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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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References

  1. Griggs, R.C. et al. Inclusion body myositis and myopathies. Ann. Neurol. 38, 705–713 (1995).

    CAS  Article  Google Scholar 

  2. Sadeh, M. & Argov, Z. Hereditary inclusion body myopathy. in Inclusion Body Myositis and Myopathies: Jews of Persian Origin: Clinical and Laboratory Data. (eds. Askanas, V., Engel, W.K. & Serratrice, G.) 191–199 (Cambridge Press, Cambridge, 1997).

    Google Scholar 

  3. Argov, Z. & Yarom, R. “Rimmed vacuole myopathy” sparing the quadriceps. A unique disorder in Iranian Jews. J. Neurol. Sci. 64, 33–43 (1984).

    CAS  Article  Google Scholar 

  4. Argov, Z. & Mitrani-Rosenbaum, S. Hereditary inclusion body myopathy (H-IBM) with quadriceps sparing: epidemiology and genetics. in Inclusion Body Myositis and Myopathies; (eds. Askanas, V., Engel, W.K. & Serratrice, G.) 200–210 (Cambridge Press, Cambridge, 1997).

    Google Scholar 

  5. Eisenberg, I. et al. Fine structure mapping of the hereditary inclusion body myopathy locus. Genomics 55, 43–48 (1999).

    CAS  Article  Google Scholar 

  6. Eisenberg, I. et al. Physical and transcriptional map of the hereditary inclusion body myopathy locus on chromosome 9p12-p13. Eur. J. Hum. Genet. 9, 501–509 (2001).

    CAS  Article  Google Scholar 

  7. Ponnambalam, S. et al. Chromosomal location and some structural features of human clathrin light-chain genes (CLTA and CLTB). Genomics 24, 440–444 (1994).

    CAS  Article  Google Scholar 

  8. Takahashi, C. et al. Regulation of matrix metalloproteinase-9 and inhibition of tumor invasion by the membrane-anchored glycoprotein RECK. Proc. Natl. Acad. Sci. USA 95, 13221–13226 (1998).

    CAS  Article  Google Scholar 

  9. Hinderlich, S., Stasche, R., Zeitler, R. & Reutter, W. A bifunctional enzyme catalyzes the first two steps in N-acetylneuraminic acid biosynthesis of rat liver. Purification and characterization of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase. J. Biol. Chem. 272, 24313–24318 (1997).

    CAS  Article  Google Scholar 

  10. Seppala, R., Lehto, V.P. & Gahl, W.A. Mutations in the human UDP-N-acetylglucosamine 2-epimerase gene define the disease sialuria and the allosteric site of the enzyme. Am. J. Hum. Genet. 64, 1563–1569 (1999).

    CAS  Article  Google Scholar 

  11. Stasche, R. et al. A bifunctional enzyme catalyzes the first two steps in N-acetylneuraminic acid biosynthesis of rat liver. Molecular cloning and functional expression of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase. J. Biol. Chem. 272, 24319–24324 (1997).

    CAS  Article  Google Scholar 

  12. Effertz, K., Hinderlich, S. & Reutter, W. Selective loss of either the epimerase or kinase activity of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase due to site-directed mutagenesis based on sequence alignments. J. Biol. Chem. 274, 28771–28778 (1999).

    CAS  Article  Google Scholar 

  13. Salzberg, S.L., White, O., Peterson, J. & Eisen, J.A. Microbial genes in the human genome: lateral transfer or gene loss? Science 292, 1903–1906 (2001).

    CAS  Article  Google Scholar 

  14. Keppler, O.T. et al. UDP-GlcNAc 2-epimerase: a regulator of cell surface sialylation. Science 284, 1372–1376 (1999).

    CAS  Article  Google Scholar 

  15. International Human Genome Sequencing Consortium. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).

  16. Claverie, J.M. Gene number. What if there are only 30,000 human genes? Science 291, 1255–1257 (2001).

    CAS  Article  Google Scholar 

  17. Nonaka, I., Sunohara, N., Ishiura, S. & Satayoshi, E. Familial distal myopathy with rimmed vacuole and lamellar (myeloid) body formation. J. Neurol. Sci. 51,141–155 (1981).

    CAS  Article  Google Scholar 

  18. Ikeuchi, T. et al. Gene locus for autosomal recessive distal myopathy with rimmed vacuoles maps to chromosome 9. Ann. Neurol. 41, 432–437 (1997).

    CAS  Article  Google Scholar 

  19. Askanas, V. & Engel, W.K. Sporadic inclusion-body myositis and hereditary inclusion-body myopathies: current concepts of diagnosis and pathogenesis. Curr. Opin. Rheumatol. 10, 530–542 (1998).

    CAS  Article  Google Scholar 

  20. Argov, Z., Eisenberg, I. & Mitrani-Rosenbaum, S. Genetics of inclusion body myopathies. Curr. Opin. Rheumatol. 10, 543–547 (1998).

    CAS  Article  Google Scholar 

  21. Mitrani-Rosenbaum, S. et al. Hereditary inclusion body myopathy maps to chromosome 9p-q1. Hum. Mol. Genet. 5, 159–163 (1996).

    CAS  Article  Google Scholar 

  22. Humbel, R. & Collart, M. Oligosaccharides in urine of patients with glycoprotein storage diseases. I. Rapid detection by thin-layer chromatography. Clin. Chim. Acta. 60, 143–145 (1975).

    Article  Google Scholar 

  23. Little, S. Amplification-refractory mutation system (ARMS) analysis of point mutations. in Current Protocols in Human Genetics (eds. Dracopoli, N.C. et al.) 9.8.1–9.8.2 (Wiley, New York, 1995).

    Google Scholar 

  24. Altschul, S.F. et al. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 25, 3389–3402 (1997).

    CAS  Article  Google Scholar 

  25. Higgins, D.G., Thompson, J.D. & Gibson, T.J. Using CLUSTAL for multiple sequence alignments. Methods Enzymol. 266, 383–402 (1996).

    CAS  Article  Google Scholar 

Download references

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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Author notes

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

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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  1. Iris Eisenberg
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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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