Human Molecular Genetics Advance Access published online on October 27, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh341
© 2004 by Oxford University Press
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1 Department of Medicine, Division of Diabetes, Endocrinology & Metabolism, Baylor College of Medicine, One Baylor Plaza, BCMA 700B, Houston, Texas, 77030, USA; Diabetes Center and Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Endocrinology & Diabetes, Saint-Louis Hospital, and University of Paris VII School of Medicine, Paris 75010, France
* To whom correspondence should be addressed. 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
Article
PAX4 gene variations predispose to ketosis-prone diabetes
2 Diabetes Center and Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
3 Division of Diabetes, Endocrinology & Metabolism and Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
4 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
5 Department of Endocrinology & Diabetes, Saint-Louis Hospital, and University of Paris VII School of Medicine, Paris 75010, France
6 Epidemiology Unit, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK
7 Department of Diabetes and Metabolic Diseases, Sud Francilien Hospital, Corbeil-Essonnes 91100, France
8 Department of Internal Medicine B, Lariboisiere Hospital, Paris, 75010, France
Franck Mauvais-Jarvis, E-mail: fmjarvis{at}bcm.tmc.edu
Abstract 
-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 suggests that KPD, like maturity onset diabetes of the young (MODY), is a rare, phenotypically-defined but genetically heterogeneous form of type 2 diabetes.
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