A homozygous RPL10L missense mutation associated with male factor infertility and severe oligozoospermia.

Objective: To identify the genetic cause of male factor infertility characterized by severe oligozoospermia.

Design: Genetic studies.

Setting: Medical university.

Patient(s): Two infertile brothers with severe oligozoospermia in a consanguineous Han Chinese family, 414 additional patients with oligo-/azoospermia, and 223 fertile (control) subjects.

Invention(s): None.

Main Outcome Measure(s): Genetic analyses using whole-exome and Sanger sequencing were performed for two brothers with severe oligozoospermia. The effects of an identified candidate causative mutation were investigated in silico and in vitro. Whole-exome sequencing screening for the candidate mutation was conducted in 414 patients with oligo-/azoospermia and 223 fertile subjects.

Result(s): A homozygous missense variant (NM_080746:c.A257C: p.H86P) in RPL10L was identified in the two affected brothers and shown to cosegregate with the severe oligozoospermia phenotype. The mutation was absent in public databases, including the 1000 Genomes Project and the Exome Aggregation Consortium. All queried databases predicted the mutation to be damaging, consistent with the fact that it decreased protein levels in vitro. Subsequent mutation screening identified three additional heterozygous RPL10L mutations in three of 414 subjects with oligo-/azoospermia, but no RPL10L mutations among 223 fertile subjects.

Conclusion(s): Our findings implicate RPL10L as a novel candidate gene in the pathogenesis of human male factor infertility and severe oligozoospermia.