Nature Genetics29, 83 - 87 (2001)
Published online: 27 August 2001; | doi:10.1038/ng718
The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy
Iris Eisenberg1, Nili Avidan3, 8, Tamara Potikha1, 8, Hagit Hochner1, Miriam Chen3, Tsviya Olender3, Mark Barash1, Moshe Shemesh1, Menachem Sadeh4, Gil Grabov-Nardini1, Inna Shmilevich1, Adam Friedmann1, George Karpati5, Walter G. Bradley6, Lisa Baumbach7, Doron Lancet3, Edna Ben Asher3, Jacques S. Beckmann3, Zohar Argov2
& Stella Mitrani-Rosenbaum1
1
Unit for Molecular Biology, Hadassah, Hospital, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
2
Department of Neurology, Hadassah Hospital, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
3
Department of Molecular Genetics and Crown Genome Center, The Weizmann Institute of Science, Rehovot, Israel.
4
Department of Neurology, Wolfson Hospital, Holon, Israel.
5
Department of Neurology and Neurosurgery, Montreal Neurological Institute, Montreal, Canada.
6
Department of Neurology, University of Miami School of Medicine, Miami, Florida, USA.
7
Department of Pediatrics, University of Miami School of Medicine, Miami, Florida, USA.
Hereditary inclusion body myopathy (HIBM; OMIM 600737) is a unique group of neuromuscular disorders characterized by adult onset, slowly progressive distal and proximal weakness and a typical muscle pathology including rimmed vacuoles and filamentous inclusions1. The autosomal recessive form described in Jews of Persian descent2 is the HIBM prototype. This myopathy affects mainly leg muscles, but with an unusual distribution that spares the quadriceps3. This particular pattern of weakness distribution, termed quadriceps-sparing myopathy (QSM), was later found in Jews originating from other Middle Eastern countries as well as in non-Jews4. We previously localized 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 around the HIBM gene region of 104 affected people from 47 Middle Eastern families 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 distinct haplotypes. After excluding other potential candidate genes, we eventually identified mutations in the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) gene in the HIBM families: all patients from Middle Eastern descent shared a single homozygous missense mutation, whereas distinct compound heterozygotes were identified in affected individuals of families of other ethnic origins. Our findings indicate that GNE is the gene responsible for recessive HIBM.
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