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Published in final edited form as: Neurobiol Aging. 2014 May 2;35(10):2421.e13–2421.e17. doi: 10.1016/j.neurobiolaging.2014.04.016

Ataxin-2 as potential disease modifier in C9ORF72 expansion carriers

Marka van Blitterswijk a, Bianca Mullen a, Michael G Heckman b, Matthew C Baker a, Mariely DeJesus-Hernandez a, Patricia H Brown a, Melissa E Murray a, Ging-Yuek R Hsiung c, Heather Stewart c, Anna M Karydas d, Elizabeth Finger e, Andrew Kertesz e, Eileen H Bigio f, Sandra Weintraub f, Marsel Mesulam f, Kimmo J Hatanpaa g, Charles L White III g, Manuela Neumann h, Michael J Strong i, Thomas G Beach j, Zbigniew K Wszolek k, Carol Lippa l, Richard Caselli m, Leonard Petrucelli a, Keith A Josephs n, Joseph E Parisi n, David S Knopman n, Ronald C Petersen n, Ian R Mackenzie o, William W Seeley d, Lea T Grinberg d, Bruce L Miller d, Kevin B Boylan k, Neill R Graff-Radford k, Bradley F Boeve n, Dennis W Dickson a, Rosa Rademakers a,*
PMCID: PMC4105839  NIHMSID: NIHMS601570  PMID: 24866401

Abstract

Repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are an important cause of both motor neuron disease (MND) and frontotemporal dementia (FTD). Currently, little is known about factors that could account for the phenotypic heterogeneity detected in C9ORF72 expansion carriers. In this study, we investigated four genes that could represent genetic modifiers: ataxin-2 (ATXN2), non-imprinted in Prader-Willi/Angelman syndrome 1 (NIPA1), survival motor neuron 1 (SMN1) and survival motor neuron 2 (SMN2). Assessment of these genes, in a unique cohort of 331 C9ORF72 expansion carriers and 376 controls, revealed that intermediate repeat lengths in ATXN2 possibly act as disease modifier in C9ORF72 expansion carriers; no evidence was provided for a potential role of NIPA1, SMN1 or SMN2. The effects of intermediate ATXN2 repeats were most profound in probands with MND or FTD/MND (2.1% versus 0% in controls, P=0.013), whereas the frequency in probands with FTD was identical to controls. Though intermediate ATXN2 repeats were already known to be associated with MND risk, previous reports did not focus on individuals with clear pathogenic mutations, such as repeat expansions in C9ORF72. Based on our present findings, we postulate that intermediate ATXN2 repeat lengths may render C9ORF72 expansion carriers more susceptible to the development of MND; further studies are needed, however, to validate our findings.

Keywords: C9ORF72, ataxin-2, ATXN2, motor neuron disease, amyotrophic lateral sclerosis, frontotemporal dementia, disease modifier

1. Introduction

To date, hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are the most frequent genetic cause of two fatal neurodegenerative diseases: motor neuron disease (MND) and frontotemporal dementia (FTD) (DeJesus-Hernandez et al., 2011; Renton et al., 2011). It is largely unknown, however, why some of those expansion carriers develop MND, whereas others develop FTD or a combination of both diseases. We have already shown that GGGGCC expansion size and the presence of additional mutations in FTD-associated genes could act as disease modifiers in expansion carriers (van Blitterswijk et al., 2013a; van Blitterswijk et al., 2013b). Moreover, we recently reported that variants in transmembrane protein 106 B (TMEM106B) protect against developing FTD in subjects harboring C9ORF72 repeat expansions (van Blitterswijk et al., 2014).

In general, an intermediate CAG repeat length in ataxin-2 (ATXN2) (Elden et al., 2010; Lee et al., 2011; Ross et al., 2011; Van Damme et al., 2011), an increased GCG repeat length in non-imprinted in Prader-Willi/Angelman syndrome 1 (NIPA1) (Blauw et al., 2012b), and abnormal copy numbers of survival motor neuron 1 (SMN1) and/or survival motor neuron 2 (SMN2) (Blauw et al., 2012a; Corcia et al., 2006; Corcia et al., 2002; Veldink et al., 2005; Veldink et al., 2001) seem to be associated with MND risk. In our present study, we investigated whether variants in these four genes may act as disease modifiers in the presence of a C9ORF72 repeat expansion.

2. Methods

2.1. Study population

Our study cohort comprised 331 carriers of C9ORF72 repeat expansions (Table 1), provided by the Mayo Clinic (n=121), Coriell Research Institute (n=71), University of British Columbia, Canada (n=58), University of California, San Francisco (n=38), Robarts Research Institute (n=11), Northwestern University Feinberg School of Medicine (n=9), Drexel University College of Medicine (n=7), University of Western Ontario, Canada (n=7), Banner Sun Health Research Institute (n=5), and University of Tübingen (n=4). Based on clinical and/or pathological data available these subjects were diagnosed with MND (n=127), FTD/MND (n=78) or FTD (n=92), with another diagnosis (n=7; e.g. Alzheimer’s disease, alcohol abuse or behavioral impairment), or they were asymptomatic at time of last evaluation (n=27; age at evaluation: 43.6±12.7).

Table 1.

Characteristics of C9ORF72 expansion carriers and controls

Group N Female gender Age Age at onset Pathological diagnosis
Controls 376 173 (46.0%) 61.2 ± 10.2 (35 – 90) N/A N/A
All expansion carriers 331 150 (45.3%) 59.3 ± 10.0 (35 – 90) 56.7 ± 9.2 (34 – 83) 124 (37.5%)
MND, FTD/MND, and FTD probands 266 116 (43.6%) 59.6 ± 10.0 (35 – 90) 56.8 ± 9.1 (34 – 83) 113 (42.5%)
MND and FTD/MND probands 191 86 (45.0%) 58.2 ± 8.7 (37 – 83) 56.4 ± 8.8 (34 – 83) 67 (35.1%)
MND probands 120 61 (50.8%) 56.9 ± 8.6 (37 – 83) 56.5 ± 8.7 (37 – 83) 16 (13.3%)
FTD/MND probands 71 25 (35.2%) 60.6 ± 8.5 (39 – 80) 56.2 ± 9.0 (34 – 74) 51 (71.8%)
FTD probands 75 30 (40.0%) 62.8 ± 12.1 (35 – 90) 57.6 ± 9.8 (34 – 79) 46 (61.3%)
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Continuous variables are summarized with the sample mean ± standard deviation (range). The age provided is age at blood draw in controls, age at onset in clinically diagnosed patients, and age at death in pathologically diagnosed patients. Information was unavailable regarding age (N=41) and age at onset (N=59).

We focused our primary analysis on the 266 unrelated probands with MND (n=120), FTD/MND (n=71) or FTD (n=75) in order to fulfill the statistical assumption of independent measurements, and on a group of neurologically normal controls of similar age and gender obtained through the Mayo Clinic (n=376; Table 1). The 65 remaining expansion carriers who were family members or who had received another diagnosis were included in secondary analyses to examine the sensitivity of our results.

2.2. Genetic analysis

The presence of a GGGGCC repeat in C9ORF72 was determined using a 2-step protocol (DeJesus-Hernandez et al., 2011). Briefly, genomic DNA was PCR-amplified with genotyping primers and one fluorescently labeled primer, followed by fragment length analysis. Repeat-primed PCR was performed for those individuals who were shown to be homozygous for C9ORF72 repeats. A characteristic stutter pattern was considered evidence of a C9ORF72 repeat expansion.

ATXN2 repeat length was assessed in cases and controls using fragment analysis with fluorescently labeled primers on an ABI 3730 Genome Analyzer (Applied Biosystems) and GeneMapper software (primer sequences are available upon request). The repeat length of NIPA1 was also determined in cases and controls with fragment analysis, as described elsewhere (Blauw et al., 2012b). SMN1 and SMN2 copy numbers were investigated in our cases with multiplex ligation-dependent probe amplification (MLPA) assays (MRC Holland, the Netherlands), using the manufacturer’s instructions.

2.3. Statistical analysis

We compared the distribution of repeat lengths and copy numbers between C9ORF72 expansion carriers and controls, utilizing Fisher’s exact test. The following categorization was used: normal (≤ 27 repeat units) and intermediate (>27 repeat units) for ATXN2, short (≤ 6 repeat units), normal (7–8 repeat units) and long (>8 repeat units) for NIPA1, and homozygous deletion (0 copies), heterozygous deletion (1 copy), normal (2 copies), duplication (3 copies) and triplication (4 copies) for both SMN1 and SMN2. The distribution was compared to controls for our entire cohort, and also separately for our disease subgroups. For ATXN2 and NIPA1 we used control data generated as part of this study, whereas a previously published meta-analysis was used for SMN1 and SMN2 (Blauw et al., 2012a). We also assessed associations of repeat lengths and copy numbers with age at onset using a Wilcoxon rank sum test or a Kruskal-Wallis rank sum test.

To allow further investigations of repeat lengths in ATXN2, we also used an alternative categorization of ≤23 repeat units versus >23 repeat units. This alternative categorization facilitated comparisons of both age at onset and survival after onset in our cases, because of the larger number of subjects in each category. For this extra analysis we used a Wilcoxon rank sum test (age at onset) and a log-rank test (survival after onset). Additionally, in making these comparisons, we utilized linear regression models adjusted for gender and disease subgroup (age at onset comparisons) and Cox proportional hazards regression models adjusted for age at onset, gender, and disease subgroup (survival after onset comparisons) to address the potential confounding influences of these variables. P-values ≤ 0.05 were considered as statistically significant. All statistical analyses were performed using R Statistical Software (version 2.14.0; R Foundation for Statistical Computing).

3. Results

The ATXN2 repeat length ranged from 14 to 31 repeat units in C9ORF72 expansion carriers, and from 17 to 27 repeat units in controls, with 22 and 23 repeats being most common (allele frequency of 96%). Intermediate ATXN2 repeat lengths were identified in 1.5% of our 266 MND, FTD/MND and FTD probands as compared to 0% of our 376 controls (P=0.029; Table 2). When focusing on disease subgroups, intermediate repeat lengths were detected in 2.1% of probands with either MND or FTD/MND (P=0.013; versus controls), in 1.7% of probands with MND (P=0.058; versus controls), in 2.8% of probands with FTD/MND (P=0.025; versus controls), and in 0% of probands with FTD (P=1.00; versus controls). These findings were comparable when including the 65 remaining expansion carriers who were family members or who had received another diagnosis (e.g. 2.1% of all expansion carriers [P=0.005; versus controls], and 2.0% of MND or FTD/MND patients [P=0.015; versus controls]; Supplementary Table 1).

Table 2.

Associations of ATXN2, NIPA1, SMN1, and SMN2 with disease – analysis of MND, FTD/MND, and FTD probands

Repeat length or copy number Controls a MND, FTD/MND, and FTD probands (N=266) MND and FTD/MND probands (N=191) MND probands (N=120) FTD/MND probands (N=71) FTD probands (N=75)
ATXN2 repeat length
 Normal 376 (100.0%) 262 (98.5%) 187 (97.9%) 118 (98.3%) 69 (97.2%) 75 (100.0%)
 Intermediate 0 (0.0%) 4 (1.5%) 4 (2.1%) 2 (1.7%) 2 (2.8%) 0 (0.0%)
 Comparison with controls N/A P=0.029 P=0.013 P=0.058 P=0.025 P=1.00
NIPA1 repeat length
 Short 2 (0.5%) 1 (0.4%) 1 (0.5%) 1 (0.8%) 0 (0.0%) 0 (0.0%)
 Normal 361 (96.0%) 257 (96.6%) 184 (96.3%) 115 (95.8%) 69 (97.2%) 73 (97.3%)
 Long 13 (3.5%) 8 (3.0%) 6 (3.1%) 4 (3.3%) 2 (2.8%) 2 (2.7%)
 Comparison with controls N/A P=0.93 P=1.00 P=0.90 P=1.00 P=1.00
SMN1 copy number
 1 39 (2.2%) 5 (2.0%) 5 (2.7%) 3 (2.5%) 2 (3.0%) 0 (0.0%)
 2 1673 (94.0%) 239 (94.1%) 172 (93.0%) 112 (94.9%) 60 (89.6%) 67 (97.1%)
 3 67 (3.8%) 10 (3.9%) 8 (4.3%) 3 (2.5%) 5 (7.5%) 2 (2.9%)
 4 1 (<0.1%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%)
 Comparison with controls N/A P=0.98 P=0.76 P=0.82 P=0.23 P=0.66
SMN2 copy number
 0 147 (8.3%) 30 (11.8%) 22 (11.9%) 13 (11.0%) 9 (13.4%) 8 (11.6%)
 1 663 (37.2%) 81 (31.9%) 61 (33.0%) 36 (30.5%) 25 (37.3%) 20 (29.0%)
 2 888 (49.9%) 134 (52.8%) 95 (51.4%) 63 (53.4%) 32 (47.8%) 39 (56.5%)
 3 79 (4.4%) 8 (3.1%) 6 (3.2%) 5 (4.2%) 1 (1.5%) 2 (2.9%)
 4 3 (0.2%) 1 (0.4%) 1 (0.5%) 1 (0.8%) 0 (0.0%) 0 (0.0%)
 Comparison with controls N/A P=0.11 P=0.21 P=0.21 P=0.44 P=0.46
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P-values results from Fisher’s exact test, comparing the repeat length or copy number distribution in the given group to that of controls.

a

Data for SMN1 and SMN2 in control subjects was not obtained in the current study (Blauw et al., 2012a).

The distribution of NIPA1 repeat lengths did not differ significantly between all probands and controls (P=0.93), or between any of the disease subgroups and controls (P≥0.90; Table 2). Eight repeat units (allele frequency of 79%) and 7 repeat units (allele frequency of 19%) were most prevalent, followed by 10 repeat units (allele frequency of <2%). For SMN1 and SMN2 we did not detect significant differences in copy number between all probands and controls (P=0.98 and P=0.11), or when comparing disease subgroups and controls (P≥0.23 and P≥0.21; Table 2). All findings were similar when including the remaining expansion carriers (Supplementary Table 1).

We also investigated associations of repeat lengths and copy numbers with age at onset in all probands and in the subgroup of probands with either MND or FTD/MND; however, there was no evidence of a difference in age at onset for any of the genes investigated in this study (Table 3), and these findings did not change when including the remaining expansion carriers (Supplementary Table 2).

Table 3.

Associations of ATXN2, NIPA1, SMN1, and SMN2 with age at disease onset – analysis of MND, FTD/MND, and FTD probands

MND, FTD/MND, and FTD probands (N=244) MND and FTD/MND probands (N=176)
Repeat length or copy number N Mean (range) age at onset N Mean (range) age at onset
ATXN2 repeat length
 Normal 240 56.8 (34 – 83) 172 56.5 (34 – 83)
 Intermediate 4 55.6 (52 – 59) 4 55.6 (52 – 59)
 Test of difference P=0.78 P=0.87
NIPA1 repeat length a
 Normal 236 56.7 (34 – 83) 170 56.3 (34 – 83)
 Long 8 60.1 (50 – 68) 6 60.2 (50 – 68)
 Test of difference P=0.22 P=0.19
SMN1 copy number
 1 4 50.3 (46 – 60) 4 50.3 (46 – 60)
 2 219 56.9 (34 – 83) 159 56.7 (34 – 83)
 3 9 54.3 (43 – 65) 7 53.2 (43 – 61)
 Test of difference P=0.22 P=0.21
SMN2 copy number
 0 26 58.1 (41 – 83) 19 56.8 (41 – 83)
 1 75 56.1 (34 – 74) 57 55.8 (34 – 74)
 2 123 56.8 (34 – 80) 88 56.6 (39 – 80)
 3 or 4 8 56.4 (46 – 66) 6 57.6 (46 – 66)
 Test of difference P=0.97 P=0.95
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a

Due to the fact that only 1 patient had a short NIPA1 repeat length, short and normal NIPA1 repeat length categories were combined in age at onset association analysis. Tests of difference in age at onset between groups result from a Wilcoxon rank sum test (ATXN2 repeat length, NIPA1 repeat length), or a Kruskal-Wallis rank sum test (SMN1 copy number, SMN2 copy number).

To further investigate ATXN2 repeat length, we also used an alternative categorization (≤23 versus >23). Due to the larger number of samples in each category this alternative categorization has more power to detect associations, and allows adjustment of potential confounding variables in age at onset and survival after onset analyses. We did not detect a significant difference in age at onset (P≥0.81; Supplementary Table 3) or survival after onset (P≥0.12; Supplementary Table 4) with this alternative categorization in all probands nor in probands with either MND or FTD/MND. These findings were consistent when including additional expansion carriers (Supplementary Table 3 and Supplementary Table 4), and when performing a multivariable analysis adjusted for age at onset, gender and disease subgroup (data not shown).

4. Discussion

We demonstrate that intermediate repeat lengths in ATXN2 might modify the disease phenotype of C9ORF72 expansion carriers. These intermediate repeats were more frequently encountered in our expansion carriers than in controls. Interestingly, they were present in 2.1% of our probands with MND or FTD/MND (P=0.013; versus controls), but in none of our probands with FTD (P=1.00; versus controls). We did not find associations between ATXN2 repeat length and age at onset or survival after onset. Furthermore, no significant differences were detected in repeat length or copy number of other genes investigated in this study (NIPA1, SMN1, and SMN2). Based on our findings, we speculate that intermediate ATXN2 repeats, previously shown to increase MND risk, may also predispose to the development of MND in carriers of C9ORF72 expansions, influencing their phenotype.

Ataxin-2 plays a vital role in RNA metabolism, associates with RNA-binding proteins, and affects many cellular processes, including calcium signaling, glutamate toxicity and mitochondrial stress (van den Heuvel et al., 2014). Importantly, a yeast screen also identified ataxin-2 as a potent enhancer of transactive response DNA-binding protein 43 (TDP-43) toxicity (Elden et al., 2010). Moreover, it has been shown that intermediate ATXN2 repeats are associated with MND (Elden et al., 2010). In Drosophila, these intermediate repeats result in even more pronounced TDP-43 toxicity than repeats in the wild-type range (Kim et al., 2013). The interaction between ataxin-2 and TDP-43 is probably mediated by poly(A)-binding protein (PABP) (Kim et al., 2013), and is thought to promote the recruitment of TDP-43 to stress granules, to affect the ability of stress granules to dissolve and/or to impair the return of TDP-43 to the nucleus, especially upon exposure to stress (Li et al., 2013).

Since the initial report in 2010, many studies have confirmed the association between intermediate ATXN2 repeat lengths and MND risk (Chen et al., 2011; Conforti et al., 2012; Corrado et al., 2011; Daoud et al., 2011; Gellera et al., 2012; Gispert et al., 2012; Laffita-Mesa et al., 2013; Lahut et al., 2012; Lee et al., 2011; Liu et al., 2013; Ross et al., 2011; Soraru et al., 2011; Van Damme et al., 2011; Van Langenhove et al., 2012). Based on these studies and on our present findings, we reanalyzed MND cases included in our original ATXN2 report (Ross et al., 2011) supplemented with new MND cases. When excluding carriers of C9ORF72 repeat expansions, and when using our cut-off of 28 ATXN2 repeats, approximately 3% of our 525 MND patients harbored intermediate ATXN2 repeats. It should be emphasized, therefore, that the frequency of intermediate ATXN2 repeats in studies investigating MND risk seems similar to that detected in our current study focusing on those patients with C9ORF72 repeat expansions. The effects of ATXN2 on MND risk, thus, are not specific to C9ORF72 expansion carriers, but it is interesting that even on the background of a strong pathogenic mutation such as a repeat expansion in C9ORF72, ATXN2 is still able to confer MND risk, thereby modulating the disease phenotype.

Several of the aforementioned studies highlighted that ATXN2 repeat length did not appear to influence clinical characteristics, including age at onset and survival after onset (Chen et al., 2011; Conforti et al., 2012; Corrado et al., 2011; Daoud et al., 2011; Gispert et al., 2012; Lee et al., 2011; Liu et al., 2013; Soraru et al., 2011; Van Damme et al., 2011), which is well in line with our present findings. Furthermore, our results are consistent with reports that did not find associations between ATXN2 repeat lengths and FTD (Ross et al., 2011; Van Langenhove et al., 2012).

Our study has some limitations. Because of the relatively low number of subjects in several categories, the possibility of type II error (i.e. a false-negative association) should be considered. Additionally, for our case-control analyses, we used 28 repeats as cut-off to define intermediate ATXN2 repeat lengths, based on the upper limit observed in our control cohort. In literature, however, there is no consensus on the definition of intermediate ATXN2 repeats and different cut-offs have been used, depending on the population studied (e.g. 24, 27, 28, 29, 30, 31 and 32 repeats) (Chen et al., 2011; Conforti et al., 2012; Corrado et al., 2011; Daoud et al., 2011; Elden et al., 2010; Gellera et al., 2012; Gispert et al., 2012; Laffita-Mesa et al., 2013; Lahut et al., 2012; Lattante et al., 2012; Lee et al., 2011; Liu et al., 2013; Ross et al., 2011; Soraru et al., 2011; Van Damme et al., 2011; Van Langenhove et al., 2012). Lastly, we used control data from a recent meta-analysis for SMN1 and SMN2 (Blauw et al., 2012a). The distribution of our SMN1 and SMN2 copy numbers in cases, and our ATXN2 and NIPA1 repeat lengths in both cases and controls, however, is very comparable to that reported in literature (Blauw et al., 2012a; Blauw et al., 2012b; Laffita-Mesa et al., 2013), and hence, it seems unlikely that usage of this data severely impacted our findings related to SMN1 and SMN2.

Previously, we showed that variants in TMEM106B protect C9ORF72 expansion carriers from developing FTD (van Blitterswijk et al., 2014). Importantly, our present findings reveal that intermediate repeat lengths in ATXN2 possibly drive C9ORF72 expansion carriers towards MND, potentially due to effects on TDP-43 toxicity, stress granule formation, RNA metabolism, and/or other cellular processes involved in MND pathogenesis. Thus, both TMEM106B and ATXN2 may contribute to the phenotypic heterogeneity detected in C9ORF72 expansion carriers. Further studies are needed, however, to confirm these interesting findings and to elucidate the underlying mechanisms.

Supplementary Material

01

Acknowledgments

Source of funding: This project was supported by NIH grants R01 NS080882, R01 NS065782, R01 AG026251, P01 AG017586, P50 NS072187, P50 AG016574, P30 AG013854, P30 AG012300, P30 AG019610, U01 AG006786, the ALS Therapy Alliance, and the Consortium for Frontotemporal Dementia Research. Data collection at University of British Columbia is supported by CIHR grant #179009. Dr. Van Blitterswijk is supported by the Milton Safenowitz Post-Doctoral Fellowship for ALS research from the ALS Association.

Footnotes

Disclosure statement: Mrs. DeJesus-Hernandez and Dr. Rademakers hold a patent on methods to screen for the hexanucleotide repeat expansion in the C9ORF72 gene; the other authors declare that they have no actual or potential conflict of interest. None of this material has been published or is under consideration for publication elsewhere. Each author has contributed to the experimental design and/or critical revision of the manuscript, and all authors have read and approved the manuscript. All subjects agreed to be in the study, and biological samples were obtained after informed consent with ethical committee approval from the respective institutions.

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