John E. Landers, Ph.D.
University of Massachusetts Medical School
Department of Neurology
Worcester MA 01605
Genetics of Familial and Sporadic ALS
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease caused by the selective loss of motor neurons. It is ultimately lethal with a typical patient survival of two to five years. Although most ALS cases are sporadic in nature (SALS), ~10% are familial. In recent years, the identification of genetic causes of familial amyotrophic lateral sclerosis (FALS) has greatly contributed to understanding the pathogenesis of ALS in general. Unfortunately, nearly half of the underlying genetic causes of FALS have been explained to date. This is due mainly to the intrinsic difficulties in finding large informative pedigrees for a late-onset disease with a short survival period. The recent development of exon capture and short-read sequencing technologies now allows screening of cohorts for rare variants at a genome-wide scale in an economically feasible way. Our laboratory is focused on adopting the exon capture and short-read sequencing approach, in combination with bioinformatics analysis, to identify novel causative genes for FALS. It is our hope that by understanding the genetic causes of ALS, we will facilitate our understanding of all forms of ALS, as well as assisting in the development of diagnostics and therapies to extend the lifespan of ALS patients.
Kwiatkowski T.J. et al. Mutations in the FUS/TLS Gene on Chromosome 16 Cause Familial Amyotrophic Lateral Sclerosis. Science 2009; 323:1205-8.
Landers J.E. et al. Genetic Variants in Kinesin-Associated Protein Gene KIFAP3 Modify Survival in Sporadic Amyotrophic Lateral Sclerosis. Proc. Natl. Acad. Sci. USA. 2009; 106:9004-9.
Ticozzi N. et al. Analysis of FUS Gene Mutation in Familial Amyotrophic Lateral Sclerosis within an Italian cohort. Neurology 2009; 73:1180-5.
van Es M.A. et al. Genome-wide association study identifies UNC13A and 9p21.2 as susceptibility loci for sporadic Amyotrophic Lateral Sclerosis. Nature Genet. 2009; 41:1083-7.
Ticozzi N. et al. Mutational analysis of TARDBP in neurodegenerative diseases. Neurobiol Aging. 2011; 32:2096-9.
Ticozzi N. et al. Paraoxonase gene mutations in amyotrophic lateral sclerosis. Ann Neurol. 2010; 68:102-7.
Blauw H.M. et al. A large genome scan for rare CNVs in amyotrophic lateral sclerosis. Hum Mol Genet. 2010; 19:4091-9.
Ticozzi N. et al. Mutational analysis reveals the FUS homolog TAF15 as a candidate gene for familial amyotrophic lateral sclerosis. Am. J. Med. Gen. Part B: Neuropsychiatric Genetics. 2011; 156:285-90.
van Es M.A. et al. Angiogenin mutations in Parkinson’s disease and amyotrophic lateral sclerosis. Ann Neurol. In Press.