A rippling muscle disease gene is localized to 1q41: evidence for multiple genes

Rippling muscle disease (RMD) is an inherited disorder of skeletal muscle in which mechanical stimuli provoke electrically silent contractions. Patient symptoms are muscle cramps, pain, and stiffness, particularly during or following exercise. Clinical signs are balling of muscle following percussion and a characteristic lateral rolling movement of muscle occurring after contraction followed by stretching. We report a new 44-member pedigree segregating RMD as an autosomal dominant trait. A genetic linkage study in this family, using a novel approach of testing closely spaced highly polymorphic markers in affected individuals, localized the responsible gene to the distal end of the long arm of chromosome 1 with a maximum multipoint lod score of 3.56 (theta = 0). In this family, RMD is localized to a 12-cM region near D1S235. We studied two previously reported German families for linkage to the same locus, and this same area did not cosegregate with the disease, a finding that shows that different genetic defects can cause a similar clinical phenotype (genetic heterogeneity). An understanding of the defect in contraction control within the muscle fibers in this disease may lead to a better understanding of muscle force transduction, intracellular calcium homeostasis, or both.