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首页> 外文期刊>Human Molecular Genetics >PAX4 gene variations predispose to ketosis-prone diabetes.
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PAX4 gene variations predispose to ketosis-prone diabetes.

机译：PAX4基因变异易患酮症易感糖尿病。

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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.
机译：易于发生酮症的糖尿病（KPD）是2型糖尿病的一种罕见形式，主要在西非血统的受试者（西非和非裔美国人）中观察到，其特征是爆发性和阶段性胰岛素依赖，但缺乏在1型中观察到的自身免疫性标志物糖尿病。 PAX4是产生胰岛素的胰岛β细胞发育所必需的转录因子。最近，在日本受试者中，PAX4的错义突变（Arg121Trp）与早期和胰岛素缺乏的2型糖尿病有关。 KPD与日本运载体Arg121Trp之间的表型相似性促使我们研究PAX4在KPD中的作用。我们筛选了101名KPD受试者，发现PAX4基因的一个新变体（Arg133Trp），该变体特定于西非血统，在隐性模型下易患KPD。纯合子Arg133Trp PAX4携带者在4％的KPD受试者中发现，但在355例对照或147名患有普通2型或1型糖尿病的受试者中未发现。在体外，Arg133Trp变体在alpha-TC1.6细胞系中显示出靶基因启动子的转录抑制降低。此外，一名KPD患者是罕见的PAX4变异体（Arg37Trp）的杂合体，该变异体在对照组中未发现，并且表现出比Arg133Trp更严重的生化表型。与其他KPD受试者相比，在胰高血糖素刺激试验期间，对纯合子Arg133Trp载体和Arg37Trp载体的临床研究表明，胰岛素分泌储备的变化更为严重。这些数据加在一起提供了第一个证据，即种族特异性基因变异可能是导致这种特殊形式糖尿病的诱因，并表明KPD像年轻人的成熟型糖尿病一样，是一种罕见的，表型定义但遗传上异质的2型糖尿病糖尿病。

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