Human MLH1/3 variants causing aneuploidy, pregnancy loss, and premature reproductive aging

Priti Singh, Robert Fragoza, Cecilia S. Blengini, Tina N. Tran, Gianno Pannafino, Najla Al-Sweel, Kerry J. Schimenti, Karen Schindler, Eric A. Alani, Haiyuan Yu and John C. Schimenti ()
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Priti Singh: Cornell University College of Veterinary Medicine
Robert Fragoza: Cornell University
Cecilia S. Blengini: Rutgers University, Dept. of Genetics
Tina N. Tran: Cornell University College of Veterinary Medicine
Gianno Pannafino: Cornell University
Najla Al-Sweel: Cornell University
Kerry J. Schimenti: Cornell University College of Veterinary Medicine
Karen Schindler: Rutgers University, Dept. of Genetics
Eric A. Alani: Cornell University
Haiyuan Yu: Cornell University
John C. Schimenti: Cornell University College of Veterinary Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract Embryonic aneuploidy from mis-segregation of chromosomes during meiosis causes pregnancy loss. Proper disjunction of homologous chromosomes requires the mismatch repair (MMR) genes MLH1 and MLH3, essential in mice for fertility. Variants in these genes can increase colorectal cancer risk, yet the reproductive impacts are unclear. To determine if MLH1/3 single nucleotide polymorphisms (SNPs) in human populations could cause reproductive abnormalities, we use computational predictions, yeast two-hybrid assays, and MMR and recombination assays in yeast, selecting nine MLH1 and MLH3 variants to model in mice via genome editing. We identify seven alleles causing reproductive defects in mice including female subfertility and male infertility. Remarkably, in females these alleles cause age-dependent decreases in litter size and increased embryo resorption, likely a consequence of fewer chiasmata that increase univalents at meiotic metaphase I. Our data suggest that hypomorphic alleles of meiotic recombination genes can predispose females to increased incidence of pregnancy loss from gamete aneuploidy.

Date: 2021
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DOI: 10.1038/s41467-021-25028-1

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