Length of normal alleles of C9ORF72 GGGGCC repeat do not influence disease phenotype

Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Neurobiology of aging (Impact Factor: 5.01). 07/2012; 33(12):2950.e5-7. DOI: 10.1016/j.neurobiolaging.2012.07.005
Source: PubMed


Expansions of the noncoding GGGGCC hexanucleotide repeat in the Chromosome 9 open reading frame 72 (C9ORF72) gene cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). In this study we aimed to determine whether the length of the normal-unexpanded-allele of the GGGGCC repeat in C9ORF72 plays a role in the presentation of disease or affects age at onset in C9ORF72 mutation carriers. We also studied whether the GGGGCC repeat length confers risk or affects age at onset in FTD and ALS patients without C9ORF72 repeat expansions. C9ORF72 genotyping was performed in 580 FTD, 995 ALS, and 160 FTD-ALS patients, and 1444 controls, leading to the identification of 211 patients with pathogenic C9ORF72 repeat expansions. No meaningful association between the repeat length of the normal alleles of the GGGGCC repeat in C9ORF72 and disease phenotype or age at onset was observed in C9ORF72 mutation carriers or nonmutation carriers.

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    • "The recent identification of aberrant GGGGCC (G4C2) intronic repeat expansions in the C9ORF72 gene (DeJesus-Hernandez et al., 2011; Renton et al., 2011) as the most common cause for both ALS and FTD have further emphasized this notion (Majounie et al., 2012). C9ORF72 patients carry from tens to hundreds of G4C2 repeats, while the majority of unaffected individuals have no more than 2 to 25 repeats (Rutherford et al., 2012). Correlation between these expanded repeats and severity of clinical manifestations has yet to be established. "
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    ABSTRACT: Expanded GGGGCC (G4C2) nucleotide repeats within the C9ORF72 gene are the most common genetic mutation associated with both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Sense and antisense transcripts of these expansions are translated to form five dipeptide repeat proteins (DRPs). We employed primary cortical and motor neuron cultures, live-cell imaging, and transgenic fly models and found that the arginine-rich dipeptides, in particular Proline-Arginine (PR), are potently neurotoxic. Factors that anticipated their neurotoxicity included aggregation in nucleoli, decreased number of processing bodies, and stress granule formation, implying global translational dysregulation as path accountable for toxicity. Nuclear PR aggregates were also found in human induced motor neurons and postmortem spinal cord tissues from C9ORF72 ALS and ALS/FTD patients. Intronic G4C2 transcripts, but not loss of C9ORF72 protein, are also toxic to motor and cortical neurons. Interestingly, G4C2 transcript-mediated neurotoxicity synergizes with that of PR aggregates, suggesting convergence of mechanisms.
    Full-text · Article · Dec 2014 · Neuron
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    • "A smaller study identified a positive correlation between repeat length and age of onset in C9ORF72-related patients with a variety of neurodegenerative phenotypes including FTLD, ALS and Alzheimer’s disease [1] but as described above, this may simply reflect the individual’s age at the time of sampling. It has also been shown that the length of the non-expanded allele is not a disease modifier in C9ORF72-related or non-C9ORF72 ALS or FTLD [71, 74, 75]. "
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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
    • "To test whether higher repeat copy numbers increase one’s risk for PD, we conducted Fisher’s exact tests using the a priori thresholds of greater than 20 or 23 repeat copies (RCs). The common maximum RCs reported in controls in this study and others is 23 repeats, while by far the majority (∼99.4%) of all reported controls have RCs lower than 20 (DeJesus-Hernandez et al., 2011; Renton et al., 2011; Byrne et al., 2012; Cooper-Knock et al., 2012; Chio et al., 2012; Daoud et al., 2012; Dejesus-Hernandez et al., 2012; Dobson-Stone et al., 2012; Ferrari et al., 2012; Garcia-Redondo et al., 2012; Gijselinck et al., 2012; Konno et al., 2012; Majounie et al., 2012b; Millecamps et al., 2012; Mok et al., 2012b; Ogaki et al., 2012; Ratti et al., 2012; Rollinson et al., 2012; Rutherford et al., 2012; Sabatelli et al., 2012; Simon-Sanchez et al., 2012; van Rheenen et al., 2012; Xi et al., 2012; Yeh et al., 2012). Odds ratios represent the effect of intermediate repeat copies relative to lower repeat copies (≤20 or ≤23 RCs depending on analysis) and are calculated using a 2×2 contingency table. "
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    ABSTRACT: We set out to determine whether expansions in the C9ORF72 repeat found in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) families are associated with Parkinson disease (PD). We determined the repeat size in a total of 889 clinically ascertained patients (including PD and essential tremor plus Parkinsonism (ETP)) and 1144 controls using a repeat-primed PCR assay. We found that large C9ORF72 repeat expansions (>30 repeats) were not contributing to PD risk. However, PD and ETP cases had a significant increase in intermediate (>20 to 30+) repeat copies compared to controls. Overall, 14 cases (13 PD, 1 ETP) and three controls had >20 repeat copies (Fisher's exact test p = 0.002). Further, seven cases and no controls had >23 repeat copies (p = 0.003). Our results suggest that intermediate copy numbers of the C9ORF72 repeat contribute to risk for PD and ETP. This also suggests that PD, ALS and FTD share some pathophysiological mechanisms of disease. Further studies are needed to elucidate the contribution of the C9ORF72 repeat in the overall PD population and to determine whether other common genetic risk factors exist between these neurodegenerative disorders.
    No preview · Article · Jul 2013 · Annals of Human Genetics
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