Genotype-specific differences in infertile men due to loss-of-function variants in M1AP or ZZS genes

Area of Science:

• Genetics
• Reproductive Biology
• Molecular Biology

Background:

• Male infertility is a significant concern, with genetic factors playing a crucial role.
• Meiotic recombination is essential for proper chromosome segregation during sperm production.
• M1AP and ZZS proteins are implicated in DNA crossover formation during meiosis in mice.

Purpose of the Study:

• To investigate the role of M1AP and ZZS proteins in human male infertility.
• To determine if loss-of-function variants in M1AP and ZZS genes cause infertility due to recombination failure.
• To characterize the specific meiotic defects associated with M1AP or ZZS deficiency.

Main Methods:

• Screening for biallelic/hemizygous loss-of-function (LoF) variants in M1AP and ZZS genes in infertile men (N=24).
• In-depth characterization of testicular phenotypes in men with identified LoF variants.
• Analysis of meiotic progression and recombination intermediates.

Main Results:

• ZZS deficiency led to early meiotic arrest, incorrect homologous chromosome synapsis, and unrepaired DNA double-strand breaks.
• M1AP deficiency resulted in a predominant metaphase I arrest with reduced recombination intermediates and class I crossovers.
• Medically assisted reproduction enabled a healthy birth for a man with M1AP LoF variants.

Conclusions:

• M1AP and ZZS proteins are crucial for successful meiotic recombination in humans.
• Deficiencies in these proteins lead to distinct patterns of meiotic failure and male infertility.
• M1AP is an important, though non-essential, enhancer of meiotic recombination, and fatherhood is possible via assisted reproduction.