The piRNA-pathway factor FKBP6 is essential for spermatogenesis but dispensable for control of meiotic LINE-1 expression in humans.
The piRNA-pathway factor FKBP6 is essential for spermatogenesis but dispensable for control of meiotic LINE-1 expression in humans.
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DOI：
10.1016/j.ajhg.2022.09.002
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发表时间：
2022-10-06
影响因子：
9.8
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中科院分区：
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大约7%的男性患有不育症，可能是由于严重的精子生成障碍(SPGF)，导致射精中没有精子或精子很少。我们最初在一名严重少精子症患者中发现了FKBP6基因的一个纯合子移码突变。随后，我们对2699名患有SPGF的男性进行了筛查，并在另外5名患者中检测到FKBP6罕见的双等位基因功能缺失变异。所有六个人的射精中都没有精子或精子极少，这不适合医学辅助生殖。对睾丸组织的评估显示，圆形精子细胞处于停滞阶段。RT-qPCR和免疫荧光染色证实FKBP6在睾丸中表达缺失。在小鼠中，Fkbp6是精子发生所必需的，并被描述为参与piRNA的生物发生和联会复合体(SC)的形成。我们没有在正常人精母细胞中检测到FKBP6作为SC的一部分，但小RNA测序表明FKBP6的缺失严重影响了piRNA的水平，支持了FKBP6在人类piRNA生物发生中的作用。与在piRNA途径的小鼠模型中的发现相反，我们没有检测到携带致病FKBP6变异的男性患者LINE-1表达的增加。根据我们的发现，根据Clingen标准，FKBP6达到了与男性不育相关的“强有力的”证据水平，使其直接适用于临床诊断。这将通过提供因果诊断来改善患者护理，并有助于预测手术取精成功的机会。FKBP6双等位基因功能丧失变异导致圆形精子细胞停滞导致男性不育。这种piRNA因子的缺失导致粗线期piRNAs的减少，这可能会从减数分裂中期开始扰乱piRNA介导的生殖细胞翻译调控。与许多piRNA因子小鼠模型相比，没有观察到Line-1的过度表达。
Infertility affects around 7% of the male population and can be due to severe spermatogenic failure (SPGF), resulting in no or very few sperm in the ejaculate. We initially identified a homozygous frameshift variant in FKBP6 in a man with extreme oligozoospermia. Subsequently, we screened a total of 2,699 men with SPGF and detected rare bi-allelic loss-of-function variants in FKBP6 in five additional persons. All six individuals had no or extremely few sperm in the ejaculate, which were not suitable for medically assisted reproduction. Evaluation of testicular tissue revealed an arrest at the stage of round spermatids. Lack of FKBP6 expression in the testis was confirmed by RT-qPCR and immunofluorescence staining. In mice, Fkbp6 is essential for spermatogenesis and has been described as being involved in piRNA biogenesis and formation of the synaptonemal complex (SC). We did not detect FKBP6 as part of the SC in normal human spermatocytes, but small RNA sequencing revealed that loss of FKBP6 severely impacted piRNA levels, supporting a role for FKBP6 in piRNA biogenesis in humans. In contrast to findings in piRNA-pathway mouse models, we did not detect an increase in LINE-1 expression in men with pathogenic FKBP6 variants. Based on our findings, FKBP6 reaches a “strong” level of evidence for being associated with male infertility according to the ClinGen criteria, making it directly applicable for clinical diagnostics. This will improve patient care by providing a causal diagnosis and will help to predict chances for successful surgical sperm retrieval. Bi-allelic loss-of-function variants in FKBP6 cause human male infertility due to round spermatid arrest. Absence of this piRNA factor leads to a reduction of pachytene piRNAs, which likely disrupts piRNA-mediated translational regulation in germ cells from mid-meiosis on. In contrast to many piRNA-factor mouse models, LINE-1 overexpression is not observed.
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影响因子：
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作者：
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MacArthur, Daniel G