Institute of Biomedical and Clinical Science, University of Exeter Medical School, EX2 5DW Exeter, UK; Institute of Biomedical and Clinical Science, Level 3, RILD Building, Barrack Road, EX2 5DW Exeter, United Kingdom.
J Mol Biol. 2020 Mar 6;432(5):1535-1550. doi: 10.1016/j.jmb.2019.08.016. Epub 2019 Aug 31.
This review focuses on gene discovery strategies used to identify monogenic forms of diabetes caused by reduced pancreatic beta-cell number (due to destruction or defective development) or impaired beta-cell function. Gene discovery efforts in monogenic diabetes have identified 36 genes so far. These genetic causes have been identified using four main approaches: linkage analysis, candidate gene sequencing and most recently, exome and genome sequencing. The advent of next-generation sequencing has allowed researchers to move away from linkage analysis (relying on large pedigrees and/or multiple families with the same genetic condition) and candidate gene (relying on previous knowledge on the gene's role) strategies to use a gene agnostic approach, utilizing genetic evidence (such as variant frequency, predicted variant effect on protein function, and predicted mode of inheritance) to identify the causative mutation. This approach led to the identification of seven novel genetic causes of monogenic diabetes, six by exome sequencing and one by genome sequencing. In many of these cases, the disease-causing gene was not known to be important for beta-cell function prior to the gene discovery study. These novel findings highlight a new role for gene discovery studies in furthering our understanding of beta-cell function and dysfunction in diabetes. While many gene discovery studies in the past were led by knowledge in the field (through the candidate gene strategy), now they often lead the scientific advances in the field by identifying new important biological players to be further characterized by in vitro and in vivo studies.
这篇综述专注于基因发现策略，用于鉴定因胰岛β细胞数量减少（由于破坏或发育缺陷）或β细胞功能受损而导致的单基因糖尿病。单基因糖尿病的基因发现工作迄今已确定了 36 个基因。这些遗传病因是使用以下四种主要方法确定的：连锁分析、候选基因测序，以及最近的外显子组和基因组测序。新一代测序技术的出现使研究人员能够摆脱连锁分析（依赖于大型家系和/或具有相同遗传条件的多个家族）和候选基因（依赖于对基因作用的先前知识）策略，转而采用基因不可知的方法，利用遗传证据（例如变异频率、预测变异对蛋白质功能的影响以及预测的遗传方式）来鉴定致病突变。这种方法导致了七种新的单基因糖尿病遗传病因的鉴定，其中六种通过外显子组测序，一种通过基因组测序。在许多情况下，在进行基因发现研究之前，致病基因并不被认为对β细胞功能很重要。这些新发现突出了基因发现研究在进一步了解糖尿病中β细胞功能和功能障碍方面的新作用。虽然过去的许多基因发现研究都是由该领域的知识（通过候选基因策略）引领的，但现在它们通常通过鉴定新的重要生物学参与者来引领该领域的科学进步，这些参与者需要通过体外和体内研究进一步进行特征描述。
