Akiba K, Ushijima K, Fukami M, Hasegawa Y
Department of Endocrinology and Metabolism, Tokyo Metropolitan Children's Medical Center.
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
Diabet Med. 2020 Oct;37(10):1772-1776. doi: 10.1111/dme.13970. Epub 2019 Jun 5.
Recently, heterozygous RFX6 mutations including p.Arg377Ter were identified in individuals with maturity-onset diabetes of the young (MODY). Clinical analysis of 36 individuals suggested that RFX6 mutation-induced MODY is characterized by low penetrance and relatively late onset. However, given the small number of previous reports and the limited clinical information of each case, further studies are necessary to clarify the phenotypic characteristics of RFX6 mutations.
We identified a previously reported p.Arg377Ter variant of RFX6 in a three-generation family with diabetes. The variant was detected through mutation screening for 30 diabetes-associated genes. The variant was not found in public databases and was predicted to encode a truncated protein or undergo nonsense-mediated mRNA decay. The proband showed glycosuria from 8 years of age and was diagnosed with MODY at 10 years of age, before the onset of puberty. She received basal and bolus insulin injection as initial therapy. The proband's mother exhibited glycosuria at 26 years of age when she conceived the first child. The mother was treated with insulin, oral hypoglycaemic drugs and diet. The proband and her mother were negative for islet cell autoantibodies. The maternal grandmother showed glycosuria around 50 years of age and was treated with oral hypoglycaemic drugs alone.
This study provides supporting evidence for the causal relationship between heterozygous RFX6 mutations and MODY. Furthermore, our results indicate that phenotypic consequences of RFX6 mutations are highly variable even within a single family, and possibly include childhood-onset and pregnancy-associated non-autoimmune diabetes.
最近，在青少年发病的成年型糖尿病（MODY）患者中发现了包括p.Arg377Ter在内的杂合RFX6突变。对36例患者的临床分析表明，RFX6突变导致的MODY具有低外显率和相对较晚发病的特点。然而，鉴于既往报道数量较少且每个病例的临床信息有限，有必要进一步研究以阐明RFX6突变的表型特征。
我们在一个三代糖尿病家族中发现了先前报道的RFX6基因p.Arg377Ter变异。该变异通过对30个糖尿病相关基因的突变筛查检测到。在公共数据库中未发现该变异，预计其编码截短蛋白或经历无义介导的mRNA降解。先证者8岁时出现糖尿，10岁时在青春期前被诊断为MODY。她最初接受基础胰岛素和餐时胰岛素注射治疗。先证者的母亲在26岁怀第一胎时出现糖尿。母亲接受胰岛素、口服降糖药和饮食治疗。先证者及其母亲胰岛细胞自身抗体均为阴性。外祖母在50岁左右出现糖尿，仅接受口服降糖药治疗。
本研究为杂合RFX6突变与MODY之间的因果关系提供了支持性证据。此外，我们的结果表明，即使在单个家族中，RFX6突变的表型后果也高度可变，可能包括儿童期发病和与妊娠相关的非自身免疫性糖尿病。
