A comprehensive gene mutation screen in men with asthenozoospermia.

Objective: To find novel genetic causes of asthenozoospermia by comprehensively screening known candidate genes derived from mouse models.

Design: Case-control study.

Setting: A fertility center based in an academic hospital.

Patient(s): Thirty men with isolated asthenozoospermia.

Intervention(s): Screening nine candidate genes for mutations: ADCY10, AKAP4, CATSPER1, CATSPER2, CATSPER3, CATSPER4, GAPDHS, PLA2G6, and SLC9A10. To account for a possible effect of heterozygous mutations, assessing imprinting of all candidate genes by studying the expression pattern of heterozygous SNPs in testis biopsies of five unrelated men.

Main Outcome Measure(s): Mutations found in patients only.

Result(s): We identified 10 heterozygous asthenozoospermia-specific mutations in ADYC10 (n = 2), AKAP4 (n =1), CATSPER1 (n = 1), CATSPER2 (n = 1), CATSPER3 (n = 1), CATSPER4 (n = 3), and PLA2G6 (n = 1). These mutations were distributed over six patients. In silico analysis showed that 8 of the 10 mutations either had a negative BLOSUM score, were located in conserved residues, and/or were located in a functional domain. Expression analysis demonstrated that CATSPER1 and CATSPER4 are imprinted.

Conclusion(s): Given their putative effect on protein structure, their location in conserved sequences or functional domains, and their absence in controls, the identified mutations may be a cause of asthenozoospermia in humans.