Sichuan University Huaxi Second Hospital: CEP78 Loss of Function Mutation Leads to male infertility in humans and mice

The World Health Organization (WHO) has recognized infertility as a global health problem, and the negative effects of infertility have affected both developed and developing countries
.
Male infertility is mainly attributed to a decrease in sperm count, decreased sperm motility (weak spermatosis), or an increase in the proportion of morphologically abnormal sperm (abnormal spermatospermia).

Although male infertility is multifactorial, including genitourinary infections, immune or hormonal abnormalities, and genetic disorders, it has a strong genetic basis that needs to be elucidated
.

A centrosome is a subcellular organelle in which two centrogranules play a key role
in various cellular processes such as cell division, movement, and ciliary formation.
Central granules are essential
for reproductive biology.
First, the formation of a complete sperm structure including sperm flagella and head-tail coupling devices requires a central granulele
.
Secondly, during fertilization, the centromere constitutes the main microtubule structural center, which facilitates the movement and fusion of the prokaryotes of both male and female; When replication and separation are completed, the centrogranular tissue of the sperm forms the poles of the mitotic spindle required for division
.
The molecular composition of centromere is complex and consists
of hundreds of proteins called centrogranulins.
It is speculated that the functional defect of centroclain is related to male infertility, but the results of relevant studies are limited
.
Functional deletion variants of centromyelobin CEP135 and CEP112 lead to various morphological abnormalities such as morphological abnormalities (MMAF) and headless sperm phenotypes in humans, respectively.
Cep55, Spata6, Cep131, Cep164, Cetn1, and Spatc1l are thought to be associated with infertility in
mice.
To date, only TSGA10 and CEP128 have been shown to be associated
with male infertility in humans and mice.

Researchers at the West China Second Hospital of Sichuan University discovered the previously unreported CEP78 homozygous splicing mutation c.
1069+1G>A
in an infertile family through whole exome sequencing (WES).
Patients exhibit a typical MMAF phenotype, including curly, curled, irregular, short or/and without flagella and spermatoflagellar ultrastructural defects
.
CEP78 is a centromere protein that is localized to mature centromeres and participates in regulating center-grain replication
.
CEP78 is typically expressed in ciliary organisms, suggesting that CEP78 may be involved in ciliary biogenesis and/or function in a variety of organisms
.
Biallele inactivation variants in CEP78 in humans are associated
with cone rod dystrophy with delayed hearing loss (CRDHL) syndrome due to degenerative degeneration of retinal pyramidal photoreceptors inherited from autosomal recessive inheritance.

The researchers further constructed Cep78 knockout (KO) mice, in which male mice exhibited oligospermia phenotypes and infertility, similar phenotypes to the patient's infertility phenotype, showing significant deficiencies
in sperm count, morphology, and motility.
In addition to the infertility phenotype, they also observed defects in the function of the retina and cochlear extraterry hair cells (OHCs) in Cep78 KO mice, and Cep78 mutations are known to cause CRDHL syndrome in
humans.
Functionally, the authors found that CEP78 promotes the expression of the deubiquitinating enzyme ubiquitin-specific peptidase 16 (USP16), which stabilizes the expression
of Tektin through the ubiquitination pathway.
Studies have shown the potential role of the CEP78 gene in human male infertility (and male infertility in mice), and the CEP78 deletion mutation can lead to CRDHL syndrome with male infertility, which the authors call CRDHLMI syndrome, which provides new insights into
the role of chrysotropin in reproductive biology.

However, the article also mentions that in the 14 reported families with CRDHL syndrome, the lineage shows that 3 male patients have offspring, and the mechanism of which needs to be confirmed
by further studies.