Novel biallelic variants in DNAH1 cause multiple morphological abnormalities of sperm flagella with favorable outcomes of fertility after ICSI in Han Chinese males

作者全名："Long, Shunhua; Fu, Longlong; Ma, Jing; Yu, Haibing; Tang, Xiangrong; Hu, Tingwenyi; Han, Wei; Liu, Weiwei; Liao, Haiyuan; Fu, Tao; Huang, Guoning; Lu, Wenhong; Lin, Tingting"

作者地址："[Long, Shunhua; Ma, Jing; Yu, Haibing; Tang, Xiangrong; Hu, Tingwenyi; Han, Wei; Liu, Weiwei; Liao, Haiyuan; Fu, Tao; Huang, Guoning; Lin, Tingting] Chongqing Med Univ, Women & Childrens Hosp, Ctr Reprod Med, Chongqing Key Lab Human Embryo Engn, Chongqing 400010, Peoples R China; [Long, Shunhua; Ma, Jing; Yu, Haibing; Tang, Xiangrong; Hu, Tingwenyi; Han, Wei; Liu, Weiwei; Liao, Haiyuan; Fu, Tao; Huang, Guoning; Lin, Tingting] Chongqing Hlth Ctr Women & Children, Chongqing Clin Res Ctr Reprod Med, Chongqing, Peoples R China; [Fu, Longlong; Lu, Wenhong] Natl Res Inst Family Planning, Natl Hlth Commiss Key Lab Male Reprod Hlth, Beijing 100081, 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, Chongqing 400010, Peoples R China.; Lu, WH (通讯作者)，Natl Res Inst Family Planning, Natl Hlth Commiss Key Lab Male Reprod Hlth, Beijing 100081, Peoples R China."

来源：ANDROLOGY

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001011540800001

JCR分区：Q1

影响因子：3.2

年份：2023

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：asthenoteratozoospermia; DNAH1; intracytoplasmic sperm injection; MMAF

摘要："BackgroundMultiple morphological abnormalities of sperm flagella is an idiopathic asthenoteratozoospermia characterized by absent, short, coiled, angulation, and irregular-caliber flagella. Genetic variants of DNAH1 gene have been identified as a causative factor of multiple morphological abnormalities of sperm flagella and intracytoplasmic sperm injection is an available strategy for infertile males with dynein axonemal heavy chain 1 defects to conceive. ObjectivesTo identify novel variants and candidate mutant hotspots of DNAH1 gene related to multiple morphological abnormalities of sperm flagella and male infertility in humans. Materials and methodsThe DNAH1 variants were identified by whole exome sequencing and confirmed with Sanger sequencing. Papanicolaou staining, scanning and transmission electron microscopy, and immunostaining were performed to investigate the morphological and ultrastructural characteristics of spermatozoa. Intracytoplasmic sperm injection was applied for the assisted reproductive therapy of males harboring biallelic DNAH1 variants. ResultsWe identified 18 different DNAH1 variants in 11 unrelated families, including nine missense variants (p.A2564T, p.T3657R, p.G1862R, p.L2296P, p.T4041I, p.L611P, p.A913D, p.R1932Q, p.R2356W) and nine loss-of-function variants (c.2301-1G>T, p.Q1518*, p.R1702*, p.D2845Mfs*2, p.P3909Rfs*33, p.Q4040Dfs*33, p.Q4058*, p.E4060Pfs*61, p.V4071Cfs*54). A total of 66.7% (12/18) of the identified variants were novel. Morphological analysis based on Papanicolaou staining and scanning electron microscopy demonstrated the typical multiple morphological abnormalities of sperm flagella characteristics of dynein axonemal heavy chain 1-deficient spermatozoa. Immunostaining further revealed the absence of inner dynein arms but not outer dynein arms, which induced a general ultrastructural disorganization, such as the loss of central pair and mis-localization of the microtubule doublets and outer dense fibers. To date, seven affected couples have accepted the intracytoplasmic sperm injection treatment, and three of them have given birth to five healthy babies. Discussion and conclusionThese findings further expand the variant spectrum of DNAH1 gene related to multiple morphological abnormalities of sperm flagella and male infertility in humans, thus providing new information for the molecular diagnosis of asthenoteratozoospermia. The favorable fertility outcomes of intracytoplasmic sperm injection will facilitate the genetic counseling and clinical treatment of infertile males with multiple morphological abnormalities of sperm flagella in the future."

基金机构："Chongqing Medical Scientific Research Project [2023MSXM008, 2023MSXM054]; Open Project Fund from National Health Commission Key Laboratory of Male Reproductive Health/National Research Institute for Family Planning [2022GJP0101]"

基金资助正文："Chongqing Medical Scientific Research Project, Grant/Award Numbers: 2023MSXM008, 2023MSXM054; Open Project Fund from National Health Commission Key Laboratory of Male Reproductive Health/National Research Institute for Family Planning, Grant/Award Number: 2022GJP0101"