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A comprehensive analysis of known and candidate amyotrophic lateral sclerosis genes
thesisposted on 2022-03-29, 00:31 authored by Emily McCann
Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND),is a debilitating and ultimately fatal neurodegenerative disease affecting 2.74/100000 Australians. ALS is caused by progressive degeneration and elimination of both upper and lower motor neurons. Muscles become progressively atrophic and weak leading to spasticity and fasciculations such that dexterity and gait are adversely affected to the point that every day activities become impossible. Voluntary muscle paralysis occurs gradually as motor neurons die, generally leading to respiratory failure causing death within three to five years of diagnosis. A family history of ALS is observed in roughly 10% of cases, while the remaining 90% are classified as sporadic. Gene mutations are the only known cause of ALS. To date, over twenty genes have been implicated as ALS genes, with hexanucleotide repeat expansions in C9ORF72 accounting for one third of familial cases and a further 20% being attributable to SOD1 mutations. As the only known cause of ALS, a thorough understanding of these causative gene mutations is imperative for an appreciation of disease pathogenesis. Here we present a comprehensive analysis of genetic investigations into ALS. Optimised protocols for known gene screening through new patients have been established. Bioinformatic scripts to interrogate patient exome sequencing data for known ALS genes and cryptic relatedness between individuals have been developed. Furthermore, detailed mutation validation and control cohort screening has been performed for several ALS candidate genes. Finally, preliminary efforts towards methylation analysis of the major ALS genes C9ORF72 and SOD1 are also underway.