Mutation in TDRD9 causes non-obstructive azoospermia in infertile men
Journal of medical genetics, 2017•jmg.bmj.com
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 …
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 …
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.
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