m.3243A>G 新生突变与 m.16093T>C 共同导致 MIDD 综合征家系中出现非典型临床特征。
De Novo Mutation of m.3243A>G together with m.16093T>C Associated with Atypical Clinical Features in a Pedigree with MIDD Syndrome.
机构信息
Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Key Laboratory of Diabetes, The Metabolic Diseases Biobank, Department of Endocrinology and Metabolism, Shanghai 200233, China.
Shanghai Jiao Tong University Affiliated Sixth People's Hospital, The Metabolic Diseases Biobank, Center for Translational Medicine, Shanghai Key Laboratory of Diabetes, Shanghai 200233, China.
出版信息
J Diabetes Res. 2019 Apr 4;2019:5184647. doi: 10.1155/2019/5184647. eCollection 2019.
BACKGROUND
The syndrome of maternally inherited diabetes and deafness (MIDD) is typically caused by the m.3243A>G mutation and widely considered maternally inherited. In our study, we aimed to investigate the heredity way of the m.3243A>G among pedigrees with MIDD and discover novel mitochondrial DNA mutations related to atypical clinical phenotypes.
METHODS
Heteroplasmy levels of the m.3243A>G mutation in peripheral blood, saliva, and urine sediment of 31 individuals from 10 unrelated pedigrees were measured by pyrosequencing. Clinical evaluations including endocrinological, audiological, and magnetic resonance imaging (MRI) examinations, mitochondrial function evaluation in peripheral blood mononuclear cells (PBMCs), and whole mitochondrial DNA (mtDNA) sequencing were performed among the spontaneous mutant pedigrees.
RESULTS
Among the 10 unrelated MIDD pedigrees, we found that the de novo m.3243A>G mutation occurred in the family 1957 (F1957). The proband (F1957-II-1) and her son (F1957-III-1) both manifested diabetes with mild bilateral sensorineural hearing loss (SNHL) and abnormal brain MRI, and F1957-III-1 also complained of severe nausea and vomiting. Mitochondrial function evaluation in PBMCs revealed an increased level of ROS generation and decreased levels of ATP and mitochondrial membrane potential (ΔΨm) in the two m.3243A>G carriers. Whole mtDNA sequencing also revealed a de novo heteroplasmic substitution at m.16093T>C in both the proband and her son.
CONCLUSIONS
Our study showed that de novo m.3243A>G mutation accompanied by other point mutations may occur in the very early embryonic or germ cell stage without maternal inheritance, bringing about both typical and atypical clinical features.
背景
母系遗传性糖尿病和耳聋（MIDD）综合征通常由 m.3243A>G 突变引起，且被广泛认为是母系遗传的。在我们的研究中，我们旨在调查 MIDD 家系中 m.3243A>G 的遗传方式，并发现与非典型临床表型相关的新的线粒体 DNA 突变。
方法
通过焦磷酸测序测量 10 个无关家系的 31 名个体的外周血、唾液和尿液沉淀物中 m.3243A>G 突变的异质性水平。对自发性突变家系进行内分泌、听力和磁共振成像（MRI）检查、外周血单个核细胞（PBMCs）中线粒体功能评估以及整个线粒体 DNA（mtDNA）测序的临床评估。
结果
在 10 个无关的 MIDD 家系中，我们发现新发的 m.3243A>G 突变发生在 1957 家系（F1957）中。先证者（F1957-II-1）及其儿子（F1957-III-1）均表现为糖尿病伴双侧感觉神经性听力损失（SNHL）和异常脑 MRI，且 F1957-III-1 还伴有严重的恶心和呕吐。PBMCs 中线粒体功能评估显示，两位 m.3243A>G 携带者的 ROS 生成水平升高，ATP 和线粒体膜电位（ΔΨm）水平降低。整个 mtDNA 测序还显示，先证者及其儿子均存在新发的 m.16093T>C 异质性替换。
结论
我们的研究表明，无母系遗传的情况下，在胚胎或生殖细胞的早期阶段可能会发生新发的 m.3243A>G 突变，并伴有其他点突变，从而导致既有典型又有非典型的临床特征。
Zotero 插件