Mutation in TDRD9 causes non-obstructive azoospermia in infertile men

Area of Science:

• Genetics
• Reproductive Biology
• Male Infertility

Background:

• Azoospermia, the absence of sperm in ejaculate, affects 1% of men and 10-20% of infertile males.
• Non-obstructive azoospermia (NOA) results from spermatogenic failure, often with unknown genetic causes.
• Maturation arrest is a severe form of NOA with limited treatment options.

Purpose of the Study:

• To investigate the genetic cause of maturation arrest in infertile males from a consanguineous family.
• To identify the specific gene and mutation responsible for this form of non-obstructive azoospermia.

Main Methods:

• Whole genome genotyping and exome sequencing were employed to identify genetic variations.
• A 4-base pair deletion frameshift mutation in the TDRD9 gene was identified.
• Immunofluorescent staining was used to analyze TDRD9 protein expression in testicular biopsies.

Main Results:

• A homozygous 4-bp deletion frameshift mutation in TDRD9 was identified as the cause of maturation arrest.
• The mutation leads to frameshift and exon skipping, affecting TDRD9 protein function.
• TDRD9 protein was present in testicular biopsies of affected individuals, indicating intracellular distribution.

Conclusions:

• This study reports the first recessive deleterious mutation in human TDRD9 associated with male infertility.
• The findings suggest TDRD9's role in DNA stability within the male germline, potentially via retrotransposon silencing.
• Understanding TDRD9's function is crucial for addressing male infertility and maintaining germline integrity.