Oligoasthenoteratozoospermia (OAT) is a common type of male infertility; however, its genetic causes remain largely unknown. Some of the genetic determinants of OAT are gene defects affecting spermatogenesis. BCORL1 (BCL6 corepressor like 1) is a transcriptional corepressor that exhibits the OAT phenotype in a knockout mouse model. A hemizygous missense variant of BCORL1 (c.2615T > G:p.Val872Gly) was reported in an infertile male patient with non-obstructive azoospermia (NOA). Nevertheless, the correlation between BCORL1 variants and OAT in humans remains unknown. In this study, we used whole-exome sequencing to identify a novel hemizygous nonsense variant of BCORL1 (c.1564G > T:p.Glu522*) in a male patient with OAT from a Han Chinese family. Functional analysis showed that the variant produced a truncated protein with altered cellular localization and a dysfunctional interaction with SKP1 (S-phase kinase-associated protein 1). Further population screening identified four BCORL1 missense variants in subjects with both OAT (1 of 325, 0.31%) and NOA (4 of 355, 1.13%), but no pathogenic BCORL1 variants among 362 fertile subjects. In conclusion, our findings indicate that BCORL1 is a potential candidate gene in the pathogenesis of OAT and NOA, expanded its disease spectrum and suggested that BCORL1 may play a role in spermatogenesis by interacting with SKP1.

中文翻译：

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BCORL1 的半合子功能丧失变异与男性不育和少弱精子症相关

少弱精子症（OAT）是一种常见的男性不育症。然而，其遗传原因仍然很大程度上未知。 OAT 的一些遗传决定因素是影响精子发生的基因缺陷。 BCORL1（BCL6 辅阻遏物样 1）是一种转录辅阻遏物，在敲除小鼠模型中表现出 OAT 表型。据报道，一名患有非梗阻性无精症 (NOA) 的不育男性患者存在BCORL1的半合子错义变异(c.2615T > G:p.Val872Gly)。然而， BCORL1变异与人类 OAT之间的相关性仍不清楚。在本研究中，我们使用全外显子组测序在一名来自汉族家庭的 OAT 男性患者中鉴定出BCORL1的新型半合子无义变异体 (c.1564G > T:p.Glu522*)。功能分析表明，该变体产生了一种截短的蛋白质，其细胞定位发生了改变，并且与 SKP1（S 期激酶相关蛋白 1）的相互作用出现功能障碍。进一步的人群筛查在同时患有 OAT（325 名受试者中的 1 名，0.31%）和 NOA（355 名受试者中的 4 名，1.13%）的受试者中发现了 4 个BCORL1错义变异，但在 362 名生育受试者中没有发现致病性BCORL1变异。总之，我们的研究结果表明，BCORL1是 OAT 和 NOA 发病机制中的潜在候选基因，扩大了其疾病谱，并表明 BCORL1 可能通过与 SKP1 相互作用在精子发生中发挥作用。