title: Limb-girdle muscular dystrophy 2I: phenotypic variability within a large consanguineous Bedouin family associated with a novel FKRP mutation.
abstract: Limb-girdle muscular dystrophies (LGMDs) represent a group of diseases characterized mainly by muscle wasting of the upper and lower limbs, with a wide range of clinical severity. The clinical heterogeneity is paralleled by molecular heterogeneity; each of the 10 forms of autosomal-recessive LGMD recognized to date is caused by mutations in a distinct gene. In a large consanguineous Bedouin tribe living in northern Israel, 15 individuals affected by LGMD demonstrate an autosomal recessive pattern of inheritance. A genome-wide screen followed by fine mapping in this family revealed linkage to a region on chromosome 19 harboring the fukutin-related protein gene (FKRP), with a maximal LOD score of 4.8 for D19S902. FKRP, encoding a putative glycosyltransferase, has been implicated in causing congenital muscular dystrophy 1C (MDC1C), and has recently been shown to be mutated in LGMD2I. We identified a novel missense mutation in exon 4 of the FKRP gene in all the patients studied. Although all affected individuals were homozygous for the same mutation, a marked phenotypic variability was apparent within the family. This finding may suggest a role of modifier genes and environmental factors in LGMD2I. Moreover, the demonstration that an identical, novel mutation in the FKRP gene can cause a muscle disease of either a congenital onset or of a later onset within a single family provides clinical support to the molecular evidence, suggesting that MDC1C and LGMD2I are overlapping ends of one and the same entity.
authors.affiliation: Laboratory of Human Molecular Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Harel
authors.forename: Yael
authors.initials: Y
authors.lastname: Goldberg
authors.forename: Stavit A
authors.initials: SA
authors.lastname: Shalev
authors.forename: Ilana
authors.initials: I
authors.lastname: Chervinski
authors.forename: Rivka
authors.initials: R
authors.lastname: Ofir
authors.forename: Ohad S
authors.initials: OS
authors.lastname: Birk
mesh_terms: D000328:Adult; D017668:Age of Onset; D018912:Arabs / Q000235:genetics*; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005260:Female; D008040:Genetic Linkage; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D007557:Israel; D008297:Male; D009136:Muscular Dystrophies / Q000235:genetics*; D020125:Mutation, Missense; D010375:Pedigree; D010430:Pentosyltransferases; D010641:Phenotype; D011506:Proteins / Q000235:genetics*
chemical_list: D011506:Proteins; C443107:FKRP protein, human; D010430:Pentosyltransferases