C9ORF72 Heralds Deeper Understanding of ALS and Its Inheritance

The past two years have seen a revolution in discovery of genes for amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. Half a dozen new genes have been reported in this time, and several of them are likely to lead to major breakthroughs in understanding the genetics of ALS, currently one of the major unsolved puzzles in neurology. Among this constellation of genes, the newest and perhaps the most significant is C9ORF72. It is now the most common genetic cause of familial ALS, and is even responsible for a proportion of sporadic cases of the disease.1,2 Athena Diagnostics is pleased to announce it now offers a diagnostic test for this important gene, available as a stand-alone test or as part of a Complete ALS Evaluation.

ALS is due to the loss of both upper and lower motor neurons. Onset is usually between the ages of 40 and 60, although it may begin earlier or later. It causes progressive muscle weakness, leading to difficulty walking, breathing, and speaking. It is a rapidly progressive disease, with a mean survival of 3 to 5 years after diagnosis.

Between 5% and 10% of cases are clearly familial, although as more genes are discovered, it is becoming evident that many apparently sporadic cases are due to gene mutations as well.1,3 The cause of the large majority of cases is still unknown.

The first ALS gene, discovered in 1993, was SOD1, encoding a ubiquitous protein called superoxide dismutase, which is responsible for neutralizing superoxide radicals that are toxic to cells. No exact disease etiology is known. Approximately 20% of familial ALS cases (2% of all ALS) are due to SOD1 mutations.4

A recently discovered gene, called TDP-43, encodes a protein that binds both DNA and RNA. While TDP-43 mutations cause relatively few cases of ALS, the discovery was highly significant, since the protein is a major component of protein aggregates, which are seen in the dying neurons of a majority of both familial and sporadic cases. How the mutation causes disease is unknown, but the protein’s normal role in handling RNA, similar to that of two other recently discovered ALS genes called FUS and angiogenin, has focused attention on RNA processing as a potential pathway for ALS pathogenesis. A fourth new gene, called UBQN2, encodes the ubiquilin-2 protein, important in routine turnover (degradation) of proteins.

The newest gene is called C9ORF72 (chromosome 9 open reading frame 72), whose function is unknown. The normal gene contains a short hexanucleotide GGGGCC repeat sequence, which is significantly expanded in symptomatic individuals. C9ORF72 also causes frontotemporal dementia (FTD),2 a progressive illness that is the second most common form of dementia, after Alzheimer’s disease. Within a family, C9ORF72 mutations may cause ALS, or FTD, or both. According to Rosa Rademakers, Ph.D., who led one of the groups that discovered the gene, “It has been clear for many years there was likely to be some genetic link between ALS and FTD,” because of an overlap in the phenotype between the two disorders in many patients. “This is the first gene that brings them together on the genetic level.”

Three aspects of this discovery have generated great excitement amongst ALS researchers. First, C9ORF72 is responsible for between 20% and 40% of all familial ALS cases, making it the most common gene for ALS yet.1,2 Bryan Traynor, M.D., who led one of the groups that discovered the gene, has said that the discovery “means we have gone from understanding only about a quarter of familial ALS, to about two thirds of familial ALS.” Second, C9ORF72 is responsible for roughly 4% of cases with no known family history (sporadic), suggesting there may be a common mechanism among the two disease types. Third, lessons from a similar situation in a repeat expansion causing myotonic dystrophy are now being explored as a possible model for ALS, with the hope that new therapies will be developed from these insights.

Additional Resource

Dr. Richard Bedlack shares his insights on ALS and genetic testing.




1. Renton AE, Majounie E, Waite A, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011 Oct 20; 72(2):257-68. 2. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011 Oct 20; 72(2):245-56. 3. Chiò A, Schymick JC, Restagno G, et al. A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis. Hum Mol Genet. 2009 Apr 15;18(8):1524-32. 4. Genetics of ALS viewed online 9 Apr 2012.

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