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Functional evidence implicating NOTCH2 missense mutations in primary ovarian insufficiency etiology
Author(s) -
Patiño Liliana C.,
Beau Isabelle,
Morel Adrien,
Delemer Brigitte,
Young Jacques,
Binart Nadine,
Laissue Paul
Publication year - 2019
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23667
Subject(s) - biology , missense mutation , mutation , genetics , phenotype , notch signaling pathway , exome sequencing , gene , cancer research , bioinformatics
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.