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    FOSL2 truncating variants in the last exon cause a neurodevelopmental disorder with scalp and enamel defects

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    URI
    https://rde.dspace-express.com/handle/11287/622737
    Author
    Cospain, A.
    Rivera-Barahona, A.
    Dumontet, E.
    Gener, B.
    Bailleul-Forestier, I.
    Meyts, I.
    Jouret, G.
    Isidor, B.
    Brewer, C.
    Wuyts, W.
    Moens, L.
    Delafontaine, S.
    Keung Lam, W. W.
    Van Den Bogaert, K.
    Boogaerts, A.
    Scalais, E.
    Besnard, T.
    Cogne, B.
    Guissard, C.
    Rollier, P.
    Carre, W.
    Bouvet, R.
    Tarte, K.
    Gómez-Carmona, R.
    Lapunzina, P.
    Odent, S.
    Faoucher, M.
    Dubourg, C.
    Ruiz-Pérez, V. L.
    Devriendt, K.
    Pasquier, L.
    Pérez-Jurado, L. A.
    Date
    #VALUE!
    Journal
    Genetics in medicine
    Type
    Journal Article
    Publisher
    Nature
    DOI
    10.1016/j.gim.2022.09.002
    Rights
    Copyright © 2022 American College of Medical Genetics and Genomics. All rights reserved.
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    Abstract
    PURPOSE: We aimed to investigate the molecular basis of a novel recognizable neurodevelopmental syndrome with scalp and enamel anomalies caused by truncating variants in the last exon of the gene FOSL2, encoding a subunit of the AP-1 complex. METHODS: Exome sequencing was used to identify genetic variants in all cases, recruited through Matchmaker exchange. Gene expression in blood was analyzed using reverse transcription polymerase chain reaction. In vitro coimmunoprecipitation and proteasome inhibition assays in transfected HEK293 cells were performed to explore protein and AP-1 complex stability. RESULTS: We identified 11 individuals from 10 families with mostly de novo truncating FOSL2 variants sharing a strikingly similar phenotype characterized by prenatal growth retardation, localized cutis scalp aplasia with or without skull defects, neurodevelopmental delay with autism spectrum disorder, enamel hypoplasia, and congenital cataracts. Mutant FOSL2 messenger RNAs escaped nonsense-mediated messenger RNA decay. Truncated FOSL2 interacts with c-JUN, thus mutated AP-1 complexes could be formed. CONCLUSION: Truncating variants in the last exon of FOSL2 associate a distinct clinical phenotype by altering the regulatory degradation of the AP-1 complex. These findings reveal a new role for FOSL2 in human pathology.
    Citation
    Genet Med. 2022 Dec;24(12):2475-2486. doi: 10.1016/j.gim.2022.09.002. Epub 2022 Oct 4.
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