Analysis of HNF-related genes responsible for the development of type 2 diabetes in Japanese

编码HNF转录因子的基因突变与MODY有关，MODY是一种早发性糖尿病的单基因形式。孤儿受体SHP调节HNF-4α (MODY1)转录活性的能力表明SHP是MODY的候选基因。我们筛选了173名无亲缘关系的日本早发性糖尿病患者进行该基因突变，并在6名受试者中发现了5种不同的突变，均以杂合状态存在。有趣的是，所有突变的受试者在糖尿病发病时都是轻度或中度肥胖，对这些个体的谱系分析表明，SHP突变与肥胖有关，而不是与MODY有关。突变蛋白的功能研究表明，突变导致SHP活性的丧失。这些结果表明，SHP基因的遗传变异有助于体重增加。为了阐明SHP突变与其他致糖尿病因素之间可能的相互作用，我们对更多具有SHP突变的c先显子进行了MODY基因突变的重新筛选，并在一名受试者中发现了一个MODY3突变。虽然MODY3的主要特征是β细胞功能障碍，但在该受试者中观察到肥胖和胰岛素抵抗，这表明SHP突变改变了表型。由于日本的2型糖尿病也主要是由于β细胞功能障碍，SHP突变可能影响高危人群的易感性。据此，对日本成人2型糖尿病患者中SHP突变的患病率进行了评估。对274名糖尿病患者和305名非糖尿病患者的基因进行了直接测序。在糖尿病组和对照组中，分别有9名（3.3%）和1名（0.3%）受试者发现活性降低的突变。两组之间的频率差异具有统计学意义（p=0.0088），表明与轻度肥胖相关的SHP突变增加了日本人晚年对2型糖尿病的易感性。少

Mutations in genes encoding HNF transcription factors are associated with MODY, a monogenic form of early-onset diabetes mellitus. The ability of the orphan receptor SHP to modulate the transcriptional activity of HNF-4α (MODY1), suggested SHP as a candidate MODY gene. We screened 173 unrelated Japanese subjects with early-onset diabetes for mutations in this gene and found five different mutations in six subjects, all present in the heterozygous state. Interestingly, all of the subjects with the mutations were mildly or moderately obese at onset of diabetes, and analysis of the lineages of these individuals indicated that the SHP mutations were associated with obesity rather than with MODY. Functional studies of the mutant proteins show that the mutations result in the loss of SHP activity. These results suggest that genetic variation in the SHP gene contributes to increased body weight.To clarify the possible interplay between the SHP mutations and other diabetogenic factors, diabeti … More c probands with the SHP mutations were re-screened for mutations in the MODY genes, and one MODY3 mutation was identified in one subject. Although MODY3 is characterized primarily by β-cell dysfunction, obesity and insulin resistance were observed in this subject, suggesting that the SHP mutation modifies the phenotype. As type 2 diabetes in Japanese also is due primarily to β-cell dysfunction, SHP mutations might influence susceptibility in people at risk. Accordingly, the prevalence of SHP mutations in adult-onset type 2 diabetes in Japanese was evaluated. Direct sequencing of the gene in 274 diabetic and 305 non-diabetic subjects was performed. Mutations with reduced activity were found in nine (3.3 %) and one (0.3 %) subjects in the diabetic and control groups, respectively. The frequency difference between the two groups was statistically significant (p=0.0088), suggesting that SHP mutations associated with mild obesity increase susceptibility to type 2 diabetes in later life in Japanese. Less