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Neuropathies Périphériques Génétiques et Surdité : Etude des Relations Génétiques et Mécanistiques

Abstract : Hereditary Peripheral Neuropathies (PN) are characterized by various phenotypes and great genetic heterogeneity. Charcot-Marie-Tooth disease (CMT) accounts for most sensori-motor peripheral neuropathies. Besides, other symptoms can be associated, such as deafness. No precise estimation of deafness within this population exist and its pathogenicity is uncertain. The aim of this PhD was to better understand the physiopathology of deafness in patients suffering from PN. Various complementary approaches were used; 1) a clinical approach on a French cohort of patients suffering from both PN and hearing loss and molecular genetic tests with NGS sequencing (PN, deafness panels, and/or exomes), 2) a biochemical approach on murine and human cochlear nerve samples and 3) a bioinformatic approach to identify protein hubs implicated in the onset of PN-associated deafness.This has enabled us to characterize the various phenotypes of patients suffering from both hereditary PN and deafness, and then notice that deafness can be endo-, retro- or endo- and retrocochlear. Thirty-six genes were reported to be associated with both PN and hearing impairment. Sixty percent of our patients were genotyped, highlighting seven novel pathogenic variants in five different genes. Our research also suggests that PMP22, the most frequent gene in CMT, is probably not or poorly implicated in deafness onset in PN patients. In two of our patients with PMP22 pathogenic variants, a second involved gene was found with COCH and MYH14 respectively. Genotype-phenotype correlations were found out with the ABHD12, SH3TC2, NEFL and PRPS1 genes. Secondly, the preliminary immunohistochemical study on wild-type rats auditory nerves highlighted the expression of pmp22, mpz, nefl and trpv4 on the cochlear nerve and tracked a different expression in CMTpmp22/+ rats. However, the study on humans was not conclusive. Recently, in silico research of pathways common to the different genes described to be involved in both PN and deafness, has found the direct link between PMP22 and MPZ. Indirect links between several other proteins have been tracked.This thesis also shows that hearing impairment is most probably under-diagnosed in this population of genetic PN sufferers. We suggest regular audiologic follow-up for PN patients and neurological assessment for deaf children.
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Justine Lerat. Neuropathies Périphériques Génétiques et Surdité : Etude des Relations Génétiques et Mécanistiques. Médecine humaine et pathologie. Université de Limoges, 2018. Français. ⟨NNT : 2018LIMO0055⟩. ⟨tel-03060393⟩

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