Genetic Basis of Male Infertility Due to Sperm Flagella Abnormalities

Male infertility attributable to defects in sperm flagella arises from mutations that disrupt the formation, structure or function of the axoneme and associated machinery. Central to flagellar motility is the 9+2 microtubule arrangement, driven by dynein arms and supported by radial spokes, nexin links and fibrous sheath components. Genetic variants in structural genes encoding dynein heavy and light chains, radial-spoke proteins and cofactors of tubulin folding impair assembly of functional flagella, causing asthenozoospermia or multiple morphological abnormalities of the sperm flagella (MMAF). Advances in next-generation sequencing have expanded the catalogue of causative genes, enabling molecular diagnosis and informing assisted-reproduction strategies such as intracytoplasmic sperm injection. Model organisms—from mice to unicellular parasites—have elucidated conserved roles of flagellar proteins, underscoring global research efforts to alleviate male infertility and improve reproductive health outcomes.

Research from Nature Portfolio

Recent studies have uncovered a germ-cell-specific regulator of tubulin folding essential for flagellar biogenesis. Deletion of a testis-expressed co-factor of the chaperonin CCT complex impairs assembly of the complex, downregulates tubulin subunits and yields sperm with malformed, immotile flagella. This work reveals how specialised chaperones ensure correct tubulin conformation during spermiogenesis.
Foundational work on co-conserved axonemal proteins has identified two coiled-coil domain proteins whose bi-allelic mutations underlie MMAF in humans. Mouse models and high-resolution microscopy in a flagellate parasite confirmed their localisation between specific microtubule doublets and demonstrated that loss of these proteins disrupts axonemal integrity and abolishes motility, establishing them as indispensable for functional sperm tails.

Genetic Basis of Male Infertility Due to Sperm Flagella Abnormalities publication trend

The graph below shows the total number of articles in genetic basis of male infertility due to sperm flagella abnormalities across all publications each year (not limited to Nature Index journals).

Technical terms

Axoneme: Core microtubule structure of a cilium or flagellum, arranged in a conserved 9+2 pattern that underpins motility.

MMAF (Multiple Morphological Abnormalities of the Flagella): A phenotype of heterogeneous sperm-tail defects—short, bent or absent flagella—leading to near-complete immotility.

Dynein arms (ODA/IDA): ATP-dependent motor complexes attached to axonemal microtubules that generate sliding forces for flagellar beating.

CCT complex: A molecular chaperone assembly that facilitates folding of cytoskeletal proteins, notably tubulins, during flagellogenesis.

Intraflagellar transport (IFT): Bidirectional trafficking of cargoes along axonemal microtubules, essential for assembly and maintenance of flagella.

Fibrous sheath: A cytoskeletal scaffold enveloping the axoneme in the principal piece of the sperm tail, crucial for elastic support and regulation of motility.

References

1. STYXL1 regulates CCT complex assembly and flagellar tubulin folding in sperm formation. Nature Communications (2024).
2. Mutations in CFAP43 and CFAP44 cause male infertility and flagellum defects in Trypanosoma and human. Nature Communications (2018).
3. CCDC189 affects sperm flagellum formation by interacting with CABCOCO1. National Science Review (2023).
4. DNALI1 deficiency causes male infertility with severe asthenozoospermia in humans and mice by disrupting the assembly of the flagellar inner dynein arms and fibrous sheath. Cell Death & Disease (2023).