Human MLH1/3 variants causing aneuploidy, pregnancy loss, and premature reproductive aging.
Nat Commun
; 12(1): 5005, 2021 08 18.
Article
em En
| MEDLINE
| ID: mdl-34408140
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Aborto Espontâneo
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Perda do Embrião
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Proteínas MutL
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Proteína 1 Homóloga a MutL
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Aneuploidia
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
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Male
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Pregnancy
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article