| Description |
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is an adult-onset fatal disease in which the upper and lower motor neurons of the body progressively degenerate. Efforts to understand the pathophysiology of ALS over the past two decades have shown that mutations in genes involved in a wide variety of cellular processes can cause ALS. Patients who develop ALS and have a family history of the disease are termed familial ALS (FALS) and represent 10% of ALS cases. However, similar genetic mutations occur in patients with no family history of ALS, which suggests genetic factors also play a role in sporadic ALS (SALS). Studies that utilize low-resolution single nucleotide variant (SNV) and microsatellite assays have identified over 30 ALS-associated genes. However, only 68% of FALS and 11% of SALS cases have an identifiable genetic cause. The identification of the genetic factors responsible for these unexplained ALS cases has been challenging because of the technological limitations of SNV and microsatellite assays. The increasing availability of next-generation sequencing (NGS) allows for the potential identification of such elusive disease-causing genetic variants. The aim of this dissertation is to better understand ALS genetic risk factors using NGS technology and computational methods. The first chapter will review ALS and the importance of genetic factors in its pathogenesis. The analyses presented in Chapter 2 try to determine whether NGS approaches can identify known and potentially novel ALS genetic risk loci in individual FALS patients. Next, efforts to better understand the importance of known ALS risk loci in SALS pathogenesis will be covered in Chapter 3. Chapter 4 will focus on attempts to find novel ALS risk genes in a cohort of SALS patients. Chapter 5 will focus on the results of functional studies aimed at validating TP73 as an ALS candidate risk gene. Lastly, Chapter 6 will be focused on determining whether SALS can be caused by deleterious genetic variation shared between distantly related patients. The |
