Ataxin-2 as potential disease modifier in C9ORF72 expansion carriers

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.

Elevated Global DNA Methylation Is Not Exclusive to Amyotrophic Lateral Sclerosis and Is Also Observed in Spinocerebellar Ataxia Types 1 and 2

“…Spinocerebellar ataxia type 1 and 2, along with Huntington’s disease, are characterized by the CAG-repeat expansion (coding for glutamine) in ATXN1 (> 40), ATXN2 (> 34), and huntingtin (> 40), respectively, and are often named polyglutamine diseases [29]. Furthermore, repeats between 27 and 33 (intermediate length expansion) in ATXN2 have also been linked to an increased risk for ALS [30] and progressive supranuclear palsy [31], and it has been suggested that it may act as a disease modifier in C9orf72 expansion carrier patients, leading to ALS rather than FTD [32]. Furthermore, recent studies have reported a reduced pathology and increased lifespan in a TDP-43 mouse model when crossed with ataxin-2 knockout mice [33].…”

C9orf72 Repeat Expansion Frequency among Patients with Huntington Disease Genetic Testing

“…Only rarely has full-penetrance repeat expansion of HTT been identified in conjunction with another disease-causing repeat expansion (ATXN8) [78]. Interestingly, the intermediate CAG repeat length of the spinocerebellar ataxia type 2-related ATXN2 gene is associated with increased risk for sporadic and familial ALS [79,80]; furthermore, it is overrepresented among individuals with C9orf72 expansion and motor neuron disease but is absent in individuals with FTD [81]. HTT repeat expansion has been investigated as an ALS genetic disease modifier, but no association was identified [82,83].…”

R-loops highlight the nucleus in ALS

“…38,40 It remains difficult to completely eliminate the possibility that particularly severe mutations/ disruptions of genes currently viewed as modifiers may actually be sufficient to trigger ALS. 38 Importantly, the fact that ALS is linked to many seemingly different genes has often hindered research aiming to decipher the pathobiological processes underlying the disease.…”

“…Consistent with this rationale, a recent study identified intermediate length polyQ expansion of ATXN2 as a critical disease modifier in C9ORF72 HRE patients. 40 Alternatively, C9ORF72 HRE may be operating upstream of wild-type ATXN2. In this case, it is possible that accumulating truncated G4RNA-containing C9ORF72 HRE transcripts may sequester the RNAbinding ATXN2 along with nucleolin within ribonucleoprotein aggregates.…”