Deletion of ACTRT1 is associated with male infertility as sperm acrosomal ultrastructural defects and fertilization failure in human

作者全名："Zhang, Qi; Jin, Huijuan; Long, Shunhua; Tang, Xiangrong; Li, Jiaxun; Liu, Weiwei; Han, Wei; Liao, Haiyuan; Fu, Tao; Huang, Guoning; Chen, Suren; Lin, Tingting"

作者地址："[Zhang, Qi; Long, Shunhua; Tang, Xiangrong; Li, Jiaxun; Liu, Weiwei; Han, Wei; Liao, Haiyuan; Fu, Tao; Huang, Guoning; Lin, Tingting] Chongqing Med Univ, Women & Childrens Hosp, Ctr Reprod Med, Chongqing Key Lab Human Embryo Engn, 64 Jintang St, Chongqing 400010, Peoples R China; [Zhang, Qi; Long, Shunhua; Tang, Xiangrong; Li, Jiaxun; Liu, Weiwei; Han, Wei; Liao, Haiyuan; Fu, Tao; Huang, Guoning; Lin, Tingting] Chongqing Clin Res Ctr Reprod Med, Chongqing Hlth Ctr Women & Children, Chongqing, Peoples R China; [Jin, Huijuan; Chen, Suren] Beijing Normal Univ, Coll Life Sci, Key Lab Cell Proliferat & Regulat Biol, Minist Educ, Beijing, Peoples R China; [Chen, Suren] Beijing Normal Univ, Coll Life Sci, Dept Biol, 19 Xinjiekouwai St, Beijing 100875, Peoples R China"

通信作者："Huang, GN; Lin, TT (通讯作者)，Chongqing Med Univ, Women & Childrens Hosp, Ctr Reprod Med, Chongqing Key Lab Human Embryo Engn, 64 Jintang St, Chongqing 400010, Peoples R China.; Chen, SR (通讯作者)，Beijing Normal Univ, Coll Life Sci, Dept Biol, 19 Xinjiekouwai St, Beijing 100875, Peoples R China."

来源：HUMAN REPRODUCTION

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001175654500001

JCR分区：Q1

影响因子：6

年份：2024

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：male infertility; ACTRT1 deletion; actin-related protein T1; acrosomal detachment; sperm head deformations; fertilization failure

摘要："STUDY QUESTION Could actin-related protein T1 (ACTRT1) deficiency be a potential pathogenic factor of human male infertility?SUMMARY ANSWER A 110-kb microdeletion of the X chromosome, only including the ACTRT1 gene, was identified as responsible for infertility in two Chinese males with sperm showing acrosomal ultrastructural defects and fertilization failure.WHAT IS KNOWN ALREADY The actin-related proteins (e.g. ACTRT1, ACTRT2, ACTL7A, and ACTL9) interact with each other to form a multimeric complex in the subacrosomal region of spermatids, which is crucial for the acrosome-nucleus junction. Actrt1-knockout (KO) mice are severely subfertile owing to malformed sperm heads with detached acrosomes and partial fertilization failure. There are currently no reports on the association between ACTRT1 deletion and male infertility in humans.STUDY DESIGN, SIZE, DURATION We recruited a cohort of 120 infertile males with sperm head deformations at a large tertiary hospital from August 2019 to August 2023. Genomic DNA extracted from the affected individuals underwent whole exome sequencing (WES), and in silico analyses were performed to identify genetic variants. Morphological analysis, functional assays, and ART were performed in 2022 and 2023.PARTICIPANTS/MATERIALS, SETTING, METHODS The ACTRT1 deficiency was identified by WES and confirmed by whole genome sequencing, PCR, and quantitative PCR. Genomic DNA of all family members was collected to define the hereditary mode. Papanicolaou staining and electronic microscopy were performed to reveal sperm morphological changes. Western blotting and immunostaining were performed to explore the pathological mechanism of ACTRT1 deficiency. ICSI combined with artificial oocyte activation (AOA) was applied for one proband.MAIN RESULTS AND THE ROLE OF CHANCE We identified a whole-gene deletion variant of ACTRT1 in two infertile males, which was inherited from their mothers, respectively. The probands exhibited sperm head deformations owing to acrosomal detachment, which is consistent with our previous observations on Actrt1-KO mice. Decreased expression and ectopic distribution of ACTL7A and phospholipase C zeta were observed in sperm samples from the probands. ICSI combined with AOA effectively solved the fertilization problem in Actrt1-KO mice and in one of the two probands.LIMITATIONS, REASONS FOR CAUTION Additional cases are needed to further confirm the genetic contribution of ACTRT1 variants to male infertility.WIDER IMPLICATIONS OF THE FINDINGS Our results reveal a gene-disease relation between the ACTRT1 deletion described here and human male infertility owing to acrosomal detachment and fertilization failure. This report also describes a good reproductive outcome of ART with ICSI-AOA for a proband.STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the Chongqing medical scientific research project (Joint project of Chongqing Health Commission and Science and Technology Bureau, 2023MSXM008 and 2023MSXM054). There are no competing interests to declare.TRIAL REGISTRATION NUMBER N/A."

基金机构："Chongqing Medical Scientific Research Project (Joint project of Chongqing Health Commission and Science and Technology Bureau) [2023MSXM008, 2023MSXM054]"

基金资助正文："Chongqing Medical Scientific Research Project (Joint project of Chongqing Health Commission and Science and Technology Bureau, 2023MSXM008 and 2023MSXM054)."