Mutation Severity of FBXO43 Determines Spermatogenic Outcome and Informs Precision ART Strategies

Area of Science:

• Genetics
• Reproductive Biology
• Molecular Biology

Background:

• FBXO43 regulates meiotic cell cycle progression by inhibiting the anaphase-promoting complex/cyclosome (APC/C).
• The impact of distinct FBXO43 mutations on APC/C inhibition and resulting clinical phenotypes in male infertility is not well understood.

Purpose of the Study:

• To elucidate how different FBXO43 mutations lead to varied clinical phenotypes in male infertility.
• To investigate the preliminary molecular mechanisms underlying these divergent phenotypes.
• To provide evidence-based guidance for precision-assisted reproduction.

Main Methods:

• Whole-exome sequencing identified compound heterozygous FBXO43 variants in two infertile patients (macrozoospermia and nonobstructive azoospermia).
• Assessed sperm morphology, chromatin status, and aneuploidy; performed testicular biopsy for the azoospermia case.
• Evaluated in vitro functional consequences including protein stability, ubiquitination, and APC/C subunit interactions.

Main Results:

• Missense mutations in the macrozoospermia case allowed meiosis completion but caused sperm defects and high aneuploidy, leading to ICSI failure.
• Truncating mutations in the NOA case resulted in meiotic arrest and absence of mature sperm.
• All mutations decreased FBXO43 stability and disrupted binding to APC3, impairing APC/C inhibition in a mutation-severity-dependent manner.

Conclusions:

• FBXO43 mutations create a spectrum of infertility phenotypes, from meiotic arrest (truncating) to severe teratozoospermia with aneuploidy (missense).
• These findings emphasize FBXO43's role in male fertility and its relevance for reproductive counseling.
• Preimplantation genetic testing for aneuploidy (PGT-A) is recommended to improve assisted reproductive technology (ART) outcomes.