Mise en évidence et caractérisation de nouveaux gènes impliqués dans les ciliopathies rénales

Abstract : The primary cilium is a sensory antenna present on the surface of most of the cells. It controls key signaling pathways during development and tissue homeostasis. Defects in cilia growth or activity are responsible for complex genetic diseases called ciliopathies. Nephronophthisis (NPH) is a ciliopathy characterized by chronic tubulointerstitial nephritis which usually progresses to end-stage renal disease (ESRD) before adulthood. NPH may be isolated or associated with extra-renal defects such as retinitis pigmentosa and skeleton involvement. The combination of these symptoms defines syndromes such as Saldino-Mainzer (MZSDS). NPH is an autosomal recessive disorder highly genetically heterogeneous and almost all of proteins encoded by the identified genes have been involved in ciliary function. The exome sequencing in patients, targeting up to 1300 ciliary genes (ciliome), highlighted new mutations in 2 NPH candidate genes: CEP83 and TEKT1. My work was to characterize the effects of the mutations and validate their involvement in patient phenotypes. CEP83 was found mutated in several unrelated patients with early-onset of NPH (IRT<5 years). CEP83 is a component of distal appendages on the mother centriole which play a crucial role in the early steps of cilia formation. I have shown that the identified mutations perturbed the distal appendages formation which might explain the defects in ciliogenesis observed in fibroblasts and kidney biopsies from patients. These results have demonstrated the involvement of a new centriolar protein in the pathophysiology of NPH severe forms. TEKT1 presents compound heterozygous mutations in a patient with a complex phenotype combining a MZSDS and primary ciliary dyskinesia (PCD) due to defects in motile cilia. The genetic analysis showed mutations in a second gene, WDR19, already characterized in NPH associated with bone defects. TEKT1 encodes the Tektin-1 protein, an uncharacterized member of the tektin family involved in motile cilia. The nasal multiciliated cells analysis showed that Tektin-1 was localized along the axoneme of control motile cilia and absent from the cilia in patient cells, which also had severe beating impairment. In parallel, defects in ciliogenesis, typical of WDR19 mutations, were observed in the fibroblasts from the patient. These results suggest that this dual ciliary phenotype is rather due to the additional effect of mutations in both TEKT1 and WDR19, responsible for the defects in motile and primary cilia, respectively.
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Marion Failler. Mise en évidence et caractérisation de nouveaux gènes impliqués dans les ciliopathies rénales. Biologie cellulaire. Université Sorbonne Paris Cité, 2015. Français. ⟨NNT : 2015USPCB023⟩. ⟨tel-01374870⟩

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