Biallelic mutations of CFAP251 cause sperm flagellar defects and human male infertility

Area of Science:

• Human Reproduction
• Genetics
• Sperm Biology

Background:

• Multiple Morphological Abnormalities of Flagella (MMAF) is a disorder impacting sperm development, leading to male infertility.
• Known genetic factors explain only about half of MMAF cases, indicating a need for further genetic discovery.
• Sperm flagella are crucial for male reproductive function, and their abnormal development is a significant cause of infertility.

Purpose of the Study:

• To identify novel genetic causes of MMAF in Han Chinese men.
• To investigate the role of CFAP251 in sperm flagellar development and function.
• To understand the genetic basis of male infertility associated with flagellar abnormalities.

Main Methods:

• Whole-exome sequencing was performed on 65 Han Chinese men diagnosed with MMAF.
• Genetic analysis focused on identifying mutations in cilia- and flagella-associated protein 251 (CFAP251).
• Functional assays, including gene expression and immunofluorescence staining, were conducted on samples from a CFAP251-deficient individual.

Main Results:

• Biallelic, loss-of-function mutations in CFAP251 were identified in 5% of the studied MMAF patients.
• These CFAP251 mutations are extremely rare in the general population.
• Functional studies confirmed CFAP251's involvement in sperm flagellar development and function.

Conclusions:

• CFAP251 is a newly identified gene associated with sperm flagellar development.
• Mutations in CFAP251 represent a significant cause of MMAF and male infertility.
• This discovery expands the genetic understanding of human male reproductive disorders.