Biallelic mutations in CFAP54 cause male infertility with severe MMAF and NOA

Area of Science:

• Genetics
• Reproductive Biology
• Human Molecular Genetics

Background:

• Spermatogenic impairments, including multiple morphological abnormalities of the sperm flagella (MMAF) and non-obstructive azoospermia (NOA), are significant causes of male infertility.
• Genetic factors are increasingly recognized as crucial contributors to impaired spermatogenesis.

Purpose of the Study:

• To investigate the genetic underpinnings of severe MMAF and NOA in a cohort of Han Chinese males.
• To identify specific gene variants associated with these infertility conditions.

Main Methods:

• Whole-exome sequencing was performed on 334 Han Chinese probands diagnosed with severe MMAF or NOA.
• Identified variants were analyzed for their novelty and predicted pathogenicity using bioinformatic tools.
• Sperm morphology, concentration, motility, and ultrastructure were assessed in affected individuals.
• Immunofluorescence assays were used to evaluate the expression of flagellar assembly-associated proteins.

Main Results:

• Biallelic variants in the CFAP54 gene were identified in three unrelated men with MMAF or NOA.
• The identified CFAP54 mutations were novel, absent in public databases, and predicted to be damaging.
• Men with CFAP54 mutations displayed abnormal sperm characteristics and ultrastructural defects.
• Reduced expression of key flagellar assembly proteins (IFT20, IFT52, IFT122, SPEF2) was observed in CFAP54-deficient spermatozoa.
• Successful clinical pregnancies were achieved using sperm from these men following intracytoplasmic sperm injection.

Conclusions:

• Biallelic deleterious mutations in CFAP54 are a cause of severe MMAF and NOA in humans.
• CFAP54 mutations disrupt sperm flagellar structure and function, leading to male infertility.
• Sperm from CFAP54 mutation carriers can be used for assisted reproductive technologies, such as intracytoplasmic sperm injection, to achieve pregnancy.