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Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus

Nature Genetics volume 26, pages 163–175 (2000)Cite this article

An Erratum to this article was published on 01 December 2000

Abstract

Type 2 or non-insulin-dependent diabetes mellitus (NIDDM) is the most common form of diabetes worldwide, affecting approximately 4% of the world's adult population. It is multifactorial in origin with both genetic and environmental factors contributing to its development. A genome-wide screen for type 2 diabetes genes carried out in Mexican Americans localized a susceptibility gene, designated NIDDM1, to chromosome 2. Here we describe the positional cloning of a gene located in the NIDDM1 region that shows association with type 2 diabetes in Mexican Americans and a Northern European population from the Botnia region of Finland. This putative diabetes-susceptibility gene encodes a ubiquitously expressed member of the calpain-like cysteine protease family, calpain-10 (CAPN10). This finding suggests a novel pathway that may contribute to the development of type 2 diabetes.

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Figure 1: Physical map of the NIDDM1 region.
Figure 2: Organization of the NIDDM1 region.
Figure 3: Tissue distribution of human CAPN10 mRNA.
Figure 4: Predicted amino acid sequence of human calpain-10a.
Figure 5: Alternative splicing of CAPN10 mRNA generates a family of proteins.
Figure 6: Binding of nuclear factors to CAPN10 intron 3.

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Acknowledgements

We thank M.M. Le Beau for carrying out FISH analysis; A. Di Rienzo for sharing unpublished results of studies of the sequence of the NIDDM1 region in other racial and ethnic groups and in higher apes; M.S. McPeek and D.L. Nicolae for advice and assistance with the statistical analyses; A. Kong, B. Suarez, M. Boehnke and M. Lathrop for their comments on the manuscript; and E. Reyes-Gonzalez for providing the Zapoteca Indian samples. This work was supported by United States Public Health Service grants DK-20595, -42086, -47486, -47487, -47494 and -55889; the American Diabetes Association; the State of Texas; a grant from the Japanese Ministry of Health and Welfare for research on the human genome and gene therapy; an unrestricted grant for cardiovascular and metabolic research from Bristol-Myers Squibb; the Blum-Kovler Foundation; and the Howard Hughes Medical Institute. The studies from the Department of Endocrinology, University of Lund were supported by grants from the Sigrid Juselius Foundation, the Albert Påhlssons Foundation, the Swedish Medical Research Council, Medical Faculty of Lund University, Malmö University Hospital, the Ernhold Lundström Foundation, the Swedish Foundation for the Study of Diabetes, the Anna-Lisa and Sven-Eric Lundgren Foundation for Medical Research, Novo Nordic Foundation, the Juvenile Diabetes Foundation International and an EEC Grant BMH4-CT95-0662.

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Author notes

  1. Yukio Horikawa, Naohisa Oda and Nancy J. Cox: These authors contributed equally to this work.

Authors and Affiliations

  1. Howard Hughes Medical Institute, The University of Chicago, Chicago, Illinois, USA

    Yukio Horikawa, Xiangquan Li, Manami Hara, Yoshinori Hinokio, Peter E.H. Schwarz, Laura del Bosque-Plata & Graeme I. Bell

  2. Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, Illinois, USA

    Yukio Horikawa, Xiangquan Li, Yoshinori Hinokio, Hirosato Mashima, Peter E.H. Schwarz, Laura del Bosque-Plata, Yohko Horikawa, Yukie Oda, Issei Yoshiuchi & Graeme I. Bell

  3. Department of Medicine, The University of Chicago, Chicago, Illinois, USA

    Naohisa Oda, Nancy J. Cox, Tom H. Lindner, Kenneth S. Polonsky & Graeme I. Bell

  4. Department of Human Genetics, The University of Chicago, Chicago, Illinois, USA

    Nancy J. Cox, Susan Colilla & Graeme I. Bell

  5. Department of Endocrinology, Malmö University Hospital, University of Lund, Malmö, Sweden

    Marju Orho-Melander & Leif Groop

  6. Molecular Genetics Program, Virginia Mason Research Center, and Department of Immunology, University of Washington, Seattle, Washington, USA

    Shan Wei & Patrick Concannon

  7. Diabetes Center, Tokyo Women's Medical University, Tokyo, Japan

    Naoko Iwasaki

  8. Department of Internal Medicine III, University Clinic Carl Gustav Carus of the Technical University, Dresden, Germany

    Jan Schulze

  9. Department of Phoenix Epidemiology and Clinical Research Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, USA

    Leslie J. Baier & Clifton Bogardus

  10. Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, Texas, USA

    Eric Boerwinkle & Craig L. Hanis

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Correspondence to Graeme I. Bell.

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Horikawa, Y., Oda, N., Cox, N. et al. Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat Genet 26, 163–175 (2000). https://doi.org/10.1038/79876

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