Elsevier

Neurobiology of Aging

Volume 64, April 2018, Pages 160.e1-160.e7
Neurobiology of Aging

Genetic report abstract
High frequency of C9orf72 hexanucleotide repeat expansion in amyotrophic lateral sclerosis patients from two founder populations sharing the same risk haplotype

https://doi.org/10.1016/j.neurobiolaging.2017.12.015Get rights and content

Abstract

We characterized the C9orf72 hexanucleotide repeat expansion (RE) mutation in amyotrophic lateral sclerosis (ALS) patients of 2 distinct origins, Ashkenazi and North Africa Jews (AJ, NAJ), its frequency, and genotype-phenotype correlations. In AJ, 80% of familial ALS (fALS) and 11% of sporadic ALS carried the RE, a total of 12.9% of all AJ-ALS compared to 0.3% in AJ controls (odds ratio [OR] = 44.3, p < 0.0001). In NAJ, 10% of fALS and 9% of sporadic ALS carried the RE, a total of 9.1% of all NAJ-ALS compared to 1% in controls (OR = 9.9, p = 0.0006). We identified a risk haplotype shared among all ALS patients, although an association with age at disease onset, fALS, and dementia were observed only in AJ. Variations were identified downstream the repeats. The risk haplotype and these polymorphisms were at high frequencies in alleles with 8 repeats or more, suggesting sequence instability. The different genotype-phenotype correlations and OR, together with the large range in age at onset, suggest that other modifiers and risk factors may affect penetrance and phenotype in ALS.

Introduction

The G4C2 hexanucleotide repeat expansion in C9orf72 gene is the most common genetic mutation that causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Since first identified (DeJesus-Hernandez et al., 2011, Renton et al., 2011), the mutation was reported in different cohorts around the world with various frequencies among familial ALS (fALS), sporadic ALS (sALS), FTD, and ethnic groups (Abramycheva et al., 2015, Beck et al., 2013, Borghero et al., 2014, Byrne et al., 2012, Chen et al., 2016, Gijselinck et al., 2012, Hubers et al., 2014, Itzcovich et al., 2016, Majounie et al., 2012, Scotter et al., 2017, Simon-Sanchez et al., 2012, Snowden et al., 2012, Stewart et al., 2012, Umoh et al., 2016, Vrabec et al., 2015). Common to all reports is the observation that the expansion of the repeat is more frequent in fALS. Moreover, the expansion is more frequent in ALS patients with dementia, as well as patients affected with FTD. In most studies, a risk haplotype was identified, although some rare cases of expansions on a nonrisk haplotype were reported.

The normal function of C9orf72 protein is still unclear but evidence supports roles in membrane trafficking and autophagy (Ciura et al., 2016, Farg et al., 2014, Sellier et al., 2016, Sullivan et al., 2016, Webster et al., 2016, Yang et al., 2016). Recently, it was shown that the normal C9orf72 protein localizes to processing bodies and is recruited to stress granules upon stress-related stimuli (Maharjan et al., 2017). Moreover, knockdown of C9orf72 completely abolishes stress granule formation and accelerates cell death.

We report here for the first time a high frequency of the G4C2 nucleotide repeat expansion in C9orf72 in a large cohort of ALS patients of Ashkenazi (AJ) and North Africa Jewish (NAJ) origins, which are genetically homogeneous populations and already proved valuable to study the genetics of neurodegenerative disorders, such as Parkinson's disease (Gan-Or et al., 2008, Orr-Urtreger et al., 2007). We further identified the mutation to be on a common, unstable risk haplotype and evaluated genotype-phenotype correlations.

Section snippets

Samples

DNA was extracted from the peripheral blood using standard protocols. Samples included 459 unrelated Jewish ALS patients followed at the ALS Clinic at Tel Aviv Sourasky Medical Center, Tel Aviv, Israel (Table 1). All patients had a diagnosis of clinically definite or probable ALS according to the revised El Escorial criteria (Brooks et al., 2000). The recruitment interval spanned from 2004 to 2016. Included in this cohort are 22 patients with known mutations in OPTN (Goldstein et al., 2016),

Wild-type alleles in the Jewish population

A total of 459 unrelated ALS patients and 900 ethnically matched controls were tested. Among the nonexpanded alleles, the most frequent number of repeats was 2, 5, and 8 in all groups (Fig. 1A, Table A.2, 60.0%, 11.1%, 12.7% of all alleles, respectively). The rest of the nonexpanded alleles were each observed at 0%–4.6% (Table A.2). Intermediate repeats (20–29 repeats) were rare and observed in 7 individuals (Fig. 1B, Table A.2). No difference in the nonexpanded allele distribution was observed

Discussion

We hereby describe for the first time the frequency of C9orf72 expansion mutation in a large cohort of ALS patients from different Jewish origins, demonstrating high carrier rates. Our study indicates that the C9orf72 expansion is the most common genetic cause of ALS in AJ (13%) but only second to the founder OPTN691_692insAG mutation in MJ-ALS patients (8% compared to 14.5%) (Goldstein et al., 2016). Mutations in C9orf72 and OPTN together explain 16% and 20% of all AJ and MJ-ALS, respectively.

Disclosure statement

Bryan J Traynor has a patent pending on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9orf72; Avi Orr-Urtreger received research support from ALS Association and from Kahn and Adelis Foundations; and Vivian E Drory received research support from ALS Association and from Adelis Foundation. Other authors report no conflicts of interest.

Acknowledgements

The authors thank Tova Naiman for her technical assistance. The authors are grateful to the patients and their families who participated in this study.

This work was supported by Adelis Foundation, by ALS Association (grant number 47717), and by Kahn Foundation.

References (34)

  • E. Majounie et al.

    Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study

    Lancet Neurol.

    (2012)
  • A.E. Renton et al.

    A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD

    Neuron

    (2011)
  • E.L. Scotter et al.

    C9ORF72 and UBQLN2 mutations are causes of amyotrophic lateral sclerosis in New Zealand: a genetic and pathologic study using banked human brain tissue

    Neurobiol. Aging

    (2017)
  • K. Vrabec et al.

    Genetic analysis of amyotrophic lateral sclerosis in the Slovenian population

    Neurobiol. Aging

    (2015)
  • G. Borghero et al.

    Genetic architecture of ALS in Sardinia

    Neurobiol. Aging

    (2014)
  • B.R. Brooks et al.

    El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis

    Amyotroph Lateral Scler. Other Motor Neuron Disord.

    (2000)
  • S. Ciura et al.

    The most prevalent genetic cause of ALS-FTD, C9orf72 synergizes the toxicity of ATXN2 intermediate polyglutamine repeats through the autophagy pathway

    Autophagy

    (2016)
  • Cited by (0)

    1

    These authors contributed equally to the manuscript.

    View full text