Human Molecular Genetics Advance Access originally published online on October 27, 2004
Human Molecular Genetics 2004 13(24):3151-3159; doi:10.1093/hmg/ddh341
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Human Molecular Genetics, Vol. 13, No. 24 © Oxford University Press 2004; all rights reserved
PAX4 gene variations predispose to ketosis-prone diabetes
1Division of Diabetes, Endocrinology and Metabolism, Department of Medicine and 2Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA, 3Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA, 4Department of Endocrinology and Diabetes, Saint-Louis Hospital, University of Paris VII School of Medicine, Paris 75010, France, 5Epidemiology Unit, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK, 6Department of Diabetes and Metabolic Diseases, Sud Francilien Hospital, Corbeil-Essonnes 91100, France and 7Department of Internal Medicine B, Lariboisiere Hospital, Paris, 75010, France
Received August 4, 2004; Accepted October 15, 2004
Ketosis-prone diabetes (KPD) is a rare form of type 2 diabetes, mostly observed in subjects of west African origin (west Africans and African-Americans), characterized by fulminant and phasic insulin dependence, but lacking markers of autoimmunity observed in type 1 diabetes. PAX4 is a transcription factor essential for the development of insulin-producing pancreatic ß-cells. Recently, a missense mutation (Arg121Trp) of PAX4 has been implicated in early and insulin deficient type 2 diabetes in Japanese subjects. The phenotype similarities between KPD and Japanese carriers of Arg121Trp have prompted us to investigate the role of PAX4 in KPD. We have screened 101 KPD subjects and we have found a new variant in the PAX4 gene (Arg133Trp), specific to the population of west African ancestry, and which predisposes to KPD under a recessive model. Homozygous Arg133Trp PAX4 carriers were found in 4% of subjects with KPD but not in 355 controls or 147 subjects with common type 2 or type 1 diabetes. In vitro, the Arg133Trp variant showed a decreased transcriptional repression of target gene promoters in an alpha-TC1.6 cell line. In addition, one KPD patient was heterozygous for a rare PAX4 variant (Arg37Trp) that was not found in controls and that showed a more severe biochemical phenotype than Arg133Trp. Clinical investigation of the homozygous Arg133Trp carriers and of the Arg37Trp carrier demonstrated a more severe alteration in insulin secretory reserve, during a glucagon-stimulation test, compared to other KPD subjects. Together these data provide the first evidence that ethnic-specific gene variants may contribute to the predisposition to this particular form of diabetes and suggest that KPD, like maturity onset diabetes of the young, is a rare, phenotypically defined but genetically heterogeneous form of type 2 diabetes.
* To whom correspondence should be addressed at: Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, One Baylor Plaza, BCMA 700B, Houston, TX 77030, USA. Tel: +1 7137987224; Fax: +1 7137983810; Email: fmjarvis{at}bcm.tmc.edu
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