OBJECTIVE Heterozygous loss-of-function mutations in HNF1A cause maturity-onset diabetes of the young (MODY). Affected individuals can be treated with low-dose sulphonylureas. Individuals with homozygous HNF1A mutations causing MODY have not been reported. RESEARCH DESIGN AND METHODS We phenotyped a kindred with young-onset diabetes and performed molecular genetic testing, a mixed meal tolerance test, a sulphonylurea challenge, and in vitro assays to assess variant protein function. RESULTS A homozygous HNF1A variant (p.A251T) was identified in three insulin-treated family members diagnosed with diabetes before 20 years of age. Those with the homozygous variant had low hs-CRP levels (0.2-0.8 mg/L), and those tested demonstrated sensitivity to sulphonylurea given at a low dose, completely transitioning off insulin. In silico modeling predicted a variant of unknown significance; however, in vitro studies supported a modest reduction in transactivation potential (79% of that for the wild type; P < 0.05) in the absence of endogenous HNF1A. CONCLUSIONS Homozygous hypomorphic HNF1A variants are a cause of HNF1A-MODY. We thus expand the allelic spectrum of variants in dominant genes causing diabetes.

中文翻译：

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纯合子亚型 HNF1A 等位基因是年轻发病糖尿病的新病因，并会导致磺酰脲类药物敏感型糖尿病。

目的 HNF1A 中的杂合性功能丧失突变导致青年人发病的成熟期糖尿病 (MODY)。受影响的个体可以用低剂量磺脲类药物治疗。尚未报道具有导致 MODY 的纯合 HNF1A 突变的个体。研究设计和方法 我们对一个患有年轻糖尿病的亲属进行了表型分型，并进行了分子遗传学测试、混合膳食耐受性测试、磺酰脲类挑战和体外测定以评估变异蛋白功能。结果 在 20 岁之前被诊断患有糖尿病的三名接受胰岛素治疗的家庭成员中鉴定出纯合 HNF1A 变异体 (p.A251T)。那些具有纯合变体的人具有较低的 hs-CRP 水平（0.2-0.8 mg/L），而那些被测试的人表现出对低剂量磺脲类药物的敏感性，完全从胰岛素转变。计算机模拟预测了一个未知意义的变体；然而，体外研究支持在没有内源性 HNF1A 的情况下适度降低反式激活潜力（野生型的 79%；P < 0.05）。结论 纯合亚型 HNF1A 变异是 HNF1A-MODY 的一个原因。因此，我们扩大了导致糖尿病的显性基因变异的等位基因谱。