title: Association of mutations in the zona pellucida binding protein 1 (ZPBP1) gene with abnormal sperm head morphology in infertile men.
abstract: Nearly 7% of men are afflicted by male infertility worldwide, and genetic factors are suspected to play a significant role in the majority of these patients. Although sperm morphology is an important parameter measured in the semen analysis, only a few genetic causes of teratozoospermia are currently known. The objective of this study was to define the association between alterations in the genes encoding the Golgi-associated PDZ- and coiled-coil motif containing protein (GOPC), the protein interacting with C kinase 1 (PICK1) and the acrosomal protein zona pellucida binding protein 1 (ZPBP1/sp38) with abnormal sperm head morphology in infertile men. Previous reports demonstrated that mice lacking Gopc, Pick1 and Zpbp1 are infertile due to abnormal head morphology. Herein, using our validated RNA-based method, we studied spermatozoal cDNA encoding the human GOPC, PICK1 and ZPBP1 genes in 381 teratozoospermic and 240 controls patients via direct sequencing. Among these genes, we identified missense and splicing mutations in the sperm cDNA encoding ZPBP1 in 3.9% (15/381) of men with abnormal sperm head morphology. These mutations were not observed in 240 matched controls and the dbSNP database (χ(2) = 9.3, P = 0.002). In contrast, statistically significant and functionally relevant mutations were not discovered in the GOPC and PICK1 genes. In our study ZPBP1 mutations are associated with abnormal sperm head morphology, defined according to strict criteria, resembling the mouse Zpbp1 null phenotype. We hypothesize that missense mutations exert a dominant-negative effect due to altered ZPBP1 protein folding and protein:protein interactions in the acrosome.
authors.affiliation: Departments of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Yatsenko
authors.forename: Derek S
authors.initials: DS
authors.lastname: O'Neil
authors.forename: Angshumoy
authors.initials: A
authors.lastname: Roy
authors.forename: Paola A
authors.initials: PA
authors.lastname: Arias-Mendoza
authors.forename: Ruihong
authors.initials: R
authors.lastname: Chen
authors.forename: Lata J
authors.initials: LJ
authors.lastname: Murthy
authors.forename: Dolores J
authors.initials: DJ
authors.lastname: Lamb
authors.forename: Martin M
authors.initials: MM
authors.lastname: Matzuk
mesh_terms: D000177:Acrosome / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D004527:Egg Proteins / Q000235:genetics / Q000378:metabolism*; D000077614:Golgi Matrix Proteins; D006801:Humans; D007248:Infertility, Male / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D013077:Sperm Head / Q000473:pathology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004527:Egg Proteins; C434484:GOPC protein, human; D000077614:Golgi Matrix Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D009687:Nuclear Proteins; C498297:PICk1 protein, human; C572207:ZPBP1 protein, human