Epigenetic Modifications of the C9Orf72 Gene: A Potential Biomarker of Disease?

Abstract

123 ISSN 1479-6708 10.2217/FNL.14.5 © 2014 Future Medicine Ltd Future Neurol. (2014) 9(2), 123–126 Frontotemporal lobar degeneration (FTLD), the most common presenile onset neurodegenerative disease [1], results from progressive neuronal death in the frontal and anterior temporal lobes, and comprises three frontotemporal dementia (FTD) syndromes characterized by changes in personality and social conduct, impairments in naming and word comprehension, or deterioration of expressive language [2]. Approximately 40% of individuals affected with FTLD will eventually develop motor dysfunctions, 15% of which will reach the diagnostic criteria of amyotrophic lateral sclerosis (ALS) [3,4], the third most common neuro degenerative disease and the most common motor neuron disease [5]. Degeneration of upper and lower motor neurons in ALS progressively leads to muscle weakness, spasticity and atrophy [6]. In addition, approximately 40–50% of ALS patients develop cognitive dysfunctions that, in 15–18% of cases, will fill the diagnostic criteria of FTD [7,8]. These two devastating, lethal disorders are now seen as being part of the same disease spectrum, but the pathological mechanisms underlying neuronal degeneration still need to be better understood. Over the last two decades, genetic studies on ALS and FTLD, in particular linkage studies using families exhibiting Mendelian inheritance, shed light on more than two dozen genes implicated in the pathogenesis of both diseases [9]. The most intriguing locus, identified in 2006 on chromosome 9p21 [10–12], has been confirmed in 2010 by a genome-wide association study using the founder Finnish population and remains the most significant genome-wide association study signal observed to date for ALS [13]. A fruitful 5-year effort led to the 2011 discovery of the chromosome 9p21 genetic culprit: a major hexanucleotide repeat expansion carried by up to 50% of familial ALS and up to 25% of familial FTD patients [14,15], making the expanded C9ORF72 gene the most common genetic cause of ALS and FTLD identified to date, and bringing a wind of change to this field of research. This genetic finding provided a further link between these two disorders; patients carrying a pathogenic C9ORF72 repeat expansion are now being collectively referred to as c9FTD/ALS. Comparable repeat expansions have been shown to alter epigenetic mechanisms while simultaneously leading to toxic RNA gainof-function and protein loss-of-function; such dual involvement of toxicity and