Last year, researchers discovered that hundreds of repeats in C9ORF72 lead to amyotrophic lateral sclerosis, frontotemporal dementia, or both. Since then, a slew of papers has appeared, making it clear that this particular mutation spans both a spectrum of neurodegenerative disease and continental borders. Studies published this month in the journals Archives of Neurology and Clinical Genetics show that the repeats contribute to parkinsonism, corticobasal syndrome, and olivopontocerebellar degeneration. Two more papers, one in the Archives and the other in Neurobiology of Aging, show the mutation appears not only in the European and North American populations where it was initially found, but also in Japan and Taiwan. Asians with the expansion share some adjacent sequences with their European counterparts, leading Shoji Tsuji of the University of Tokyo to speculate that perhaps European seafarers brought the mutation to Asian shores hundreds of years ago (thank you very much). These studies fit with other recent C9ORF72 data, including eight papers last March in the journal Brain, characterizing diseases associated with the repeats (reviewed in Hodges, 2012).

The infamous repeat is a GGGGCC hexanucleotide expansion located in an intron on chromosome 9 (see ARF related news story on Dejesus-Hernandez et al., 2011, and Renton et al., 2011). The gene’s normal function remains a mystery. Researchers estimate that people with symptoms possess between 700 and 1,600 repeats. Healthy people, in contrast, appear to carry fewer than 100 repeats. However, a precise measure of the number of hexanucleotides eludes geneticists, because the repeats themselves interfere with standard DNA amplification and sequencing techniques. Scientists cannot delineate the exact cutoff between health and C9ORF72 expansion disease without extensive analysis of patient DNA.

Many Repeats Yield Many Phenotypes
Bradley Boeve of the Mayo Clinic in Rochester, Minnesota, collaborated in the original C9ORF72 discovery; since then, he and his colleagues have been examining the expansion region in other families. In the June 4 Archives of Neurology online, Boeve, first author Rodolfo Savica, and colleagues report on a C9ORF72 expansion in a clan Boeve initially encountered two decades ago. The first member Boeve examined developed symptoms of FTD, ALS, and parkinsonism at 62 years of age, and died a year later. That person’s sibling and child also visited the Mayo Clinic, both exhibiting signs of FTD. Several other family members, who were not examined, reportedly had some form of dementia. All three people seen at the Mayo had the C9ORF72 expansion.

In the Clinical Genetics paper, online May 31, researchers led by first author Suzanne Lindquist and senior author Jorgen Nielsen describe their search for the expansion among 280 people with neurodegenerative disease at the Copenhagen University Hospital in Denmark. Fourteen carried the repeats. Of these, six had FTD, one had ALS, and four had combined FTD-ALS. Three more people presented new conditions for the C9ORF72 spectrum. One had been diagnosed with corticobasal syndrome due to symptoms including cognitive impairment and muscle spasms in the right hand. Another suffered from an atypical parkinsonian syndrome that evolved over time toward an FTD-ALS phenotype. Finally, one person, who had difficulty walking and speaking, had been diagnosed with olivopontocerebellar degeneration. This condition, marked by atrophy of the cerebellum, pons, and inferior olives, typically causes ataxia.

“C9ORF72 phenotypes are more diverse than anticipated, and may involve different diseases within the cognitive motor spectrum,” concluded Nielsen in an e-mail to ARF. Boeve predicted that, in the future, “We will probably see a lot more Alzheimer-ish phenotypes that have this mutation, too.” With so many kinds of C9ORF72-linked conditions popping up, researchers may wonder if the mutation is truly linked to disease, especially since there have been control subjects who turned out to have the expansion (e.g., in Renton et al., 2011). However, the link between C9ORF72 and neurodegeneration is solid, according to Stuart Pickering-Brown of the University of Manchester, U.K. “Even though there is the occasional elderly unaffected [carrier], the number of patients with the expansion is massive,” wrote Pickering-Brown, who was part of the team that originally identified the expansion, in an e-mail to Alzforum.

Perhaps those elderly carriers are simply lucky not to exhibit symptoms yet. Not only is the physical manifestation of C9ORF72 heterogeneous, so is age of onset—between 42 and 85 in these two studies—and disease duration, which ranged from four months to 16 years. Why such a mélange of effects from the same expansion? “It is hard to know,” Boeve said. “The obvious question is, Is the size of the repeat expansion affecting age of onset?” This is the case in Huntington’s disease, a triplet repeat disorder, in which the unstable expansion can both grow and shrink (see ARF related news story on Kovtun et al., 2007; ARF related news story on Lin et al., 2006). The unstable C9ORF72 expansion can also change size. Boeve told Alzforum that the number of repeats can vary even between different organs in the same person. He theorized that a person’s particular distribution of different-sized repeats might determine symptoms. Another possibility, Pickering-Brown suggested, is that a second, as-yet-unidentified gene acts as a modifier to determine a person’s symptom set.

Did C9ORF72 Sail the Seven Seas?
C9ORF72 was discovered in Finnish and other European populations, but it is not limited to Caucasians. Researchers at the Taipei Veterans General Hospital and National Yang-Ming University School of Medicine in Taipei, Taiwan, report in the June 4 Neurobiology of Aging online their examination of 124 people with ALS who were of Han Chinese descent. This group makes up the majority of Taiwan’s population, senior author Yi-Chung Lee said in an interview with ARF. Joint first authors Ching-Paio Tsai and Bing-Wen Soong discovered the expansion in six participants.

As reported in the June 4 Archives of Neurology online, senior author Tsuji and first author Hiroyuki Ishiura, of the University of Tokyo performed a similar study with 37 people with ALS on the nation’s Kii peninsula, southeast of Osaka. The peninsula contains two historically isolated regions that are ALS hotspots, one along the Koza River and another in the Hohara district. There, ALS rates far exceed those in the rest of Japan. Three of the 21 people analyzed from the Koza River area carried the C9ORF72 expansion; none of the 16 people from Hohara did.

How did such distant locales as Finland and Japan acquire similar expansions? One possibility, Boeve noted, is that the C9ORF72 region is inherently unstable, and expansions arose multiple times. The other is that there was a single founder. Both Tsoji’s and Lee’s teams analyzed the haplotypes of the people with the expansions. The Han Chinese group shared with the Finns nearly 100 kilobases, the Kii people 130 kilobases, suggesting a common ancestor (Majounie et al., 2012).

Visiting sailors may have brought the faulty gene with them, both Tsoji and Lee speculated. Transportation on the Kii peninsula was mainly by sea, and the island state Taiwan was under European rule during the 1600s. However, Tsoji added, “130 kilobases is very short from the genetic point of view.” The idea is far from proven. The C9ORF72 expansion currently explains 20 percent of the Koza River cases. That is a significant percentage for a single genetic defect, but clearly leaves unexplained other reasons for the high incidence of ALS in that area.—Amber Dance


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News Citations

  1. Corrupt Code: DNA Repeats Are Common Cause for ALS and FTD
  2. A Growing Problem: Oxidative Damage Drives Trinucleotide Expansions in Aging Brain
  3. Huntingtin and Transcription: A Story of the Incredible Shrinking CAG Repeats

Paper Citations

  1. . Familial frontotemporal dementia and amyotrophic lateral sclerosis associated with the C9ORF72 hexanucleotide repeat. Brain. 2012 Mar;135(Pt 3):652-5. PubMed.
  2. . Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011 Oct 20;72(2):245-56. Epub 2011 Sep 21 PubMed.
  3. . A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011 Oct 20;72(2):257-68. Epub 2011 Sep 21 PubMed.
  4. . OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells. Nature. 2007 May 24;447(7143):447-52. PubMed.
  5. . Transcription promotes contraction of CAG repeat tracts in human cells. Nat Struct Mol Biol. 2006 Feb;13(2):179-80. PubMed.
  6. . Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol. 2012 Apr;11(4):323-30. PubMed.

Further Reading


  1. . Analysis of the hexanucleotide repeat in C9ORF72 in Alzheimer's disease. Neurobiol Aging. 2012 Aug;33(8):1846.e5-6. PubMed.
  2. . Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72. Brain. 2012 Mar;135(Pt 3):765-83. PubMed.
  3. . Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics. Brain. 2012 Mar;135(Pt 3):794-806. PubMed.
  4. . Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain. 2012 Mar;135(Pt 3):693-708. PubMed.
  5. . Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72. Acta Neuropathol. 2011 Dec;122(6):673-90. PubMed.
  6. . Cognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: a population-based cohort study. Lancet Neurol. 2012 Mar;11(3):232-40. PubMed.
  7. . An MND/ALS phenotype associated with C9orf72 repeat expansion: Abundant p62-positive, TDP-43-negative inclusions in cerebral cortex, hippocampus and cerebellum but without associated cognitive decline. Neuropathology. 2011 Dec 19; PubMed.

Primary Papers

  1. . Characterization of a Family With c9FTD/ALS Associated With the GGGGCC Repeat Expansion in C9ORF72Characterization of a Family With c9FTD/ALS. Arch Neurol. 2012 Jun 4;:1-6. PubMed.
  2. . C9ORF72 Repeat Expansion in Amyotrophic Lateral Sclerosis in the Kii Peninsula of JapanC9ORF72 Repeat Expansion in ALS. Arch Neurol. 2012 Jun 4;:1-5. PubMed.
  3. . A hexanucleotide repeat expansion in C9ORF72 causes familial and sporadic ALS in Taiwan. Neurobiol Aging. 2012 Sep;33(9):2232.e11-2232.e18. PubMed.
  4. . Corticobasal and ataxia syndromes widen the spectrum of C9ORF72 hexanucleotide expansion disease. Clin Genet. 2012 May 31;9999(9999) PubMed.