'Repeats' in Normal C9ORF72 Gene Don't Affect ALS, FTD

Humans carry two copies of the C9ORF72 gene, each containing a stretch of DNA in which a sequence of DNA building blocks coded GGGGCC is repeated a number of times. (Each six-letter sequence is called a "repeat.")

When one of the two copies is mutated so that it contains a far greater than normal number of GGGGCC repeats (a repeat expansion mutation), it can cause some forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).

Scientists had hypothesized that the number of repeats in a person's normal (unmutated) copy of C9ORF72 might be a genetic modifier of ALS and FTD, but a new study shows no evidence to support the hypothesis.

The study team suggests that "other genetic or environmental factors are responsible" for determining disease risk and variability in disease onset in people who have ALS or FTD with or without a C9ORF72 mutation.

About the new findings

The investigators studied 995 people with ALS, 580 people with FTD, 160 with FTD-ALS and 1,444 unaffected individuals. Disease-causing C9ORF72 mutations were identified in 211 people: 94 of those with ALS, 59 with FTD, and 58 with ALS-FTD.

In people with C9ORF72 mutations, the team studied the unmutated copy of C9ORF72. In individuals without a C9ORF72 mutation, the investigators evaluated the longer of each person's two normal copies of the gene.

Note: In people unaffected by ALS, the average number of repeats appears to be about three, with the maximum number rising to around 30. In individuals with ALS, a possible range of 700 to 1,600 repeats has been suggested by several investigators, but the exact number has yet to be determined.

Study highlights:

• In mutation carriers, the investigators found no evidence to suggest any connection between a greater number of repeats in the normal copy of C9ORF72 and increased risk of developing one disease (ALS, FTD or ALS-FTD) over another.
• In individuals without a mutated C9ORF72 gene, the team did not find any correlation between number of GGGGCC repeats and disease risk or age at onset for either ALS or FTD.   
• In people with or without a mutation in the C9ORF72 gene, no association was observed between the number of repeats in the unmutated copy of C9ORF72 (or the longer copy in those with two normal copies) and type of onset (limb or bulbar) or age at onset.

The research team included first study author Nicola J. Rutherford, research associate, and senior author Rosa Rademakers, associate professor of neuroscience, both at the Mayo Clinic Florida in Jacksonville. Full study results were published online July 30, 2012, in Neurobiology of Aging.

To read the abstract, see Length of Normal Alleles of C9ORF72 GGGGCC Repeat Do Not Influence Disease Phenotype (readers can access the full-length paper with a subscription or by paying a one-time fee).

More information

C9ORF72 is the first repeat expansion mutation found to directly cause ALS, although repeat expansions in the ataxin 2 and NIPA1 genes have been identified as significant contributors to the risk of developing the disease.

To learn more about the C9ORF72 mutation in ALS and FTD, read:

• C9ORF72: Bound to Repeat Itself (MDA/ALS Newsmagazine, July-September 2012)
• C9ORF72 Mutation Most Common Cause of Familial ALS, FTD, ALS-FTD (MDA/ALS Newsmagazine online, Sept. 21, 2011)