Background and aim

Neonatal diabetes mellitus (NDM) is a rare monogenic disorder of pancreatic beta cell mass and/or function. In the present study we aimed to evaluate the INS gene mutations in a cohort of children with Permanent Neonatal Diabetes Mellitus (PNDM) and to explore the clinical and genetic characteristics of PNDM caused by INS mutations.

Methods

Direct sequencing of all exons of INS genes was carried out in 189 children with PNDM. Clinical and biochemical data were collected and correlated. The pathogenicity of mutations was determined based on the American College of Medical Genetics and Genomics and Association of Medical Pathology guidelines.

Results

Two novel mutations (His34Pro, Leu35Met) in a compound heterozygous state and seven known mutations (Gly32Ser, Phe48Cys, Arg89Cys, Cys96Tyr, Ser98Ile, Try108Asp and Cys109Phe) in the INS gene were identified in 8 patients out of the total of 189 PNDM children studied. Four mutations were involved in defects with disulphide bond formation and hence were in crucial regions of the gene. All the mutations were de novo in origin.

Conclusions

This is the first comprehensive study from India to investigate the insulin gene mutations in PNDM and to show that INS gene mutations also contribute to the causation of PNDM.

中文翻译：

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印度人群中与永久性新生儿糖尿病相关的胰岛素基因突变

背景和目的

新生儿糖尿病 (NDM) 是一种罕见的胰腺 β 细胞质量和/或功能的单基因疾病。在本研究中，我们旨在评估一组永久性新生儿糖尿病（PNDM）儿童的INS基因突变，并探索由INS突变引起的 PNDM 的临床和遗传特征。

方法

对 189 名 PNDM 儿童进行了INS基因所有外显子的直接测序。收集并关联临床和生化数据。突变的致病性是根据美国医学遗传学和基因组学学院和医学病理学协会指南确定的。

结果

在总共研究的 189 名 PNDM 儿童中，有 8 名患者在INS基因中发现了 2个复合杂合状态的新突变（His34Pro、Leu35Met）和 7 个已知突变（Gly32Ser、Phe48Cys、Arg89Cys、Cys96Tyr、Ser98Ile、Try108Asp 和 Cys109Phe）. 四个突变与二硫键形成的缺陷有关，因此位于基因的关键区域。所有的突变都是从头开始的。

结论

这是印度第一项调查 PNDM 中胰岛素基因突变的综合研究，并表明INS基因突变也有助于 PNDM 的病因。