Truncating mutations in TAF4B and ZMYND15 causing recessive azoospermia

Area of Science:

• Genetics
• Reproductive Biology

Background:

• Azoospermia, affecting 1% of men, is the absence of sperm in semen, with unknown genetic causes for most idiopathic cases.
• Two unrelated consanguineous families with idiopathic azoospermia were studied, involving multiple affected brothers.

Purpose of the Study:

• To identify the genetic basis of idiopathic azoospermia in two consanguineous families.
• To investigate novel genes associated with male infertility and spermatogenic failure.

Main Methods:

• Linkage mapping using single nucleotide polymorphism (SNP) genome scans to identify candidate disease loci.
• Exome sequencing to pinpoint specific genetic variants within identified loci.

Main Results:

• Homozygous mutations p.R611X in TAF4B were found in family 1, and p.K507Sfs*3 in ZMYND15 in family 2.
• Neither mutation was detected in a control cohort of 45 azoospermic and 15 oligozoospermic men.
• ZMYND15 exhibited highest expression in the testis, suggesting a role in spermatogenesis.

Conclusions:

• TAF4B and ZMYND15 are the first identified genes for recessive idiopathic spermatogenic failure in humans.
• These genes are known to play roles in mouse spermatogenesis but were previously unstudied in humans.
• Recessive genes may account for a small fraction of human azoospermia cases, similar to findings in mice.