ALS Associated Gene Identified Using Innovative Strategy

Exome sequencing, in contrast to whole genome sequencing, relies on sequencing only the protein-coding genes in a genome and has been an effective and cost-efficient strategy for identifying disease-causing genetic mutations.

A team of scientists led by those at University of Massachusetts Medical School (Worcester, MA, USA) performed an exome-wide screen on 363 people with familial ALS (FALS) each of whom also had a family member with the condition. The investigators went onto analyze a further 272 FALS cases and 5,510 internal controls to confirm the overrepresentation as statistically significant and replicable. An analysis of every coding gene in the genome of these patients was performed and then searched for patterns of rare, damaging mutations that appeared more frequently in patients with ALS than in the general population.

The results revealed an excess of patient variants within TUBA4A, the gene encoding the Tubulin, Alpha 4A protein. Analysis of the extra 272 FALS cases and 5,510 internal controls confirmed the overrepresentation as statistically significant and replicable. The protein TUBA4A helps build the microtubule network, one of the most important structural components of the nerve cell. The scientists found that the mutated TUBA4A protein is toxic to the neuron by weakening the entire microtubule network.

ALS is a progressive, neurodegenerative disorder affecting the motor neurons in the central nervous system. As motor neurons die, the brain's ability to send signals to the body's muscles is compromised. This leads to a loss of voluntary muscle movement, paralysis and eventually respiratory failure. The cause of most cases of ALS is not known and approximately 10% of cases are inherited.

John E. Landers, PhD, a professor of Neurology and senior author of the study said, “Every single one of us carries rare mutations which make the identification of disease-associated genes difficult. By analyzing the mutation rate of every gene in our patients and comparing them to the general population, we were able to show that the TUBA4A gene had an elevated frequency of mutation in patients.” The study was published on October 22, 2014, in the journal Neuron.

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