title: Mutations in the fukutin-related protein gene (FKRP) identify limb girdle muscular dystrophy 2I as a milder allelic variant of congenital muscular dystrophy MDC1C.
abstract: 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 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 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.
authors.affiliation: Dubowitz Neuromuscular Centre, Department of Paediatrics, Faculty of Medicine, Imperial College, Hammersmith Hospital Campus, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Brockington
authors.forename: Y
authors.initials: Y
authors.lastname: Yuva
authors.forename: P
authors.initials: P
authors.lastname: Prandini
authors.forename: S C
authors.initials: SC
authors.lastname: Brown
authors.forename: S
authors.initials: S
authors.lastname: Torelli
authors.forename: M A
authors.initials: MA
authors.lastname: Benson
authors.forename: R
authors.initials: R
authors.lastname: Herrmann
authors.forename: L V
authors.initials: LV
authors.lastname: Anderson
authors.forename: R
authors.initials: R
authors.lastname: Bashir
authors.forename: J M
authors.initials: JM
authors.lastname: Burgunder
authors.forename: S
authors.initials: S
authors.lastname: Fallet
authors.forename: N
authors.initials: N
authors.lastname: Romero
authors.forename: M
authors.initials: M
authors.lastname: Fardeau
authors.forename: V
authors.initials: V
authors.lastname: Straub
authors.forename: G
authors.initials: G
authors.lastname: Storey
authors.forename: C
authors.initials: C
authors.lastname: Pollitt
authors.forename: I
authors.initials: I
authors.lastname: Richard
authors.forename: C A
authors.initials: CA
authors.lastname: Sewry
authors.forename: K
authors.initials: K
authors.lastname: Bushby
authors.forename: T
authors.initials: T
authors.lastname: Voit
authors.forename: D J
authors.initials: DJ
authors.lastname: Blake
authors.forename: F
authors.initials: F
authors.lastname: Muntoni
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D015153:Blotting, Western; D002154:Calpain / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000235:genetics; D017931:DNA Primers / Q000737:chemistry; D049030:Dystroglycans; D005260:Female; D008040:Genetic Linkage; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007124:Immunoenzyme Techniques; D007223:Infant; D007797:Laminin / Q000172:deficiency / Q000235:genetics; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics; D018895:Microsatellite Repeats; D008875:Middle Aged; D009136:Muscular Dystrophies / Q000151:congenital* / Q000235:genetics* / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010430:Pentosyltransferases; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D003598:Cytoskeletal Proteins; C483081:DAG1 protein, human; D017931:DNA Primers; D007797:Laminin; D008562:Membrane Glycoproteins; D011506:Proteins; C102645:laminin alpha 2; D049030:Dystroglycans; C443107:FKRP protein, human; D010430:Pentosyltransferases; D002154:Calpain