New Gene Mutations Discovered in ALS

Pauline Anderson

April 03, 2014

Researchers have made more headway in zeroing in on the genetic drivers behind amyotrophic lateral sclerosis (ALS).

A team led by investigators at the National Institutes of Health's National Institute on Aging have identified mutations in the Matrin 3 gene, located on chromosome 5, and revealed that MATR3, an RNA- and DNA-binding protein, interacts with TDP-43, a protein linked to ALS.

"The identification of this gene mutation gives us another target to explore in the pathogenesis of this disease," said senior author Bryan J. Traynor, MD, PhD, from the National Institute of Aging Laboratory of Neurogenetics, in a press release. "It also provides additional evidence that some disruption in RNA metabolism, an essential process within all cells, is involved in neuron death in ALS."

The research was published online March 30 in Nature Neuroscience.

Using exome sequencing, Janel O. Johnson, PhD, from the Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, and colleagues found 2 previously unknown heterozygous missense variants in MATR3 in a family of European ancestry, several members of which had been diagnosed with ALS and dementia. Neither of these variants was present in population polymorphism databases or in the Human Gene Diversity Panel of 2102 chromosomes screened in the neurogenetics laboratory. The MATR3 variant was also not present in another 5190 neurologically normal subjects genotyped in the laboratory.

A MATR3 mutation was previously reported as the cause of autosomal-dominant, distal asymmetrical myopathy with vocal cord paralysis in a large multigenerational family. In light of the new genetic findings, the researchers decided to reevaluate this family.

They found that affected individuals developed progressive respiratory failure resulting in death, typically after 15 years. Pathologically brisk knee reflexes, indicative of upper motor neuron lesions, were present in 4 of 6 patients examined. All cases displayed a "split hand" pattern of weakness suggestive of a lesion in the anterior horn of the cervical spinal cord, a sign commonly observed in patients with ALS.

"These clinical findings supported reclassification of this condition as slowly progressive ALS, and the presence of upper motor neuron signs in the form of brisk reflexes rule out myopathy as the only cause of disease in this family," the authors write.

Additional Cases

To determine the frequency of MATR3 mutations as a cause of ALS, the researchers examined exome sequence data using DNA from 108 additional familial ALS cases (including 6 Canadians, 14 Germans, 9 Israelis, 32 Italians, and 47 Americans) who were negative for mutations in known ALS-associated genes. The authors found a variant in MTR3 in a 66-year-old patient diagnosed with familial ALS and in an individual diagnosed with sporadic disease. Again, neither mutation was present in population polymorphism databases or in the Human Gene Diversity Panel.

The investigation revealed an interaction between the MATR3 protein and the TDP-43 protein, an RNA-binding protein whose mutation is known to cause ALS.

The mutation discovery should allow more complete mapping of the cellular pathways underlying ALS, the study authors said. The new data, they write, "identify mutations of the MATR3 gene as a rare cause of familial ALS and broaden the phenotype associated with this gene beyond the previously reported distal myopathy. This," they add, "provides further insight into the importance of RNA metabolism in this fatal neurodegenerative disease."

Characterized by progressive paralysis and respiratory failure leading to death, ALS kills about 6000 Americans each year. About 10% of people with ALS have a directly inherited form of the disease. The genetic etiology of two thirds of the familial form of ALS and 11% of the more common sporadic form of the disease are known.

The study was funded in part by the Packard Center for ALS Research at Johns Hopkins. Dr. Traynor and other authors have a patent pending on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9ORF72. Full conflict-of-interest information is available on the journal's Web site.

Nat Neurosci. Published online March 30, 2014. Abstract

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