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.

Anti-ACTL7a antibodies: a cause of infertility

“…In the immunized testes there were numerous abnormalities within the seminiferous tubules, such as spermatid expulsion, absence of germ cells, pyknotic cells, and Sertoli cells only (data not shown). Similar to the location of ACTL7a, the ZPBP (zona pellucida binding protein) is located within the acrosome of mouse spermatids and spermatozoa (26)(27)(28). A noteworthy finding was that immunization with ACTL7a caused a decrease in the transcription of the zpbp gene in mouse testis (Fig.…”

“…In actively immunized male mice there was a delay in the development of the acrosome, and numerous abnormalities in the germ cells of the seminiferous tubules were observed. The inhibition of acrosome development caused animal sterility (28)(29)(30)(31)(32)(33)(34)(35), and a reduction in the sugar residues on the acrosome surface caused infertility in these animals (36).…”

The control of male fertility by spermatid-specific factors: searching for contraceptive targets from spermatozoon’s head to tail

“…Among them, deletions and/or mutations in SPATA16 , 36, 37 PICK1 , 38 DPY19L2 , 39 ZPBP1 40 and DNAH1 41 have been identified in globozoospermia patients. The involvement of the human orthologues of the other above-mentioned mouse genes in human globozoospermia requires further investigation.…”

Genetic variants in the ETV5 gene in fertile and infertile men with nonobstructive azoospermia associated with Sertoli cell–only syndrome

“…Known genetic causes of male infertility comprise defects ranging from chromosomal anomalies to monogenic mutations. A range of numeric and structural chromosomal defects are found in $7% of azoospermic and oligozoospermic men, most often Klinefelter syndrome (47,XXY) and microdeletions of the long arm of the Y chromosome, whereas monogenic causes of human infertility are rarely described but include mutations in the cystic fibrosis transmembrane conductance receptor, several genes associated with axoneme function and primary ciliary dyskinesia, aurora kinase C, phospholipase C zeta, and zona pellucida binding protein 1 (3)(4)(5)(6). Several other genetic variations have been proposed as risk factors for male infertility (7)(8)(9)(10).…”