Physical mapping of the rippling muscle disease locus

Rippling muscle disease (RMD) is an autosomal dominant disorder characteriz ed by electrically silent, percussion induced muscular contractions. We pre viously reported the localization of a gene for RMD to 1q41-q42 by genome-w ide linkage analysis in a large family from Oregon. This RMD gene was initi ally found to be contained within a 12-cM interval with a maximum multipoin t lod score of 3.56. A YAC/BAC contig was assembled by STS content mapping and database searches spanning the nonrecombinant interval containing the R MD gene (RMD1). The physical map, in conjunction with recent mapping inform ation from various other sources, clarified the order of genetic markers in this region and necessitated redefinition of the RMD genetic interval by l inkage analysis with the newly ordered markers. Polymorphisms that mapped t o the YACs in this contig were genotyped in this family and used to provide statistical support for narrowing of the critical genetic interval to 3 cM , corresponding to a maximum possible physical distance of 4.0 Rib. In addi tion, recombination breakpoint mapping supported the evidence that RMD1 mus t reside within this interval between markers D1S446 and D1S2680. ESTs (82) were mapped to the YACs spanning the region known to contain the RMD1 gene , and of these, 9 become strong positional candidates. The physical and ref ined genetic maps of this RMD locus set the stage for isolation of the resp onsible gene and elucidation of a novel patho-mechanism of calcium homeosta sis in skeletal muscle. (C) 1999 Academic Press.