Cottenie, E; (2015) Genetic and functional investigation of inherited neuropathies. Doctoral thesis , UCL (University College London).

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Abstract

With the discovery of next generation sequencing techniques the landscape of pathogenic gene discovery has shifted drastically over the last ten years. For the purpose of this thesis, focus was applied on finding genetic causes of inherited neuropathies, mainly Charcot-Marie-Tooth disease, by using both old and new genetic techniques and the accompanying functional investigations to prove the pathogenicity of these variants. Mutations in ATPase 6, the first mitochondrially encoded gene responsible for an isolated neuropathy, were found in five families with CMT2 by a traditional Sanger sequencing approach. The same approach was used to expand the phenotype associated with FIG4 mutations, known as CMT4J. Compound heterozygous mutations were found in a patient with a proximal and asymmetric weakness and rapid deterioration of strength in a single limb, mimicking CIDP. Several appropriate cohorts were screened for mutations in candidate genes with the traditional Sanger sequencing approach; however, no new pathogenic genes were found. In the case of the HINT1 gene, the originally stated frequency of 11% could not be replicated and a founder effect was suggested, underlying the importance of considering the ethnic background of a patient when screening for mutations in neuropathy-related genes. After the incorporation of exome sequencing, five CMT families were provided with a genetic diagnosis due to mutations in three novel genes and two previously known pathogenic genes. Many more families are currently under investigation and candidate genes have been found in some. Lastly, a series of divergent functional techniques was used to investigate the pathogenicity of IGHMBP2 mutations in 11 families with CMT2. IGHMBP2 mutations normally lead to SMARD1 and fibroblast and lymphoblast studies indicate that the IGHMBP2 protein levels are significantly higher in CMT2 than SMARD1, but lower than controls, suggesting that the clinical phenotype differences correlate to the IGHMBP2 protein levels.

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