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）是一种临床和病因异质性疾病，其特征是月经不调和40岁之前的FSH水平升高。遗传异常是POI的公认原因之一。在这里，我们的目的是在具有9个POI和2个受鱼鳞病影响的成员的近交系中鉴定POI的遗传原因。POI和鱼鳞病的遗传分别为显性和隐性。获得了生殖相关信息和相关激素的测量值。遗传研究包括纯合性作图，连锁分析，外显子组测序和候选变体的筛选。ALOX12B内部的突变是已知的鱼鳞病致病基因，被鉴定为鱼鳞病的病因。ALOX12B编码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，考虑了ALOX12B突变也是POI引起的可能性。筛选显示该突变与POI状态分离。关于POI的连锁分析确定了包括ALOX12B的单个强连锁基因座（LOD> 3）。对受POI影响的雌性进行外显子组测序可确定ALOX12B中的突变，以及所连锁基因座中SPNS2中的序列变异。SPNS2的可能贡献严格排除POI的变异，但本文中提供的各种数据包括报道的相关基因ALOX12的变异与绝经年龄之间的关联以及ALOX12B在牛毛囊泡形成中的作用，都支持ALOX12B。因此，可以得出结论，ALOX12B中的突变是谱系中POI的可能原因。