Science Advances: A rare mutation in the CEP78 gene is a new genetic cause of aberrant spermia

Our country is facing the dual pressures
of declining population growth and rising infertility rates.
In infertility, the male factor accounts for about half, and patients often manifest as oligospermia, weakness, aberration and unexplained infertility, covering azoospermia and oligospermia characterized by a decrease in sperm count, weak spermia with weakened sperm motility, and malformed spermatozoa
with abnormal sperm morphology.
A recent large cohort study showed that only about
4% of male infertility patients currently have a definite genetic diagnosis.

The flagella of the sperm are very similar
to the structural composition of the motor cilia.
Multiple morphological abnormalities of the sperm flagella (MMAF) refers to a serious type of weak spermatospermia that results in decreased or lost
sperm motility and fertilization due to malformations in the sperm flagella such as short tails, no tails, curly tails, folded tails, and irregular tails 。 The etiology of MMAF is closely related to gene mutations, and more than 20 genes such as DNAH1, CFAP43, CFAP44, CFAP65, CFAP47, CFAP58, QRICH2 and CEP128 have been reported to be MMAF-related genes
.
However, there are still many patients with MMAF whose genetic causes are unclear
.

On October 7, 2022, the Chen Suren Research Group of the School of Life Sciences of Beijing Normal University and the collaborators of the West China Second School of Sichuan University published a research paper
entitled Loss-of-function mutations in CEP78 cause male infertility in humans and mice online in the authoritative comprehensive journal Science Advances 。 In the study, the authors recruited a close relative to marry a family with several men examined for MMAF
.
Using Whole exon sequencing (WES), the researchers identified homozygous splicing mutations in the CEP78 gene (c.
1069+1G>A/c.
1069+1G>A) of the CEP78 gene (CED78) as likely the genetic cause
of the MMAF family 。 To reveal the physiological function of CEP78, the researchers constructed Cep78 gene knockout mice and reported for the first time that the deletion of CEP78 protein led to male infertility, and the knockout mouse sperm flagella showed a similar MMAF phenotype
such as short tail and capuchin tail that was consistent with the patient.
Second-generation test tubes, Intra-cytoplasmic sperm injection (ICSI), using the sperm of patients with CEP78 gene mutations, do not provide satisfactory pregnancy outcomes
.
Family members of the CEP78 gene mutation also showed varying degrees of visual and hearing impairment (both the cone rod and the hearing hair are sporty cilia
).
The study revealed that the CEP78 gene is the causative gene of human "Cone–rod dystrophy with hearing loss, CRDHL, OMIM# 617236)" and MMAF (OMIM# 617576), providing valuable information
for genetic diagnosis, genetic counseling and assisted reproductive treatment in patients with corresponding genetic diseases.

The research was funded
by funds such as the National Key Research and Development Program of the Ministry of Science and Technology.
Chen Suren of the Academy of Biological Sciences of Beijing Normal University and Shen Ying, Yang Yiyu and Wang Yan of the Second School of West China of Sichuan University are co-corresponding authors
of the paper.

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