The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene ismutated in recessive hereditary inclusion body myopathy

Hereditary inclusion body myopathy (HIBM; OMIM 600737) is a unique group of neuromuscular disorders characterized by adult onset, slowly progressive d istal and proximal weakness and a typical muscle pathology including rimmed vacuoles and filamentous inclusions'. The autosomal recessive form describ ed in Jews of Persian descent(2) is the HIBM prototype. This myopathy affec ts mainly leg muscles, but with an unusual distribution that spares the qua driceps(3). This particular pattern of weakness distribution, termed quadri ceps-sparing myopathy (QSM), was later found in Jews originating from other Middle Eastern countries as well as in non-Jews(4). We previously localize d the gene causing HIBM in Middle Eastern Jews on chromosome 9p12-13 (ref. 5) within a genomic interval of about 700 kb (ref. 6). Haplotype analysis a round the HIBM gene region of 104 affected people from 47 Middle Eastern fa milies indicates one unique ancestral founder chromosome in this community. By contrast, single non-Jewish families from India, Georgia (USA) and the Bahamas, with QSM and linkage to the same 9p12-13 region, show three distin ct haplotypes. After excluding other potential candidate genes, we eventual ly identified mutations in the UDP-N-acetylglucosamine-2-epimerase/N-acetyl mannosamine kinase (GIVE) gene in the HIBM families: all patients from Midd le Eastern descent shared a single homozygous missense mutation, whereas di stinct compound heterozygotes were identified in affected individuals of fa milies of other ethnic origins. our findings indicate that GIVE is the gene responsible for recessive HIBM.