C9ORF72 hexanucleotide repeat expansions in patients with ALS from the Coriell Cell Repository

Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Neurology (Impact Factor: 8.29). 07/2012; 79(5):482-3. DOI: 10.1212/WNL.0b013e31826170f1
Source: PubMed


Amyotrophic lateral sclerosis (ALS) is a neurologic disorder, characterized by progressive degeneration of both upper and lower motor neurons in the brain and spinal cord. Previous genetic studies have identified mutations in Cu/Zn superoxide dismutase (SOD1), transactive response binding protein 43 (TARDBP), fused in sarcoma (FUS), and valosin containing protein (VCP) genes as being causative of disease.(1) Recently, an expansion of the noncoding GGGGCC hexanucleotide repeat in chromosome 9 open reading frame 72 (C9ORF72) was identified as an important novel genetic defect in patients with ALS without or with frontotemporal dementia (FTD-ALS).(2,3) Here we report the frequency of this new mutation and its associated clinical features in a cohort of patients obtained from the Coriell Cell Repository.

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Available from: Nicola Jayne Rutherford, Mar 27, 2014
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    • "These three disorders are considered to form part of a spectrum of disease. However, screening for the C9ORF72 expansion found the expanded repeats at relatively low frequencies in the PMA and PLS cohorts, at 1.6 and 0.9 %, respectively [43], and in a smaller cohort of PMA, PLS and progressive bulbar palsy patients, no expansions were found [44]. Thus, C9ORF72 expansions appear to be more commonly associated with an ALS phenotype within this spectrum of disease. "
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    ABSTRACT: The GGGGCC (G4C2) repeat expansion in C9ORF72 is the most common cause of familial amyotrophic lateral sclerosis (ALS), frontotemporal lobar dementia (FTLD) and ALS-FTLD, as well as contributing to sporadic forms of these diseases. Screening of large cohorts of ALS and FTLD cohorts has identified that C9ORF72-ALS is represented throughout the clinical spectrum of ALS phenotypes, though in comparison with other genetic subtypes, C9ORF72 carriers have a higher incidence of bulbar onset disease. In contrast, C9ORF72-FTLD is predominantly associated with behavioural variant FTD, which often presents with psychosis, most commonly in the form of hallucinations and delusions. However, C9ORF72 expansions are not restricted to these clinical phenotypes. There is a higher than expected incidence of parkinsonism in ALS patients with C9ORF72 expansions, and the G4C2 repeat has also been reported in other motor phenotypes, such as primary lateral sclerosis, progressive muscular atrophy, corticobasal syndrome and Huntington-like disorders. In addition, the expansion has been identified in non-motor phenotypes including Alzheimer's disease and Lewy body dementia. It is not currently understood what is the basis of the clinical variation seen with the G4C2 repeat expansion. One potential explanation is repeat length. Sizing of the expansion by Southern blotting has established that there is somatic heterogeneity, with different expansion lengths in different tissues, even within the brain. To date, no correlation with expansion size and clinical phenotype has been established in ALS, whilst in FTLD only repeat size in the cerebellum was found to correlate with disease duration. Somatic heterogeneity suggests there is a degree of instability within the repeat and evidence of anticipation has been reported with reducing age of onset in subsequent generations. This variability/instability in expansion length, along with its interactions with environmental and genetic modifiers, such as TMEM106B, may be the basis of the differing clinical phenotypes arising from the mutation.
    Full-text · Article · Feb 2014 · Acta Neuropathologica
    • "A third possibility is that SNPs showing residual association tag repeat alleles greater than size 2 because such repeats are themselves pathogenic. Case and control samples share the same frequency and distribution of repeat lengths (Rutherford et al., 2012) making this unlikely, but recent evidence suggests that moderate expansion in the number of repeats can actually be pathogenic (Gomez-Tortosa et al., 2013). "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons. Single-nucleotide polymorphism rs3849942 is associated with ALS, tagging a hexanucleotide repeat mutation in the C9orf72 gene. It is possible that there is more than 1 disease-causing genetic variation at this locus, in which case association might remain after removal of cases carrying the mutation. DNA from patients with ALS was therefore tested for the mutation. Genome-wide association testing was performed first using all samples, and then restricting the analysis to samples not carrying the mutation. rs3849942 and rs903603 were strongly associated with ALS when all samples were included (rs3849942, p = [3 × 2] × 10(-6), rank 7/442,057; rs903603, p = [7 × 6] × 10(-8), rank 2/442,057). Removal of the mutation-carrying cases resulted in loss of association for rs3849942 (p = [2 × 6] × 10(-3), rank 1225/442,068), but had little effect on rs903603 (p = [1 × 9] × 10(-5), rank 8/442,068). Those with a risk allele of rs903603 had an excess of apparent homozygosity for wild type repeat alleles, consistent with polymerase chain reaction failure of 1 allele because of massive repeat expansion. These results indicate residual association at the C9orf72 locus suggesting a second disease-causing repeat mutation.
    No preview · Article · Apr 2013 · Neurobiology of aging
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    ABSTRACT: Hexanucleotide expansions in the C9ORF72 gene are frequently found in patients with amyotrophic lateral sclerosis, frontotemporal dementia or both, some of whom exhibit concurrent extrapyramidal symptoms. To determine if repeat expansions are a cause of Parkinson's disease (PD), we used repeat-primed polymerase chain reaction to investigate the frequency of C9ORF72 repeat expansions in a cohort of 478 patients with PD and 662 control subjects. Three control subjects were found to be expansion carriers, and no expansions were found among patients, suggesting that C9ORF72 expansions are not a common cause of PD.
    Full-text · Article · Oct 2012 · Neurobiology of aging
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