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

• DOI: 10.1016/j.gim.2022.09.002
• Publication Date: 2022-10-05T00:07:11Z
• Authors: Auriane Cospain; Ana Rivera-Barahona; Erwan Dumontet; Blanca Gener; Isabelle Bailleul...; Isabelle Meyts; Guillaume Jouret; Bertrand Isidor; Carole Brewer; Wim Wuyts; Leen Moens; Selket Delafontaine; Wayne Wing Keung Lam; Kris Van Den Bogaert; Anneleen Boogaerts; Emmanuel Scalais; Thomas Besnard; Benjamin Cogne; Christophe Guissard; Paul Rollier; Wilfrid Carre; Regis Bouvet; Karin Tarte; Ricardo Gómez-Car...; Pablo Lapunzina; Sylvie Odent; Marie Faoucher; Christele Dubourg; Víctor L. Ruiz-Pérez; Koen Devriendt; Laurent Pasquier; Luis A. Pérez-Jurado
• Keywords: 0301 basic medicine; 570; Enamel hypoplasia; FOSL2 FRA-2 aplasia cutis congenita of scalp enamel hypoplasia AP-1 complex Adams-Oliver syndrome; Autism Spectrum Disorder; Messenger; Fos-Related Antigen-2/genetics; MESH: Fos-Related Antigen-2; FOSL2; Fos-Related Antigen-2; *Autism Spectrum Disorder/genetics; qGenomics Laboratories; MESH: Scalp; *Neurodevelopmental Disorders/genetics; 03 medical and health sciences; Adams-Oliver syndrome; Ectodermal Dysplasia; Exons/genetics; AP-1 complex; Humans; Aplasia cutis congenita of scalp; RNA, Messenger; FRA-2; MESH: Neurodevelopmental Disorders; MESH: RNA, Messenger; enamel hypoplasia; MESH: Autism Spectrum Disorder; MESH: Humans; MESH: Ectodermal Dysplasia; Scalp; *Ectodermal Dysplasia/genetics; Exons; MESH: Transcription Factor AP-1; Transcription Factor AP-1; aplasia cutis congenita of scalp; HEK293 Cells; [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics; Neurodevelopmental Disorders; MESH: HEK293 Cells; RNA; Scalp/abnormalities/metabolism; Human medicine; MESH: Exons; Transcription Factor AP-1/genetics

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.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.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.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.