Functional evidence implicating NOTCH2 missense mutations in primary ovarian insufficiency etiology

Primary ovarian insufficiency (POI) is a frequently occurring disease affecting women under 40 years old. Recently, we have analyzed unrelated POI women via whole exome sequencing (WES) and identified NOTCH2 mutations underlying possible functional effects. The present study involved reanalyzing of WES assays. We used in the KGN granulosa-like cell model, a synthetic gene reporter construct driving luciferase gene expression to assess the functional effects of five NOTCH2 mutations identified in POI patients. We found that NOTCH2-p.Ser1804Leu, p.Ala2316Val, and p.Pro2359Ala mutations had a functional impact on the protein's transcriptional activity. The results have demonstrated for the first time that NOTCH2 mutations contribute to POI etiology. We therefore recommend sequencing NOTCH2's open reading frame in large panels of POI patients to establish an accurate genotype–phenotype correlation. We cannot rule out the fact that patients affected by Alagille syndrome carrying NOTCH2 mutations may suffer ovarian dysfunction. © 2018 Wiley Periodicals, Inc.

• Fecha de publicación: 2019
• Institución: Universidad del Rosario
• Repositorio: Repositorio EdocUR - U. Rosario
• Idioma: eng
• OAI Identifier: oai:repository.urosario.edu.co:10336/24228
• Acceso en línea: https://doi.org/10.1002/humu.23667; https://repository.urosario.edu.co/handle/10336/24228
• Palabra clave: Luciferase; Notch2 receptor; Notch2 receptor; Article; Female; Gene expression; Genotype phenotype correlation; Human; Missense mutation; Open reading frame; Premature ovarian failure; Priority journal; Whole exome sequencing; Amino acid sequence; Chemistry; Genetic predisposition; Genetic transcription; Genetics; Missense mutation; Premature ovarian failure; Amino acid sequence; Female; Genetic predisposition to disease; Humans; Primary ovarian insufficiency; Female infertility; Notch2 mutations; Primary ovarian insufficiency; Whole-exome sequencing; human; notch2; missense; genetic; Notch2 protein; Mutation; Receptor; Transcription
• License: Abierto (Texto Completo)