Novel biallelic CFAP43 mutations induce MMAF with mitochondrial abnormalities and successful ICSI outcomes

Area of Science:

• Genetics
• Reproductive Biology
• Cell Biology

Background:

• Multiple morphological abnormalities of the sperm flagellum (MMAF) is a rare genetic cause of primary male infertility.
• Genetic variants in cilia- and flagella-associated protein 43 (CFAP43) are linked to asthenoteratospermia and MMAF, but pathogenic mechanisms require further elucidation.

Purpose of the Study:

• To identify and characterize novel mutations in CFAP43 associated with MMAF.
• To investigate the underlying pathogenic mechanisms of CFAP43 mutations in male infertility.
• To explore the link between CFAP43 dysfunction, mitochondrial integrity, and infertility.

Main Methods:

• Whole-exome sequencing (WES) to identify genetic variants.
• Sanger sequencing for mutation confirmation and cosegregation analysis.
• Sperm analysis to assess morphological abnormalities, RNA splicing, mitochondrial sheath integrity, and protein expression (TOM20).

Main Results:

• Identified compound heterozygous mutations (c.1859_1860+8delinsGT and c.3071A>G) in CFAP43 in a patient with MMAF.
• Confirmed mutations cause aberrant RNA splicing and lead to disturbance/deletion of the mitochondrial sheath.
• Observed reduced expression of translocase of outer mitochondrial membrane 20 (TOM20), suggesting mitochondrial dysfunction.

Conclusions:

• Loss of CFAP43 function contributes to male infertility through impaired sperm flagellar structure and mitochondrial dysfunction.
• The findings expand the spectrum of pathogenic CFAP43 mutations and their associated phenotypes.
• Successful assisted reproductive technology (ART) using intracytoplasmic sperm injection (ICSI) offers a viable option for affected individuals, informing genetic counseling and personalized reproductive strategies.