MDC1C

Martin Brockington, Yeliz Yuva, Paola Prandini, Susan C. Brown, Silvia Torelli, Matthew A. Benson, Ralf Herrmann, Louise V.B. Anderson, Rumaisa Bashir, Jean-Marc Burgunder, Shari Fallet, Norma Romero, Michel Fardeau, Volker Straub, Gillian Storey, Christine Pollitt, Isabelle Richard, Caroline A. Sewry, Kate Bushby, Thomas Voit, Derek J. Blake and Francesco Muntoni

in Human Molecular Genetics

Volume 10, issue 25, pages 2851-2859
Published in print December 2001 | ISSN: 0964-6906
Published online December 2001 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/10.25.2851
Mutations in the fukutin-related protein gene (FKRP) identify limb girdle muscular dystrophy 2I as a milder allelic variant of congenital muscular dystrophy MDC1C

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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 α2 and α-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 FKRP in 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 α-dystroglycan expression was observed in the skeletal muscle biopsy of all individuals studied. In addition, several cases showed a deficiency of laminin α2 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.

Journal Article.  4853 words.  Illustrated.

Subjects: Genetics and Genomics

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