Voxel location in a 60-year-old man with definite ALS
and clinically severe UMN signs. A, Precentral gyrus.
B, Cuneus gyrus. Image Credit.
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. However, exome sequencing can be limited in its application because all people harbor many rare genetic variants that don't cause disease and are nothing more than normal genetic background noise. Isolating disease-causing genetic variants requires DNA from multiple people in an affected family to be successful. For late-onset diseases such as ALS, finding enough patients to sequence in a single family is not always possible.
To overcome this limitation, the researchers performed an exome-wide screen on 363 people with familial ALS, each of whom also had a family member with the condition. Researchers performed an analysis of every coding gene in the genome of these patients and then they searched for patterns of rare, damaging mutations that appeared more frequently in patients with ALS than in the general population.
Additional testing by the researchers found that mutation to the TUBA4A gene was, in fact, associated with ALS. TUBA4A encodes for the Tubulin Alpha 4A protein and is found in all human tissue with its highest levels of expression in the brain. In nerve cells, TUBA4A is responsible for moving vital building blocks from one part of the cell to another. Specifically, TUBA4A helps build the microtubule network, one of the most important structural components of the nerve cell. The researchers 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 loss of voluntary muscle movement, paralysis and eventually respiratory failure. The cause of most cases of ALS is not known. Approximately 10 percent of cases are inherited. Though investigators at UMMS and elsewhere have identified several genes shown to cause inherited or familial ALS, nearly one-third of these cases have an unknown genetic cause.
The ongoing efforts from the ALS research community to sequence thousands of patient genomes through large international collaborations such as this will be an invaluable resource to identifying new disease-causing genes and pathways that could potentially be targeted for therapeutic intervention.