ZAR1 pathogenic variants disrupt maternal mRNA storage and cause oocyte maturation defects in humans

Zygote arrest 1 (Zar1) was one of the earliest identified maternal-effect genes that function during the maternal-to-zygotic transition (MZT) in mice. However, the role of human ZAR1 remains unclear. In this study, we investigated the association of ZAR1 gene variants with infertility in women, focusing on their impact on oocyte maturation and early embryonic development. Using whole-exome sequencing, we identified homozygous and compound heterozygous ZAR1 variants in two independent families with female patients diagnosed with primary infertility owing to oocyte maturation and early embryonic arrest. Functional analysis revealed that the V118A variant disrupted the localization of ZAR1 to the mitochondria-associated ribonucleoprotein domain (MARDO) structure, which is a key mRNA storage site in oocytes. The R397Q and S121* mutations impaired ZAR1’s RNA-binding capability, indirectly affecting its subcellular localization and the integrity of MARDO. These variants disrupted MARDO formation and function, leading to defective oocyte maturation and early embryonic development. This study highlights the critical roles of ZAR1 and MARDO in human reproduction and provides insights into the molecular mechanisms underlying some forms of female infertility.