Kline Brianna L, Siddall Nicole A, Wijaya Fernando, Stuart Catherine J, Orlando Luisa, Bakhshalizadeh Shabnam, Afkhami Fateme, Bell Katrina M, Jaillard Sylvie, Robevska Gorjana, van den Bergen Jocelyn A, Shahbazi Shirin, van Hoof Ambro, Ayers Katie L, Hime Gary R, Sinclair Andrew H, Tucker Elena J
Murdoch Children's Research Institute, Royal Children's Hospital, 50 Flemington Rd, Parkville VIC 3052, Melbourne, Australia.
Department of Paediatrics, The University of Melbourne, Grattan Street, Parkville, VIC 3010, Melbourne, Australia.
Biol Reprod. 2025 Jan 14;112(1):102-118. doi: 10.1093/biolre/ioae148.
Premature ovarian insufficiency (POI) is characterized by the loss or complete absence of ovarian activity in women under the age of 40. Clinical presentation of POI varies with phenotypic severity ranging from premature loss of menses to complete gonadal dysgenesis. POI is genetically heterogeneous with >100 causative gene variants identified thus far. The etiology of POI varies from syndromic, idiopathic, monogenic to autoimmune causes the condition. Genetic diagnoses are beneficial to those impacted by POI as it allows for improved clinical management and fertility preservation. Identifying novel variants in candidate POI genes, however, is insufficient to make clinical diagnoses. The impact of missense variants can be predicted using bioinformatic algorithms but computational approaches have limitations and can generate false positive and false negative predictions. Functional characterization of missense variants, is therefore imperative, particularly for genes lacking a well-established genotype:phenotype correlation. Here we used whole-exome sequencing (WES) to identify the first case of a homozygous missense variant in DIS3 (c.2320C > T; p.His774Tyr) a critical component of the RNA exosome in a POI patient. This adds to the previously described compound heterozygous patient. We perform the first functional characterization of a human POI-associated DIS3 variant. A slight defect in mitotic growth was caused by the variant in a Saccharomyces cerevisiae model. Transgenic rescue of Dis3 knockdown in Drosophila melanogaster with human DIS3 carrying the patient variant led to aberrant ovarian development and egg chamber degeneration. This supports a potential deleterious impact of the human c.2320C > T; p.His774Tyr variant.
卵巢早衰（POI）的特征是40岁以下女性卵巢功能丧失或完全缺失。POI的临床表现因表型严重程度而异，从月经过早丧失到完全性腺发育不全。POI具有遗传异质性，迄今为止已鉴定出100多个致病基因变异。POI的病因从综合征性、特发性、单基因到自身免疫性病因不等。基因诊断对受POI影响的人有益，因为它有助于改善临床管理和生育力保存。然而，在候选POI基因中鉴定新的变异不足以进行临床诊断。错义变异的影响可以使用生物信息学算法进行预测，但计算方法有局限性，可能会产生假阳性和假阴性预测。因此，对错义变异进行功能表征至关重要，特别是对于缺乏成熟基因型与表型相关性的基因。在这里，我们使用全外显子组测序（WES）在一名POI患者中鉴定出DIS3（c.2320C>T；p.His774Tyr）纯合错义变异的首例病例，DIS3是RNA外切体的关键组成部分。这增加了之前描述的复合杂合患者。我们对与人类POI相关的DIS3变异进行了首次功能表征。酿酒酵母模型中的变异导致有丝分裂生长出现轻微缺陷。用携带患者变异的人类DIS3对黑腹果蝇中Dis3基因敲低进行转基因拯救，导致卵巢发育异常和卵室退化。这支持了人类c.2320C>T；p.His774Tyr变异可能具有有害影响。
