Background Azoospermia is diagnosed when sperm cells are completely absent in the ejaculate even after centrifugation. It is identified in approximately 1% of all men and in 10%–20% of infertile males. Non-obstructive azoospermia (NOA) is characterised by the absence of sperm due to either a Sertoli cell-only pattern, maturation arrest, hypospermatogenesis or mixed patterns. NOA is a severe form of male infertility, with limited treatment options and low fertility success rates. In the majority of patients, the cause for NOA is not known and mutations in only a few genes were shown to be causative.
Aim We investigated the cause of maturation arrest in five azoospermic infertile men of a large consanguineous Bedouin family.
Methods and results Using whole genome genotyping and exome sequencing we identified a 4 bp deletion frameshift mutation in TDRD9 as the causative mutation with a Lod Score of 3.42. We demonstrate that the mutation results in a frameshift as well as exon skipping. Immunofluorescent staining with anti-TDRD9 antibody directed towards the N terminus demonstrated the presence of the protein in testicular biopsies of patients with an intracellular distribution comparable to a control biopsy. The mutation does not cause female infertility.
Conclusion This is the first report of a recessive deleterious mutation in TDRD9 in humans. The clinical phenotype recapitulates that observed in the Tdrd9 knockout mice where this gene was demonstrated to participate in long interspersed element-1 retrotransposon silencing. If this function is preserved in human, our data underscore the importance of maintaining DNA stability in the human male germ line.
- germ line DNA stability
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Contributors MA performed the genetic anayses.
IH-V was responsible of the semen and testicular tissue analyses, definition of the sperm defect and in vitro fertilisations.
AH participated in recruiting the patients and clinical data.
AZ participated in recruiting the patients and clinical data.
MA-A performed the immunostaining analyses on the patients ‘testicular biopsies’.
VD performed the pathohistological analyses.
VCS participated in designing the genetic study.
EL coordinated the clinical research and participated in recruiting the patients and clinical data.
MH was responsible for the histology and immunostaining analyses on the patients ‘testicular biopsies’.
RP designed the genetics analyses and coordinated the research.
Funding This study was partially supported by The Natural Science Foundation of China (NSFC) - Israel Science Foundation (ISF) (NSFC-ISF) (1183/14), (MH and EL). This work was partly supported by an internal grant from Ben-Gurion University of the Negev, Faculty of Health Sciences.
Competing interests None declared.
Ethics approval Soroka Medical Center Institutional Review Board.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement The manuscript presents a mutation in a gene not previously associated with human disease that causes male infertility. There is no additional unpublished data from the study that is available.