Searching for candidate genes for male infertility

Aim: We describe an approach to search for candidate genes for male infertility using the two human genome databases: the public University of California at Santa Cruz (UCSC) and private Celera databases which list known and predicted gene sequences and provide related information such as gene function, tissue expression, known mutations and single nucleotide polymorphisms (SNPs). Methods and Results: To demonstrate this in silico research, the following male infertility candidate genes were selected: (1) human BOULE, mutations of which may lead to germ cell arrest at the primary spermatocyte stage, (2) mutations of casein kinase 2 alpha genes which may cause globozoospermia, (3) DMR-N9 which is possibly involved in the spermatogenic defect of myotonic dystrophy and (4) several testes expressed genes at or near the breakpoints of a balanced translocation associated with hypospermatogenesis. We indicate how information derived from the human genome databases can be used to confirm these candidate genes may be pathogenic by studying RNA expression in tissue arrays using in situ hybridization and gene sequencing. Conclusion: The paper explains the new approach to discovering genetic causes of male infertility using information about the human genome

Defective protein kinase A and C pathways are common causes of disordered zona pellucida (ZP)-induced acrosome reaction in normozoospermic infertile men with normal sperm-ZP binding

OBJECTIVE: To determine association between defective protein kinases C (PKC) and A (PKA) and disordered zona pellucida (ZP)-induced acrosome reaction (DZPIAR) in normozoospermic infertile men with normal sperm-ZP binding. DESIGN: Sperm from DZPIAR infertile men were treated without (control) or with (test) phorbol myristate acetate (PMA, PKC activator) or dibutyryl cyclic AMP (dbcAMP, PKA activator) under in vitro standard culture condition. The ZP-induced AR was assessed and compared between control and test. SETTING: Public and private hospital-based clinical assisted reproduction technology (ART) centers. PATIENT(S): A total of 51 DZPIAR infertile men were involved in this study. INTERVENTION(S): None. MAIN OUTCOMES MEASURE(S): Sperm-ZP binding and the ZP-induced IAR. RESULT(S): Both PMA and dbcAMP enhanced ZP-induced AR up to a normal level (≥25%) in some subjects with DZPIAR: 29 (57%) with PMA and 27 (53%) with dbcAMP. Overall 35 (69%) had the ZP-induced AR enhanced to normal by PMA or dbcAMP but 16 (31%) had little or no response to either agent. Fourteen men responded to the two activators differently: 8 effective only with PMA and 6 effective only with dbcAMP. CONCLUSION(S): Defective upstream of PKC and PKA pathways are highly associated with disordered ZPIAR in normozoospermic infertile men with normal sperm-ZP binding