Mutations in CCIN cause teratozoospermia and male infertility
Mutations in CCIN cause teratozoospermia and male infertility
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CCIN突变导致畸形精子症和男性不育
DOI：
10.1016/j.scib.2022.09.026
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发表时间：
2022-10-29
期刊：
影响因子：
18.9
通讯作者：
Lei, Ming
中科院分区：
文献类型：
--
作者：
Fan, Yong;Huang, Chenhui;Lei, Ming
畸形精子症通常与精子发生缺陷有关，并且是一种具有相当大遗传异质性的疾病。尽管之前的研究已经确定了几种与畸形精子症相关的基因，但大多数受影响男性的病因仍然未知。在这里，我们在患有畸形精子症的患者中鉴定出 CCIN 的纯合错义突变和复合杂合突变。 CCIN编码细胞骨架蛋白Calicin，参与哺乳动物精子花萼高度规则组织的形成和维持，并被认为在精子发生过程中的精子头部结构重塑中发挥作用。我们对从所有三名携带有害 CCIN 突变体的男性中获得的精子进行形态学和超微结构分析，结果显示严重的头部畸形。进一步的免疫荧光测定表明，精子中的钙素水平显着降低。这些患者表型在表达疾病相关变异的小鼠模型中成功重现，证实了 Calicin 在男性生育力中的作用。值得注意的是，所有来自小鼠和人类患者的突变精子都无法粘附在透明带团块上，这可能是 CCIN 突变精子源性不孕的主要原因。最后，使用胞浆内单精子注射（ICSI）成功地使突变小鼠和两对携带CCIN变异的夫妇生育了健康的后代。总而言之，我们的研究结果确定了 Calicin 在精子头部成形和男性生育能力中的作用，为遗传咨询和辅助生殖治疗提供了重要指导。 (c) 2022 年科学中国出版社。由 Elsevier B.V. 和中国科学出版社出版。
Teratozoospermia is usually associated with defective spermiogenesis and is a disorder with considerable genetic heterogeneity. Although previous studies have identified several teratozoospermia-associated genes, the etiology remains unknown for a majority of affected men. Here, we identified a homozygous missense mutation and a compound heterozygous mutation of CCIN in patients suffering from teratozoospermia. CCIN encodes the cytoskeletal protein Calicin that is involved in the formation and maintenance of the highly regular organization of the calyx of mammalian spermatozoa, and has been proposed to play a role in sperm head structure remodeling during the process of spermiogenesis. Our morphological and ultrastructural analyses of the spermatozoa obtained from all three men harboring deleterious CCIN mutants reveal severe head malformation. Further immunofluorescence assays unveil markedly reduced levels of Calicin in spermatozoa. These patient phenotypes are successfully recapitulated in mouse models expressing the disease-associated variants, confirming the role of Calicin in male fertility. Notably, all mutant spermatozoa from mice and human patients fail to adhere to the zona mass, which likely is the major mechanistic reason for CCIN-mutant sperm-derived infertility. Finally, the use of intracytoplasmic sperm injections (ICSI) successfully makes mutated mice and two couples with CCIN variants have healthy offspring. Taken together, our findings identify the role of Calicin in sperm head shaping and male fertility, providing important guidance for genetic counseling and assisted reproduction treatments. (c) 2022 Science China Press. Published by Elsevier B.V. and Science China Press.