Identification of genetic factor for type 1 diabetes mellitus

1型糖尿病(T1D)的病因是异质性的，根据胰腺自身抗体的存在与否分为两个亚型：1A型(自身免疫介导的)和1B型(非自身免疫介导的)。尽管有几个基因与1A型糖尿病有关，但日本人患1B型糖尿病的遗传原因还远未被了解。这项研究的目的是在自身抗体阴性的患有T1D的日本儿童中检测单基因形式的糖尿病。我们在5名儿童中发现了3个新的INS基因突变(C31Y、C96R和C109F)和一个先前报道的突变(R89C)，另外在1名儿童中发现了KCNJ11基因的一个突变(H46R)。这些突变很可能是致病的，因此是携带者患糖尿病的原因。我们的结果表明，单基因形式的糖尿病，特别是INS基因突变，可以在被归类为1B型的日本患者中检测到。建议对5岁时被诊断为自身抗体阴性的日本患者进行突变筛查，至少是INS基因。建议对所有6个月前被诊断为糖尿病的患者进行基因检测。需要对其他1B型糖尿病患者及其家人进行进一步的研究，以阐明突变对T1D表型的贡献。

The etiology of type 1 diabetes (T1D) is heterogeneous and is according to presence or absence of pancreatic auto antibodies divided into two subtypes: type 1A (autoimmune-mediated) and type 1B (non-autoimmune-mediated). Although several genes have been linked to type 1A diabetes, the genetic cause of type 1B diabetes in Japanese individuals is far from understood. The aim of this study was to test for monogenic forms of diabetes in auto antibody-negative Japanese children with T1D. We identified three novel (C31Y, C96R and C109F) mutations and one previously reported mutation (R89C) in the INS gene in five children, in addition to one mutation in the KCNJ11 gene (H46R) in one child. These mutations are most likely pathogenic and therefore the cause of diabetes in carriers. Our results suggest that monogenic forms of diabetes, particularly INS gene mutations, can be detected in Japanese patients classified with type 1B. Mutation screening, at least of the INS gene, is recommended for Japanese patients diagnosed as autoantibody negative at < 5 years of age. Genetic testing is recommended in all patients diagnosed with diabetes before 6 months of age. Further studies in other patients with type 1B diabetes and their families are needed to elucidate the contributions of mutations to the T1D phenotype.