Loss-of-Function Mutations in CEP78 May Cause Male Infertility

Loss-of-Function Mutations in CEP78 May Cause Male Infertility

Centrosomal protein dysfunction might cause ciliopathies — an emerging class of genetic multisystemic human disorders that are caused by a multitude of largely unrelated genes that affect ciliary structure/function.

At least 35 different ciliopathies collectively affect nearly all organ systems, with prevalent phenotypes including polycystic kidney disease, retinal degeneration, obesity, skeletal malformations and brain anomalies. There are more than 180 known ciliopathy-associated proteins, and over 240 established ciliary proteins that represent candidate ciliopathy proteins.

While the role of centrosomal proteins in male infertility remains inadequately defined, a recent study identified a pathogenic splicing mutation in CEP78 in male infertile patients with severely reduced sperm number and motility, and the typical multiple morphological abnormalities of the sperm flagella phenotype.

Male infertility, which affects approximately 20 to 70 percent of couples facing infertility, is mainly attributed to a decreased sperm count (azoospermia or oligozoospermia), attenuated sperm motility (asthenozoospermia), or a greater proportion of morphologically abnormal sperm (teratozoospermia).

What is CEP78?

CEP78 is a centriole wall protein that localizes to mature centrioles and is involved in regulating centrosome duplication. It is generally expressed in ciliated organisms, suggesting that it might be involved in cilia biogenesis and/or function in several organisms.

In a recent study, researchers identified the previously unreported homozygous splicing mutation c.1069+1G>A in CEP78 in an infertile family through whole-exome sequencing (WES). The patients presented a characteristic MMAF phenotype, including coiled, bent, irregular, short, or/and absent flagella and defects in sperm flagellar ultrastructure.

They further generated Cep78 knockout (KO) mice, and the phenotype of Cep78 KO male mice resembled the infertile phenotype of the patients, showing marked defects in sperm count, morphology, and motility. Functionally, the data showed that CEP78 promotes the expression of the deubiquitinating enzyme ubiquitin specific peptidase 16 (USP16), which stabilizes Tektin expression via the ubiquitination pathway.

In addition to the infertile phenotype, researchers observed inadequate function of the retina and outer hair cells of the cochlea (OHCs) in Cep78 KO mice, as CEP78 mutations have indicated CRDHL syndrome in humans. Together, they revealed CEP78 as a causative gene of male infertility in both humans and mice, providing unexplored insights into the roles of centrosomal proteins in reproductive biology.

Identification of a CEP78 for Male Infertility

A 28-year-old man from a family who was diagnosed with 7 years of primary infertility was recruited for a study. The somatic cell karyotype, bilateral testicular size, secondary sex characteristics, and hormone levels were normal. A semen analysis of this patient revealed an extremely reduced sperm count and motility as well as an abnormal sperm morphology. In addition to the proband, two other male individuals in the family were affected, his brother and great uncle, who had never conceived during their marriages or while engaging in unprotected sexual intercourse.

Noticeably, the patient indicated that he also suffered from hearing and vision defects, and his great uncle and great aunt had experienced similar problems. CEP78 was suggested to be the potential genetic cause of oligoasthenoteratospermia and hearing and vision defects afflicting this patient. These observations suggested that the loss-of-function mutations of CEP78 are also associated with oligoasthenoteratospermia and subsequently cause male infertility.

CEP78 is essential for spermatogenesis and its loss might lead to impairments in the centriole development of germ cells, causing male infertility related to aberrant sperm morphology and a diminished sperm count, as well as the disorganization of sperm ultrastructure.

Although findings from human and mouse experiments unveiled a pivotal role for CEP78 in male reproduction, the frequency of CEP78 variants in a sporadic male sterile population remains unclear. Findings explain the potential mechanisms by which CEP78 regulates sperm formation and provide additional insights for future research on the functions of CEP78 in spermatogenesis.

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