PDF(Pubmed)
Abstract：
OBJECTIVE: The protein interacting with C kinase 1 (PICK1) plays a critical role in vesicle trafficking, and its deficiency in sperm cells results in abnormal vesicle trafficking from Golgi to acrosome, which eventually disrupts acrosome formation and leads to male infertility.
METHODS: An azoospermia sample was filtered, and the laboratory detection and clinical phenotype indicated typical azoospermia in the patient. We sequenced all of the exons in the PICK1 gene and found that there was a novel homozygous variant in the PICK1 gene, c.364delA (p.Lys122SerfsX8), and this protein structure truncating variant seriously affected the biological function. Then we constructed a PICK1 knockout mouse model using clustered regularly interspaced short palindromic repeat cutting technology (CRISPRc).
RESULTS: The sperm from PICK1 knockout mice showed acrosome and nucleus abnormalities, as well as dysfunctional mitochondrial sheath formation. Both the total sperm and motility sperm counts were decreased in the PICK1 knockout mice compared to wild-type mice. Moreover, the mitochondrial dysfunction was verified in the mice. These defects in the male PICK1 knockout mice may have eventually led to complete infertility.
CONCLUSIONS: The c.364delA novel variant in the PICK1 gene associated with clinical infertility, and pathogenic variants in the PICK1 may cause azoospermia or asthenospermia by impairing mitochondrial function in both mice and humans.
METHODS: An azoospermia sample was filtered, and the laboratory detection and clinical phenotype indicated typical azoospermia in the patient. We sequenced all of the exons in the PICK1 gene and found that there was a novel homozygous variant in the PICK1 gene, c.364delA (p.Lys122SerfsX8), and this protein structure truncating variant seriously affected the biological function. Then we constructed a PICK1 knockout mouse model using clustered regularly interspaced short palindromic repeat cutting technology (CRISPRc).
RESULTS: The sperm from PICK1 knockout mice showed acrosome and nucleus abnormalities, as well as dysfunctional mitochondrial sheath formation. Both the total sperm and motility sperm counts were decreased in the PICK1 knockout mice compared to wild-type mice. Moreover, the mitochondrial dysfunction was verified in the mice. These defects in the male PICK1 knockout mice may have eventually led to complete infertility.
CONCLUSIONS: The c.364delA novel variant in the PICK1 gene associated with clinical infertility, and pathogenic variants in the PICK1 may cause azoospermia or asthenospermia by impairing mitochondrial function in both mice and humans.
摘要：
目的：与C激酶1相互作用的蛋白（PICK1）在囊泡运输中起关键作用，它在精子细胞中的缺乏导致从高尔基体到顶体的异常囊泡运输，最终破坏顶体形成并导致男性不育。
方法：过滤无精子症样本，实验室检测和临床表型提示患者典型的无精子症。我们对PICK1基因的所有外显子进行了测序，发现PICK1基因中存在一个新的纯合变体，c.364delA（p。Lys122SerfsX8),这种蛋白质结构截短变异体严重影响了其生物学功能。然后，我们使用成簇的规则间隔短回文重复切割技术（CRISPRc）构建了PICK1敲除小鼠模型。
结果：PICK1基因敲除小鼠精子显示顶体和细胞核异常，以及功能失调的线粒体鞘形成。与野生型小鼠相比，PICK1敲除小鼠的总精子和运动性精子计数均降低。此外，在小鼠中证实了线粒体功能障碍。雄性PICK1基因敲除小鼠的这些缺陷可能最终导致完全不育。
结论：PICK1基因的c.364delA新变异与临床不孕症相关，PICK1中的致病变体可能通过损害小鼠和人类的线粒体功能而导致无精子症或弱精子症。
方法：过滤无精子症样本，实验室检测和临床表型提示患者典型的无精子症。我们对PICK1基因的所有外显子进行了测序，发现PICK1基因中存在一个新的纯合变体，c.364delA（p。Lys122SerfsX8),这种蛋白质结构截短变异体严重影响了其生物学功能。然后，我们使用成簇的规则间隔短回文重复切割技术（CRISPRc）构建了PICK1敲除小鼠模型。
结果：PICK1基因敲除小鼠精子显示顶体和细胞核异常，以及功能失调的线粒体鞘形成。与野生型小鼠相比，PICK1敲除小鼠的总精子和运动性精子计数均降低。此外，在小鼠中证实了线粒体功能障碍。雄性PICK1基因敲除小鼠的这些缺陷可能最终导致完全不育。
结论：PICK1基因的c.364delA新变异与临床不孕症相关，PICK1中的致病变体可能通过损害小鼠和人类的线粒体功能而导致无精子症或弱精子症。
