Identification and characterisation of disease genes in early onset amyotrophic lateral sclerosis (ALS) by exome sequencing of patient-parent trios

• Applicant: Privatdozent Dr. Alexander Volk
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Human Genetics
• Term: from 2014 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 248208234

Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disease characterized by adult-onset progressive loss of primary upper and lower motor neurons, resulting in progressive paralysis and ultimately death due to respiratory failure. Average disease duration is 2-3 years. Sporadic ALS (~90%) and familial cases of ALS (FALS) can be distinguished. In the latter form ALS can be inherited in an autosomal-dominant, autosomal-recessive or X-linked manner. To date, in around 60% of FALS a mutation in one of the know ALS genes can be identified. Mutations in SOD1 and the recently identified expansion of the intronic hexanucleotide repeat of the C9ORF72 gene are the most frequent causes and account for around 40% of FALS. In around 15 % of sporadic ALS a mutation in one of the known genes can be identified. Next generation sequencing technologies led to the identification of causative mutations in different genes in a number of genetic disorders. A trio sequencing approach should now be applied in this study for ALS. 30 patients with early-onset ALS (<35 yrs) and their unaffected parents will be included. Bioinformatic filtering will show de novo, biallelic or hemizygous mutations. After molecular validation pathogenicity will be proven by different bioinformatics tools and molecular analyses. Follow-up studies in a large series of up to 5000 sporadic and 700 familial ALS will reveal prevalence of mutations in the corresponding genes. In the long term the identification of novel ALS genes is the basis for the development of novel therapeutic approaches and treatments of neurodegenerative disorders.

• DFG Programme: Research Grants
• Participating Person: Professor Dr. Albert Christian Ludolph