Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
School of Biology, University College of Science, University of Tehran, Tehran, Iran.
Mol Genet Genomics. 2020 Jul;295(4):1039-1053. doi: 10.1007/s00438-020-01663-z. Epub 2020 Apr 6.
Premature ovarian insufficiency (POI) is a clinically and etiologically heterogeneous disorder characterized by menstrual irregularities and elevated levels of FSH before age of 40 years. Genetic anomalies are among the recognized causes of POI. Here, we aimed to identify the genetic cause of POI in an inbred pedigree with nine POI and two ichthyosis-affected members. Inheritance of POI and ichthyosis were, respectively, dominant and recessive. Reproduction-related information and measurements of relevant hormones were obtained. Genetic studies included homozygosity mapping, linkage analysis, exome sequencing, and screening of candidate variants. A mutation within ALOX12B, which is a known ichthyosis causing gene, was identified as cause of ichthyosis. ALOX12B encodes a protein involved in steroidogenesis and lipid metabolism. Considering the importance of steroidogenesis in reproduction functions, the possibility that the ALOX12B mutation is also cause of POI was considered. Screenings showed that the mutation segregated with POI status. Linkage analysis with respect to POI identified a single strongly linked locus (LOD > 3) that includes ALOX12B. Exome sequencing on POI-affected females identified the mutation in ALOX12B and also a sequence variation in SPNS2 within the linked locus. A possible contribution of the SPNS2 variation to POI was not strictly ruled out, but various data presented in the text including reported association of variations in related gene ALOX12 with menopause-age and role of ALOX12B in atretic bovine follicle formation argue in favor of ALOX12B. It is, therefore, concluded that the mutation in ALOX12B is the likely cause of POI in the pedigree.
卵巢早衰（POI）是一种临床上和病因学上具有异质性的疾病，其特征是在 40 岁之前出现月经不规律和 FSH 水平升高。遗传异常是 POI 的公认原因之一。在这里，我们旨在确定一个具有 9 名 POI 和 2 名鱼鳞病受累成员的近交系中 POI 的遗传原因。POI 和鱼鳞病的遗传分别为显性和隐性。获得了与生殖相关的信息和相关激素的测量值。遗传研究包括纯合子作图、连锁分析、外显子组测序和候选变体筛查。在已知导致鱼鳞病的基因 ALOX12B 内发现了一个突变，这是鱼鳞病的病因。ALOX12B 编码一种参与类固醇生成和脂质代谢的蛋白质。考虑到类固醇生成在生殖功能中的重要性，认为 ALOX12B 突变也是 POI 的原因。筛查显示该突变与 POI 状态分离。针对 POI 的连锁分析确定了一个包含 ALOX12B 的单一强连锁位点（LOD>3）。在受 POI 影响的女性中进行外显子组测序发现了 ALOX12B 中的突变，以及连锁位点内 SPNS2 的序列变异。不能严格排除 SPNS2 变异对 POI 的可能贡献，但文中提供的各种数据，包括报道的与相关基因 ALOX12 变异相关的绝经年龄的关联以及 ALOX12B 在牛闭锁卵泡形成中的作用，都支持 ALOX12B。因此，结论是 ALOX12B 中的突变是该系中 POI 的可能原因。
