Zhou Zhou1, Xiaoyan Mao2, Biaobang Chen3, Jian Mu1, Wenjing Wang1, Bin Li2, Zheng Yan2, Jie Dong1, Qiaoli Li1, Yanping Kuang2, Lei Wang1,4, Ling Wu5, Qing Sang6. 1. Institute of Pediatrics, Children's Hospital of Fudan University, the Institutes of Biomedical Sciences, and the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China. 2. Reproductive Medicine Center, Shanghai Ninth Hospital, Shanghai Jiao Tong University, Shanghai, 200011, China. 3. NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, Shanghai, 200032, China. 4. Shanghai Center for Women and Children's Health, Shanghai, 200062, China. 5. Reproductive Medicine Center, Shanghai Ninth Hospital, Shanghai Jiao Tong University, Shanghai, 200011, China. wuling9hospital@126.com. 6. Institute of Pediatrics, Children's Hospital of Fudan University, the Institutes of Biomedical Sciences, and the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China. sangqing@fudan.edu.cn.
Abstract
PURPOSE: To identify the genetic factors responsible for asthenozoospermia, which is a major cause of male infertility characterized by immotile and malformed spermatozoa. METHODS: Whole-exome sequencing was performed in two brothers from a family with asthenozoospermia to identify pathogenic variants. The functional effect of the identified variant was investigated in HEK293T cells using a minigene assay. RESULTS: We identified a novel homozygous splicing variant c.6311-2A>G in DNAH8 from two affected brothers belonging to the same consanguineous family. The splicing variant altered a consensus splice acceptor site of DNAH8 intron 44, which led to the deletion of exon 45 and resulted in a frameshift and a predicted truncated protein (p.G2104Efs*19). Although most spermatozoa from the patients presented with reduced sperm motility, intracytoplasmic sperm injection was able to overcome the inability of the spermatozoa to reach the ovum and thus produce a healthy child for the proband. CONCLUSIONS: This finding expands the mutational spectrum of DNAH8, making it a potential genetic diagnostic marker for those suffering from primary male infertility.
PURPOSE: To identify the genetic factors responsible for asthenozoospermia, which is a major cause of male infertility characterized by immotile and malformed spermatozoa. METHODS: Whole-exome sequencing was performed in two brothers from a family with asthenozoospermia to identify pathogenic variants. The functional effect of the identified variant was investigated in HEK293T cells using a minigene assay. RESULTS: We identified a novel homozygous splicing variant c.6311-2A>G in DNAH8 from two affected brothers belonging to the same consanguineous family. The splicing variant altered a consensus splice acceptor site of DNAH8 intron 44, which led to the deletion of exon 45 and resulted in a frameshift and a predicted truncated protein (p.G2104Efs*19). Although most spermatozoa from the patients presented with reduced sperm motility, intracytoplasmic sperm injection was able to overcome the inability of the spermatozoa to reach the ovum and thus produce a healthy child for the proband. CONCLUSIONS: This finding expands the mutational spectrum of DNAH8, making it a potential genetic diagnostic marker for those suffering from primary male infertility.
Entities:
Keywords:
Asthenozoospermia; DNAH8; Male infertility; Variant
Authors: Christopher M Watson; Laura A Crinnion; Joanne E Morgan; Sally M Harrison; Christine P Diggle; Julian Adlard; Helen A Lindsay; Nick Camm; Ruth Charlton; Eamonn Sheridan; David T Bonthron; Graham R Taylor; Ian M Carr Journal: Hum Mutat Date: 2014-04 Impact factor: 4.878