Kanazawa University finds that autism-causing protein is involved in male infertility — CHD8-deficient mice do not produce sperm

A joint research group of Professor Masaaki Nishiyama of the Institute for Frontier Science Initiative at Kanazawa University, Graduate Student Kenta Nitahara of the Graduate School of Medical Sciences at Kanazawa University, Professor Satoshi Namekawa of the University of California, Davis in the USA, and Professor Kiyoko Kato of the Graduate School of Medical Sciences at Kyushu University discovered that CHD8, one of the causative proteins of autism spectrum disorder (autism), is involved in male infertility. CHD8 participates in the onset of the distinct diseases of autism and infertility through a common mechanism of histone methylation modification. The results are expected to lead to clarification of the mechanism and development of treatments for both diseases. The results were published in the international academic journal Nucleic Acids Research.

Autism is a developmental disorder characterized by impaired social interaction, limited interests, and obsessions. The gene mutation analysis of patients with autism revealed that CHD8, a chromatin modeling factor, has the highest mutation rate in this disease. Recently, there have been several reports that the pregnancy rate of patients with autism is low, but the relationship with infertility was not well understood. The research group analyzed the expression of CHD8 in different organs in the body and found that CHD8 is strongly expressed in the testes as well as the brain.

When mice were genetically engineered to lack CHD8 in their germ cells and the testes were examined, they found that they were substantially smaller and that no sperm cells formed. Germ cells ultimately differentiate into sperm and undergo a special cell division known as meiosis unlike other cells. It was observed that, in CHD8-deficient germ cells, meiotic progression was stopped midway, eventually resulting in cell death. CHD8 deletion impairs DNA double-strand breakage that occurs early in meiosis.

Gene expression analysis revealed that CHD8 regulates the expression levels of genes important for meiosis. They found that PRDM9, a histone methylation-modifying enzyme required for DNA double-strand breakage during meiosis, is involved in the expression level to a significant extent. During early meiosis, the histone methylation by PRDM9 specifies the location where DNA double-strand breakage occurs.

Nishiyama stated, "Although autism is more common in males, we discovered that an abnormality in the protein that causes autism also causes male infertility through a common mechanism. Our research results are expected to lead to the treatment of not only male infertility but also autism."

Journal Information
Publication: Nucleic Acids Research
Title: Chromatin remodeler CHD8 is required for spermatogonial proliferation and early meiotic progression
DOI: 10.1093/nar/gkad1256