Elsevier

Neurobiology of Aging

Volume 33, Issue 12, December 2012, Pages 2950.e5-2950.e7
Neurobiology of Aging

Genetic reports abstract
Negative results
Length of normal alleles of C9ORF72 GGGGCC repeat do not influence disease phenotype

https://doi.org/10.1016/j.neurobiolaging.2012.07.005Get rights and content

Abstract

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.

Introduction

Clinical, genetic, and histopathological evidence suggests that similar pathological processes underlie amyotrophic lateral sclerosis (ALS) and some types of frontotemporal dementia (FTD); a notion which was reinforced by the discovery of GGGGCC repeat expansions in a noncoding region of Chromosome 9 open reading frame 72 (C9ORF72) (DeJesus-Hernandez et al., 2011; Renton et al., 2011). In this study, we focused on the length of the normal alleles of the C9ORF72 repeat in patients with or without repeat expansions, to determine whether the length of this “wild type” allele has any effect on the disease phenotype or age of disease onset in FTD and ALS patients. We hypothesized that longer GGGGCC repeats within the normal range, suggested to be <30 repeats (Cerami et al., 2012), in C9ORF72 would lead to an increase in disease risk or an earlier age at disease onset.

Section snippets

Methods

Our study cohort consisted of 3179 individuals, 1735 patients (580 FTD, 995 ALS, and 160 FTD-ALS) and 1444 controls. Demographic information on these individuals is summarized in Supplementary Table 1. All patients and controls were genotyped for the C9ORF72 GGGGCC repeat using our previously published 2-step protocol (DeJesus-Hernandez et al., 2011). Statistical analyses were performed using R Statistical Software v2.11.0 (open source software, available at http://cran.r-project.org). To

Results

We identified 211 patients (59 FTD, 94 ALS, and 58 FTD-ALS) carrying a pathogenic GGGGCC repeat expansion. The maximum number of repeats within the normal range that we identified was 25 in a patient and 23 in a control. For a complete overview of the allele counts in patients and controls see Supplementary Tables 2 and 3. A graphical representation of the number of repeats on the normal alleles in nonmutation carriers in each of the disease groups compared with controls is provided in

Discussion

This is the first study to examine whether normal—unexpanded—C9ORF72 GGGGCC hexanucleotide repeat alleles, play a role in disease presentation or affect age at disease onset in patients with or without a pathogenic C9ORF72 repeat expansion. C9ORF72 mutation carriers can present with FTD, ALS, or a combination of both diseases and the age at which first symptoms appear varies widely. However, using our large collection of 211 C9ORF72 mutation carriers, we did not observe any evidence for a role

Disclosure statement

RR and MD-J have a patent on the discovery of the hexanucleotide repeat expansion in C9ORF72. All other authors report no conflict of interest.

Acknowledgements

We would like to thank all the patients and their families who took part in this study. ALS samples from the NINDS Human Genetics Resource Center DNA and Cell Line Repository (ccr.coriell.org/ninds) were included in this study. This work was supported by the ALS Therapy Alliance, the Consortium for Frontotemporal Dementia (CFR), The Winspear Family Center for Research on the Neuropathology of Alzheimer Disease, the McCune Foundation, NIH grants R01 NS065782, P50 AG16574, P50 NS072187-01S2 and

References (0)

Cited by (84)

  • Invited review: Unearthing the mechanisms of age-related neurodegenerative disease using Caenorhabditis elegans

    2022, Comparative Biochemistry and Physiology -Part A : Molecular and Integrative Physiology
  • FDG-PET in presymptomatic C9orf72 mutation carriers

    2021, NeuroImage: Clinical
    Citation Excerpt :

    Rohrer et al., 2013) Furthermore, the size of the pathogenic C9orf72 repeat expansion does not seem to influence its phenotypic expression; therefore, the C9orf72+ individuals can be considered genetically homogeneous. ( Rutherford et al., 2012) Characterization of the longitudinal change in early disease stage is essential to better understand the natural history of disease and to develop rational clinical endpoints for therapeutic trials. Our current findings demonstrate that FDG-PET hypometabolism is detectable in asymptomatic C9orf72 mutation carriers on average up to 10 years prior to onset of dementia.

  • Quadruplex targets in neurodegenerative diseases

    2020, Annual Reports in Medicinal Chemistry
  • C9orf72 and intracerebral hemorrhage

    2019, Neurobiology of Aging
    Citation Excerpt :

    We evaluated the number of repeats as continuous (dominant and additive) and binary variable (dichotomized into <20 and ≥20 repeats) (Rutherford et al., 2012; Van Mossevelde et al., 2017). To evaluate for dominant effect, we used the number of repeats of the longer of the 2 normal alleles and for additive effect the summed repeat number of both alleles (Rutherford et al., 2012). Outcome variables in patients with ICH were history of dementia, SVD burden, and CAA.

View all citing articles on Scopus
View full text