Fine-Structure Mapping of the Hereditary Inclusion Body Myopathy Locus

Abstract

The gene responsible for a recessive form of hereditary inclusion body myopathy (HIBM) has previously been mapped to a 10-cM interval on chromosome 9p1–q1. We report the results of further mapping studies using two-point linkage analyses and linkage disequilibrium analyses with 20 HIBM families. We demonstrate that the HIBM gene (HGMW-approved symbol IBM2) lies between lociD9S1791andD9S50,which are about 1 Mb apart. Genetic analyses in 56 affected individuals of Persian, Afghani, and Iraqi Jewish descent demonstrated a common haplotype at these loci, indicating that a founding mutation accounts for disease in these related ethnic groups. β-Tropomyosin, an abundant skeletal muscle protein that maps within 1 cM ofD9S1791,was excluded as the disease gene because an intragenic polymorphism did not exhibit linkage disequilibrium in HIBM probands. We conclude that the disease gene resides in a 1-Mb interval on chromosome 9 and speculate that a novel muscle protein encoded there is mutated in HIBM.