Caracterización de las bases moleculares de neuropatías hereditarias sensitivo-motoras

Abstract

[EN] Inherited peripheral neuropathies comprise a large group of related diseases primarily affecting the peripheral nervous system. They include the hereditary motor neuropathies (HMN), the hereditary sensory neuropathies (HSN) and the hereditary motor and sensory neuropathies (HMSN) or Charcot-Marie-Tooth (CMT) disease. CMT affects approximately one in 2500 people and is characterized by a wide genetic heterogeneity: more than 40 are associated with this group of neuropathies. The aim of this work is to identify the molecular bases of the patients with CMT/HMN belonging to the families fCMT-424 and fCMT-411, using Whole Exome Sequencing (WES). To achieve this, we filtered the obtained data, searching for candidate genes that could cause the CMT/HMN phenotypes. In family fCMT-424, we identified the p.N88S mutation in the BSCL2 gene. This mutation has been previously described as a pathological change. In family fCMT-411, we detected the novel p.Q434H variant in the MFSD1 gene. We further performed a search for the MFSD1 p.Q434H mutation in families that remain without genetic diagnosis and we did not identify other CMT patients who carry this mutation. To gain an insight into the pathogenicity of this change, we carried out a study of silencing and overexpression of the MFSD1 gene in Drosophila melanogaster. The findings showed that neither the silencing nor the overexpression modify the external phenotype, although the silencing can alter the capacity of climbing of the transgenic flies, suggesting that the absence of MFSD1 could be involved in a motor deficit.