Genetic fine mapping of the Miyoshi myopathy locus and exclusion of eight candidate genes

Abstract

Miyoshi myopathy (MM) is an early adult-onset, autosomal recessive disorder characterized by weakness and muscular atrophy starting in the distal muscles. The disease locus has been previously mapped by linkage analysis to chromosome 2p using the microsatellite marker D2S291. Initial haplotype analysis of markers in families from three different origins (North American, Japanese, and Tunisian) suggested that the MM gene is located in a 4-cM region flanked by markers D2S292 on the telomeric side and D2S286 on the centromeric side. To delineate critical recombination events revealing a more refined localization of the MM gene, we have determined the pattern of segregation of 12 marker loci in two consanguineous families of Tunisian origin. In this study we have: (1) detected recombination events with the disease locus in one family, placing the MM gene most likely between markers D2S443 (CHLC.GGAA4D07.1876) and D2S2109; (2) generated a yeast artificial chromosome contig that spans approximately 3.8 megabases and extends from marker D2S358 to marker D2S286; (3) physically mapped 21 polymorphic markers, 5 genes, 3 STSs, and 1 EST within this contig; (4) detected and mapped a new polymorphism within this interval, allowing us to further reduce the MM locus to a 360-kilobase segment; (5) mapped the gene for the cytoskeletal protein beta-adducin within the MM candidate region, failing to find a consistent pattern of mutation of this gene in our MM patients; (6) excluded seven other candidate myopathy genes from the Miyoshi locus.

Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy

“…This high-resolution PAC contig resolved the marker order discrepancies in previous studies 6,8,13 . The physical size of the PAC contig also indicated that the previous minimal size estimation based on YAC mapping data was underestimated.…”

“…Subsequently, our genetic mapping in MM families placed the MM locus between markers GGAA-P7430 and D2S2109 (ref. 6). At approximately the same time, Bushby and colleagues localized limb-girdle muscular dystrophy (LGMD-2B) to the same genetic interval 7−9 .…”

“…We analysed these markers in a large, consanguineous MM family 5,6 . MM is a recessive condition, so the locus can be defined by identifying regions of the genome that show homozygosity in affected individuals.…”

Genetic linkage of Welander distal myopathy to chromosome 2p13

“…In the region on 2p13, the loci for at least three other neuromuscular disorders have been mapped (Table 2): LGMD2B, 26 -28 MM7, 29 and a recently described Spanish distal anterior compartment myopathy (DACM). 30 Furthermore, a distal myopathy of slow progression has been described in a Russian LGMD2B family, 31,32 in which both disorders share a common haplotype.…”

A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B

“…Without a clear functional or positional candidate, we have identified LGMD2B by positional cloning 22,23 . This novel gene on chromosome 2p13 is highly expressed in muscle.…”