• PMID: 28536242
• Gene Name: TDRD9
• Condition: Non-obstructive azoospermia, cryptozoospermia, Male infertility
• Association: Associated
• Mutation: c.720_723 del TAGT causing p.Ser241Pro fs Ter 4
• Population size: 238
• Population details: 238 (5 cases, 233 controls)
• Sex: Male
• Infertility type: Male infertility
• Associated genes: NGS

Mutation in TDRD9 causes non-obstructive azoospermia in infertile men

Arafat M, Har-Vardi I, Harlev A, Levitas E, Zeadna A, Abofoul-Azab M, Dyomin V, Sheffield VC, Lunenfeld E, Huleihel M, Parvari R.

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. CI - © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted. FAU - Arafat, Maram AU - Arafat M AD - The Shraga Segal Department of Microbiology, Immunology & Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. AD - The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel. FAU - Har-Vardi, Iris AU - Har-Vardi I AD - Fertility and IVF Unit, Department of Obstetrics and Gynecology, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. FAU - Harlev, Avi AU - Harlev A AD - Fertility and IVF Unit, Department of Obstetrics and Gynecology, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. FAU - Levitas, Eliahu AU - Levitas E AD - Fertility and IVF Unit, Department of Obstetrics and Gynecology, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. AD - The Center of Advanced Research and Education in Reproduction (CARER), Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. FAU - Zeadna, Atif AU - Zeadna A AD - Fertility and IVF Unit, Department of Obstetrics and Gynecology, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. AD - The Center of Advanced Research and Education in Reproduction (CARER), Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. FAU - Abofoul-Azab, Maram AU - Abofoul-Azab M AD - The Shraga Segal Department of Microbiology, Immunology & Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. AD - The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel. AD - The Center of Advanced Research and Education in Reproduction (CARER), Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. FAU - Dyomin, Victor AU - Dyomin V AD - The Center of Advanced Research and Education in Reproduction (CARER), Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. AD - Institute of Pathology, Soroka University Medical Center, Beer-Sheva, Israel. FAU - Sheffield, Val C AU - Sheffield VC AD - Department of Pediatrics, Division of Medical Genetics, University of Iowa, Iowa City, USA. FAU - Lunenfeld, Eitan AU - Lunenfeld E AD - Fertility and IVF Unit, Department of Obstetrics and Gynecology, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. AD - The Center of Advanced Research and Education in Reproduction (CARER), Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. FAU - Huleihel, Mahmoud AU - Huleihel M AD - The Shraga Segal Department of Microbiology, Immunology & Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel. AD - The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel. AD - The Center of Advanced Research and Education in Reproduction (CARER), Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.