The C42R mutation in the Kir6.2 (KCNJ11) gene as a cause of transient neonatal diabetes, childhood diabetes, or later-onset, apparently type 2 diabetes mellitus
The C42R mutation in the Kir6.2 (KCNJ11) gene as a cause of transient neonatal diabetes, childhood diabetes, or later-onset, apparently type 2 diabetes mellitus
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DOI：
10.1210/jc.2005-0096
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发表时间：
2005-06-01
影响因子：
5.8
通讯作者：
Nakahata, T
中科院分区：
文献类型：
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作者：
Yorifuji, T;Nagashima, K;Nakahata, T
背景：在日本，年轻人成熟型糖尿病的已知基因仅占显性遗传糖尿病家族的一小部分。应该有尚未确定的基因，占其余的patients.Objective：为了确定和表征突变负责一个日本家庭与显性遗传diabetes.Subjects：成员的一个四代家庭与显性遗传糖尿病观察到的三代。这个家庭中没有一个患者患有永久性新生儿糖尿病。一个有短暂的新生儿糖尿病，一个有儿童糖尿病，和其他成人发病的糖尿病，没有自身抗体或insulin resistance.Methods：筛选的染色体位置的基因的全基因组连锁分析，然后由候选基因测序。通过群体调查和生理分析证实了所鉴定突变的功能意义。结果：我们在KCNJ11基因中鉴定出一个新的突变（C42 R），该突变编码胰腺ATP敏感性钾通道的Kir6.2亚基。使用突变的KCNJ11的膜片钳实验表明，突变导致自发开放概率增加和ATP敏感性降低。然而，这种效应部分地被细胞表面功能性ATP敏感性钾通道表达的减少所补偿，这可以解释我们患者较轻的表型。这些结果拓宽了KCNJ 11突变引起的糖尿病表型的范围，并表明该基因的突变不仅应考虑永久性新生儿糖尿病，还应考虑其他形式的糖尿病表现型较轻且发病较晚
Context: Known genes in maturity-onset diabetes of the young account for only a fraction of families with dominantly inherited diabetes in Japan. There should be as-yet-unidentified genes that account for the rest of the patients.Objective: To identify and characterize the mutation responsible for a Japanese family with dominantly inherited diabetes mellitus.Subjects: Members of a four-generation family with dominantly inherited diabetes mellitus observed in three generations. None of the patients in this family had permanent neonatal diabetes. One had transient neonatal diabetes, one had childhood diabetes, and the others had adult-onset diabetes without autoantibodies or insulin resistance.Methods: Screening of the chromosomal location of the gene by a genome-wide linkage analysis followed by candidate gene sequencing. Confirmation of the functional significance of the identified mutation by the population survey and the physiological analysis.Results: We identified a novel mutation (C42R) in the KCNJ11 gene coding for the Kir6.2 subunit of the pancreatic ATP-sensitive potassium channel. The patch-clamp experiments using the mutated KCNJ11 showed that the mutation causes increased spontaneous open probability and reduced ATP sensitivity. The effect, however, was partially compensated by the reduction of functional ATP-sensitive potassium channel expression at the cell surface, which could account for the milder phenotype of our patients.Conclusions: These results broaden the spectrum of diabetes phenotypes caused by mutations of KCNJ11 and suggest that mutations in this gene should be taken into consideration for not only permanent neonatal diabetes but also other forms of diabetes with milder phenotypes and later onset.