The type and the position of HNF1A mutation modulate age at diagnosis of diabetes in patients with maturity-onset diabetes of the young (MODY)-3
The type and the position of HNF1A mutation modulate age at diagnosis of diabetes in patients with maturity-onset diabetes of the young (MODY)-3
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DOI：
10.2337/db07-0859
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发表时间：
2008-02-01
期刊：
影响因子：
7.7
通讯作者：
Timsit, Jose
中科院分区：
文献类型：
--
作者：
Bellanne-Chantelot, Christine;Carette, Claire;Timsit, Jose
年轻人成熟型糖尿病（MODY）-3的临床表现是高度可变的。这可能是由于环境和/或遗传因素，包括肝细胞核因子1-α的分子特征。（HNF 1A）基因突变。研究设计和方法-我们分析了在356个无关的MODY 3患者中鉴定的突变，包括118个新的突变，并寻找诊断糖尿病时基因型和年龄之间的相关性。大多数（83%）突变位于外显子1-6，从而影响三种HNF 1A亚型。截短突变患者诊断糖尿病的年龄低于错义突变患者（18岁对22岁，P = 0.005）。影响二聚化/DNA结合结构域的错义突变与较低的诊断年龄比影响反式激活结构域的错义突变相关（20岁对30岁，P = 10（-4））。错义突变影响三种亚型的患者在诊断时比错义突变涉及一种或两种亚型的患者年轻（P = 0.03）。结论-这些数据表明，MODY 3患者的临床表达的变异性的一部分可能是由HNF 1A突变的类型和位置来解释的。这些发现应在研究中考虑，以寻找额外的修饰遗传因素。
OBJECTIVE-The clinical expression of maturity-onset diabetes of the young (MODY)-3 is highly variable. This may be due to environmental and/or genetic factors, including molecular characteristics of the hepatocyte nuclear factor 1-alpha. (HNF1A) gene mutation.RESEARCH DESIGN AND METHODS-We analyzed the mutations identified in 356 unrelated MODY3 patients, including 118 novel mutations, and searched for correlations between the genotype and age at diagnosis of diabetes.RESULTS-Missense mutations prevailed in the dimerization and DNA-binding domains (74%), while truncating mutations were predominant in the transactivation domain (62%). The majority (83%) of the mutations were located in exons 1-6, thus affecting the three HNF1A isoforms. Age at diagnosis of diabetes was lower in patients with truncating mutations than in those with missense mutations (18 vs. 22 years, P = 0.005). Missense mutations affecting the dimerization/DNA-binding domains were associated with a lower age at diagnosis than those affecting the transactivation domain (20 vs. 30 years, P = 10(-4)). Patients with missense mutations affecting the three isoforms were younger at diagnosis than those with missense mutations involving one or two isoforms (P = 0.03).CONCLUSIONS-These data show that part of the variability of the clinical expression in MODY3 patients may be explained by the type and the location of HNF1A mutations. These findings should be considered in studies for the search of additional modifier genetic factors.