Novel frameshift mutation in STK33 is associated with asthenozoospermia and multiple morphological abnormalities of the flagella
Novel frameshift mutation in STK33 is associated with asthenozoospermia and multiple morphological abnormalities of the flagella
复制标题
STK33 中的新移码突变与弱精子症和鞭毛的多种形态异常相关
DOI：
10.1093/hmg/ddab165
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发表时间：
2021-06-21
影响因子：
3.5
通讯作者：
Shi, Qinghua
中科院分区：
文献类型：
--
作者：
Ma, Hui;Zhang, Beibei;Shi, Qinghua
丝氨酸/苏氨酸激酶（Serine/Threonine Kinases，KKKs）结构域蛋白在精子鞭毛和男性生育力中起重要作用。然而，这些蛋白质在人类生殖中的作用仍然知之甚少，其变体是否与人类弱精子症有关尚未报道。在这里，我们招募了一个巴基斯坦家庭，有四个不孕症患者诊断为特发性弱精子症，没有任何纤毛相关的症状。全外显子组测序鉴定了丝氨酸/苏氨酸激酶33（STK 33）中一个新的纯合移码突变（c.1235del，p.T412Kfs（*）14），该突变在人类睾丸中显示高度保守和优势表达。这种变异导致患者中STK 33信使RNA（mRNA）的急剧减少。STK 33变异纯合子患者精子活力降低，精子鞭毛频繁形态异常和鞭毛超微结构完全紊乱，这是典型的鞭毛（MMAF）表型的多种形态异常。总的来说，这些发现提供了证据，确立STK 33是一个MMAF相关基因，并为了解丝氨酸/苏氨酸激酶结构域蛋白在人类男性生殖中的作用提供了新的见解。
Serine/threonine kinases domain-containing proteins are known to play important functions in sperm flagella and male fertility. However, the roles of these proteins in human reproduction remain poorly understood and whether their variants are associated with human asthenozoospermia have not been reported. Here, we recruited a Pakistani family having four infertile patients diagnosed with idiopathic asthenozoospermia without any ciliary-related symptoms. Whole-exome sequencing identified a novel homozygous frameshift mutation (c.1235del, p.T412Kfs(*)14) in serine/threonine kinase 33 (STK33), which displays a highly conserved and predominant expression in testis in humans. This variant led to a dramatic reduction of STK33 messenger RNA (mRNA) in the patients. Patients homozygous for the STK33 variant presented reduced sperm motility, frequent morphological abnormalities of sperm flagella and completely disorganized flagellar ultrastructures, which are typical for multiple morphological abnormalities of the flagella (MMAF) phenotypes. Overall, these findings present evidence establishing that STK33 is an MMAF-related gene and provide new insights for understanding the role of serine/threonine kinases domain-containing proteins in human male reproduction.