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

Nature Genetics volume 29, pages 83–87 (2001)Cite this article

Abstract

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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Figure 1: Physical map of the HIBM locus and genomic organization of GNE.
Figure 2: GNE mutation in Middle Eastern Jewish HIBM families.
Figure 3: GNE mutations in non–Middle Eastern, non-Jewish HIBM families.
Figure 4: Blocks of multiple alignments of GNE with epimerases (a,b) and sugar kinases (c); bacterial orthologs are shown around each amino acid substitution.

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Acknowledgements

We are grateful to all of the family members who made these studies possible, and we extend our appreciation to S. Nazarian for her extensive efforts and our special thanks to M. Banayan for his endless and warm support. We also thank M. Korner, A.Tuvy, M. Mordechaishvili and all the staff from The Laboratory of DNA Analysis for skillful assistance in sequencing, A. Sanilevich for oligonucleotide synthesis, M.E. Ahearn for technical help, M. Zeigler for sialic acid measurements, D. Darvish and H. Raz for their involvement in blood collection, and T. Levi for her continuous support. This study was supported by Hadasit (Medical Research Services Development Co., a subsidiary for R&D of Hadassah Medical Organization; S.M.-R., Z.A.); by a special donation from Hadassah Southern California– Persian Group Council, Haifa Metro Group, Malka Group, Haifa San Diego Group, Vanguard II, Healing Spirit and the ARM organization (S.M.-R., Z.A.); by a special donation in memory of N. Hollo-Bencze (Z.A.); by an Israel Ministry of Science grant to the National Laboratory for Genome Infrastructure, The Crown Human Genome Center (D.L.); by the Krupp foundation (D.L.); and by the Weizmann Institute Glasberg, Levy, N. Brunschwig and Levine funds (D.L.). T.P. is a recipient of a Kamea fellowship from the Israeli Ministry of Science and Ministry of Absorption.

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  1. Nili Avidan and Tamara Potikha: These authors contributed equally to this work.

Authors and Affiliations

  1. Unit for Molecular Biology, Hadassah, Hospital, The Hebrew University-Hadassah Medical School, Jerusalem, Israel

    Iris Eisenberg, Tamara Potikha, Hagit Hochner, Mark Barash, Moshe Shemesh, Gil Grabov-Nardini, Inna Shmilevich, Adam Friedmann & Stella Mitrani-Rosenbaum

  2. Department of Neurology, Hadassah Hospital, The Hebrew University-Hadassah Medical School, Jerusalem, Israel

    Zohar Argov

  3. Department of Molecular Genetics and Crown Genome Center, The Weizmann Institute of Science, Rehovot, Israel

    Nili Avidan, Miriam Chen, Tsviya Olender, Doron Lancet, Edna Ben Asher & Jacques S. Beckmann

  4. Department of Neurology, Wolfson Hospital, Holon, Israel

    Menachem Sadeh

  5. Department of Neurology and Neurosurgery, Montreal Neurological Institute, Montreal, Canada

    George Karpati

  6. Department of Neurology, University of Miami School of Medicine, Miami, Florida, USA

    Walter G. Bradley

  7. Department of Pediatrics, University of Miami School of Medicine, Miami, Florida, USA

    Lisa Baumbach

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Correspondence to Stella Mitrani-Rosenbaum.

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Eisenberg, I., Avidan, N., Potikha, T. et al. The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy. Nat Genet 29, 83–87 (2001). https://doi.org/10.1038/ng718

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