Lambert A Paul, Ellard Sian, Allen Lisa I S, Gallen Ian W, Gillespie Kathleen M, Bingley Polly J, Hattersley Andrew T
Department of Diabetes and Metabolism, Division of Medicine, University of Bristol, UK.
Diabetes Care. 2003 Feb;26(2):333-7. doi: 10.2337/diacare.26.2.333.
HNF-1alpha gene mutations (MODY3) present with marked hyperglycemia in lean young adults and may, therefore, be mistaken for type 1 diabetes, with implications for individual treatment and risk of diabetes in other family members. We examined the prevalence of HNF-1alpha mutations in families with three generations of diabetes identified in a population-based study of childhood diabetes, representing a subpopulation in which misclassification was likely.
In a study population of 1,470 families, 36 families (2.4%) with three affected generations were identified. In the 18 families in whom DNA samples were available, islet autoantibody testing, HLA class II genotyping, and HNF-1alpha sequencing were performed.
At least one islet autoantibody was found in 13 of 14 probands, and diabetes-associated HLA class II haplotypes were found in 17 of 18. One proband, who had no islet autoantibodies and was homozygous for the protective HLA haplotype DRB102-DQB10602, had a novel HNF-1alpha heterozygous nonsense mutation (R54X). This mutation cosegregated with diabetes in the family. The proband, his brother, mother, and maternal grandmother were diagnosed with type 1 diabetes aged 14-18 years and treated with insulin (0.39-0.74 units/kg) from diagnosis. The mother has since been successfully transferred to sulfonylurea treatment.
Family history alone is of limited value in identification of individuals with HNF-1alpha mutations, and we propose a stepwise approach that restricts sequencing of the HNF-1alpha gene to those with a family history of diabetes who also test negative for islet autoantibodies.
肝细胞核因子-1α（HNF-1α）基因突变（MODY3）在体型偏瘦的年轻成年人中表现为显著高血糖，因此可能被误诊为1型糖尿病，这对个体治疗以及其他家庭成员患糖尿病的风险均有影响。我们在一项基于人群的儿童糖尿病研究中，对三代均患糖尿病的家庭进行了调查，以确定HNF-1α基因突变的患病率，该人群是一个可能存在误诊的亚组。
在1470个家庭的研究人群中，识别出36个（2.4%）三代均患病的家庭。在可获取DNA样本的18个家庭中，进行了胰岛自身抗体检测、HLA II类基因分型以及HNF-1α基因测序。
14名先证者中有13名至少检测到一种胰岛自身抗体，18名中有17名发现了与糖尿病相关的HLA II类单倍型。一名先证者没有胰岛自身抗体，且对保护性HLA单倍型DRB102-DQB10602呈纯合状态，其存在一种新的HNF-1α杂合无义突变（R54X）。该突变在家族中与糖尿病共分离。先证者、其兄弟、母亲和外祖母均在14 - 18岁时被诊断为1型糖尿病，自诊断起接受胰岛素治疗（0.39 - 0.74单位/千克）。其母亲后来成功改用磺脲类药物治疗。
仅依靠家族史来识别携带HNF-1α基因突变的个体价值有限，我们提出一种逐步筛查方法，将HNF-1α基因测序限制在有糖尿病家族史且胰岛自身抗体检测呈阴性的个体中。
