Meiotic Chromosome Structure, the Synaptonemal Complex, and Infertility

In meiosis, homologous chromosome synapsis is mediated by a supramolecular protein structure, the synaptonemal complex (SC), that assembles between homologous chromosome axes. The mammalian SC comprises at least eight largely coiled-coil proteins that interact and self-assemble to generate a long, zipper-like structure that holds homologous chromosomes in close proximity and promotes the formation of genetic crossovers and accurate meiotic chromosome segregation. In recent years, numerous mutations in human SC genes have been associated with different types of male and female infertility. Here, we integrate structural information on the human SC with mouse and human genetics to describe the molecular mechanisms by which SC mutations can result in human infertility. We outline certain themes in which different SC proteins are susceptible to different types of disease mutation and how genetic variants with seemingly minor effects on SC proteins may act as dominant-negative mutations in which the heterozygous state is pathogenic.

Automated summary

In meiosis, the synaptonemal complex (SC) plays a crucial role in facilitating the synapsis of homologous chromosomes. Mutations in SC genes have been linked to male and female infertility in humans. This article integrates structural information and genetics to explain how SC mutations can lead to human infertility, highlighting different susceptibility of SC proteins to disease mutations and the pathogenic effects of seemingly minor genetic variants.