Dominik, Natalia; (2024) Genetic and functional characterisation of ataxias and neuropathies with a focus on biallelic expansions in RFC1 and biallelic variants in ARHGAP19. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The understanding of genetic and functional aspects of neuropathies and ataxias can provide evidence for therapeutic targets and translation into clinic. In my work, I employed genetic screening and sequencing techniques, optical genome mapping and disease modelling using Drosophila melanogaster. In Chapter 2, I describe the work performed to characterise the RFC1 spectrum disorder. Screening a large cohort of patients for repeat expansions in the gene together with the phenotypic data can give a detailed picture of the disease progression. Here, we demonstrate that RFC1 repeat size is a key predictor of disease onset, phenotype and severity therefore providing evidence for unmet need of sizing the RFC1 repeat expansions in diagnostic settings. In Chapter 3, I describe the genetic heterogeneity in RFC1 disease, and investigate novel pathogenic repeat expansion motifs in RFC1. Here, we address a need for additional genetic testing beyond PCR screening in patients presenting with typical CANVAS symptoms but negative screening for the most common biallelic pathogenic AAGGG expansion to correctly diagnose patients. In chapter 4, I describe the work performed to identify and characterise a novel recessive Charcot-Marie-Tooth (CMT) gene, ARHGAP19. Here, we add another important gene to the growing list of CMT genes and we demonstrate loss of activity of the GTPase activating protein domain in functional and in-silico assays. Finally, in chapter 5, I describe the utility of Drosophila melanogaster as a model organism in neurogenetic research. I use various tools to knock down gene expression in the fly to recapitulate the phenotype of the patients with RFC1 and ARHGAP19 diseases. In conclusion, in my thesis, I present functional and genetic characterisation of two important genes – RFC1 and ARHGAP19 - that will enable me and other members of the neurogenetic field to further research the disease mechanisms and address the need of translation into diagnostic and potentially therapeutic avenues.

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