Les voies Hedgehog et NF-κB au coeur de l'homéostasie cutanée : apport de la caractérisation génétique et physiopathologique de deux dysplasies ectodermiques liées à l'X, le syndrome de Bazex-Dupré-Christol et l'Incontinentia Pigmenti

Abstract : Genodermatoses are rare genetic diseases with cutaneous expression. Among them, ectodermal dysplasia (ED) characterized by abnormal development of at least two ectodermal structures (teeth, nails, sweat glands and hair) constitute a heterogeneous group of genodermatoses of more than 200 rare syndromes. While most of these syndromes associate only abnormalities of the ectodermal derivatives, others more complex, such as Bazex-Dupré-Christol syndrome and Incontinentia Pigmenti, bring together disparate manifestations. Bazex-Dupré-Christol syndrome (BDCS) associates ED with predisposition to early basal cell carcinoma (BCCs). The study of 6 families allowed us to identify, in 2 of them, a truncated mutation in the ACTRT1 gene, encoding the Arp-T1 protein. In the epidermis, Arp-T1 protein is decreased in all patients with BDCS, carrying or not of mutations in ACTRT1 gene. High-throughput sequencing of the candidate region allowed to identify mutations in transcribed enhancer regions, regulating the ACTRT1 gene in patients of the remaining 4 families. Noting that the Hedgehog pathway is deregulated in more than 70% of BCCs, we have demonstrated that ACTRT1 is a novel inhibitor of this pathway, via its binding to GLI1 promoter and inhibiting its expression. Finally, ACTRT1 is a new tumor suppressor gene capable of reducing in vivo the tumor progression of certain cancer lines by the regulation of genes involved in proliferation, death and cell survival, or migration. Incontinentia Pigmenti (IP) is a multisystemic disorder characterized by involvement of skin, teeth, eyes and sometimes the central nervous system. It results from mutation in the NEMO gene and the abolition of activation of NF-KB pathway. The study of a family concerned with IP allowed to identify a new splicing mutation of NEMO gene leading to a truncated protein expression. This protein retains all the functional domains of NEMO known. Its characterization revealed a loss of interaction with SHARPIN, components of LUBAC complex allowing linear ubiquitination. This is the first human mutation of NEMO showing the importance of its linear ubiquitination in the activation of the NF-KB pathway. Thus, my thesis work revealed novel physiopathological mechanisms responsible for two forms of ectodermal dysplasia. These mechanisms reflect the complexity of the molecular pathways involved in the development of the skin and the maintenance of its homeostasis during adult life.
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Élodie Bal. Les voies Hedgehog et NF-κB au coeur de l'homéostasie cutanée : apport de la caractérisation génétique et physiopathologique de deux dysplasies ectodermiques liées à l'X, le syndrome de Bazex-Dupré-Christol et l'Incontinentia Pigmenti. Génétique. Université Sorbonne Paris Cité, 2016. Français. ⟨NNT : 2016USPCB116⟩. ⟨tel-02180565v2⟩

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