RGD Reference Report - PAX4 gene variations predispose to ketosis-prone diabetes. - Rat Genome Database

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PAX4 gene variations predispose to ketosis-prone diabetes.

Authors: Mauvais-Jarvis, F  Smith, SB  Le May, C  Leal, SM  Gautier, JF  Molokhia, M  Riveline, JP  Rajan, AS  Kevorkian, JP  Zhang, S  Vexiau, P  German, MS  Vaisse, C 
Citation: Mauvais-Jarvis F, etal., Hum Mol Genet. 2004 Dec 15;13(24):3151-9. Epub 2004 Oct 27.
RGD ID: 2311634
Pubmed: PMID:15509590   (View Abstract at PubMed)
PMCID: PMC6145178   (View Article at PubMed Central)
DOI: DOI:10.1093/hmg/ddh341   (Journal Full-text)

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 beta-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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
type 1 diabetes mellitus  IAGP 2311634DNA:polymorphism: :p.R133W (human)RGD 
type 1 diabetes mellitus  ISOPAX4 (Homo sapiens)2311634; 2311634DNA:polymorphism: :p.R133W (human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Pax4  (paired box 4)

Genes (Mus musculus)
Pax4  (paired box 4)

Genes (Homo sapiens)
PAX4  (paired box 4)


Additional Information