UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Dissecting the genetic basis of neurodevelopmental disorders and demyelinating neuropathies

Efthymiou, Stephanie; (2021) Dissecting the genetic basis of neurodevelopmental disorders and demyelinating neuropathies. Doctoral thesis (Ph.D), UCL (University College London).

[thumbnail of PhD_Thesis_EfthymiouS_corrected_final.pdf] Text
PhD_Thesis_EfthymiouS_corrected_final.pdf - Submitted version
Access restricted to UCL open access staff until 1 April 2022.

Download (57MB)

Abstract

The understanding of the pathophysiology of most rare, complex neurological disorders has been elusive, especially in the case of complex demyelinating neuropathies and neurodevelopmental disorders. In my work, I learnt to employ two main techniques that will help advance the search for better understanding of neurodevelopmental disorders: next generation sequencing and functional validation of rare genetic variants. The main aim of my research was to establish the genetic diagnosis in several patients affected by complex syndromes such as peripheral neuropathy with central nervous system involvement (Chapter 3), neurodevelopmental disorders (Chapter 4) and epilepsy (Chapter 5). The phenotypic and genotypic correlations of identified gene variants were investigated in these chapters and is a profound theme in my project. To achieve this, an integrated approach combining next generation sequencing (NGS) technology, homozygosity mapping, array genotyping, traditional Sanger sequencing and functional experiments was undertaken. Firstly, I describe the work performed in an attempt to identify the causative gene in a cohort of young children presented with an early-onset hereditary form of chronic inflammatory demyelinating polyneuropathy with a central and peripheral involvement. My key findings were that: i) neurofascin is the first gene causally responsible for an inherited disorder that resembles CIDP, ii) this is the largest clinical cohort to date of patients with NFASC mutations with 10 individuals, and iii) the functional evidence implicate the major protein isoforms, which were also shown to be the main targets for the autoantibodies in CIDP pathogenesis. Secondly, I describe the work done on various neurodevelopmental disorder (NDD) genes, with particular focus on a newly identified gene presenting with a complex neurodevelopmental phenotype comprised of developmental delay, epilepsy, and/or a demyelinating neuropathy. My key findings were that: i) NARS1, a cytoplasmic aminoacyl-tRNA synthetase enzyme can be causative for this disorder by either a de-novo heterozygous or a biallelic inheritance mode, ii) functional investigations showed reduced aminoacylation activity in the disease-associated biallelic mutations using fibroblasts and iNPCs transcriptomics, suggesting that the majority of NARS1 mutations cause a loss of function of the protein by reduced expression and disruption of dimer formation suggesting a loss-of-function mechanism, and iii) increased yeast growth in the disease-associated heterozygous mutations showing near normal protein expression are suggestive of a gain-of-function mechanism. Finally, I describe the work done on two relative new genes (PIGS and TARS1) in an attempt to expand the patient phenotypic spectrum, as well as an interesting candidate gene (SLITRK3) linked with epilepsy. I present my understanding for disease-gene discovery that will enable me and other members of the neurogenetics field to identify disease-mechanisms and address important gaps of translational research into rare neurological diseases such as those described in this thesis.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Dissecting the genetic basis of neurodevelopmental disorders and demyelinating neuropathies
Event: UCL
Language: English
Additional information: Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10125015
Downloads since deposit
3Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item