Department of Diabetes and Endocrinology, Graduate School of Medicine, Gifu University, Gifu, Japan.
Department of Bioinformatics and Genomics, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, Japan.
J Hum Genet. 2018 Jul;63(7):821-829. doi: 10.1038/s10038-018-0449-4. Epub 2018 Apr 18.
MODY 5 and 6 have been shown to be low-penetrant MODYs. As the genetic background of unknown MODY is assumed to be similar, a new analytical strategy is applied here to elucidate genetic predispositions to unknown MODY. We examined to find whether there are major MODY gene loci remaining to be identified using SNP linkage analysis in Japanese. Whole-exome sequencing was performed with seven families with typical MODY. Candidates for novel MODY genes were examined combined with in silico network analysis. Some peaks were found only in either parametric or non-parametric analysis; however, none of these peaks showed a LOD score greater than 3.7, which is approved to be the significance threshold of evidence for linkage. Exome sequencing revealed that three mutated genes were common among 3 families and 42 mutated genes were common in two families. Only one of these genes, MYO5A, having rare amino acid mutations p.R849Q and p.V1601G, was involved in the biological network of known MODY genes through the intermediary of the INS. Although only one promising candidate gene, MYO5A, was identified, no novel, high penetrant MODY genes might remain to be found in Japanese MODY.
MODY5 和 MODY6 被认为是低外显率的 MODY。由于未知 MODY 的遗传背景被假定为相似，因此在这里应用了一种新的分析策略来阐明未知 MODY 的遗传易感性。我们检查了使用 SNP 连锁分析在日本是否存在尚未鉴定的主要 MODY 基因座。对 7 个具有典型 MODY 的家族进行了全外显子组测序。结合计算机网络分析，检查了新 MODY 基因的候选者。一些峰仅在参数或非参数分析中发现;然而，这些峰中没有一个的 LOD 得分大于 3.7，这被认为是连锁证据的显著阈值。外显子组测序显示，3 个家族中有 3 个突变基因常见，2 个家族中有 42 个突变基因常见。这些基因中只有一个，即 MYO5A，其罕见的氨基酸突变 p.R849Q 和 p.V1601G，通过 INS 中介与已知 MODY 基因的生物网络有关。尽管只鉴定出一个有希望的候选基因 MYO5A，但在日本 MODY 中可能没有新的、高外显率的 MODY 基因。
