FOSL2 truncating variants in the last exon cause a neurodevelopmental disorder with scalp and enamel defects - Archive ouverte HAL Access content directly
Journal Articles Genetics in Medicine Year : 2022

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

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Blanca Gener
  • Function : Author
Carole Brewer
  • Function : Author
Wayne Wing Keung Lam
  • Function : Author
Pablo Lapunzina
  • Function : Author

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 by RT-PCR. 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 mRNAs escaped nonsensemediated mRNA decay. Truncated FOSL2 interact 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.
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Dates and versions

hal-03954791 , version 1 (24-01-2023)

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Auriane Cospain, Ana Rivera-Barahona, Erwan Dumontet, Blanca Gener, Isabelle Bailleul-Forestier, et al.. FOSL2 truncating variants in the last exon cause a neurodevelopmental disorder with scalp and enamel defects. Genetics in Medicine, 2022, 24 (12), pp.2475-2486. ⟨10.1016/j.gim.2022.09.002⟩. ⟨hal-03954791⟩
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