Renton AE, Majounie E, Waite A, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD

Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
Neuron (Impact Factor: 15.05). 09/2011; 72(2):257-68. DOI: 10.1016/j.neuron.2011.09.010
Source: PubMed


The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases. We have previously shown that a founder haplotype, covering the MOBKL2b, IFNK, and C9ORF72 genes, is present in the majority of cases linked to this region. Here we show that there is a large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 on the affected haplotype. This repeat expansion segregates perfectly with disease in the Finnish population, underlying 46.0% of familial ALS and 21.1% of sporadic ALS in that population. Taken together with the D90A SOD1 mutation, 87% of familial ALS in Finland is now explained by a simple monogenic cause. The repeat expansion is also present in one-third of familial ALS cases of outbred European descent, making it the most common genetic cause of these fatal neurodegenerative diseases identified to date.

Download full-text


Available from: Michael Sendtner
  • Source
    • "Immunocytochemistryanalysisonhumanfibloblastsandmouse motorneuronNSC-34celllinerevealedapredominantnuclear localizationofC9ORF72protein(Rentonetal.,2011).Immuno- histochemicalanalysisshowedC9ORF72expressioninneurons andinFTD-andALS-affectedregionswithapredominantcytoplasmicstainingandasynapticlocalization ,butthequantitative mRNAanalysisdemonstratedthattherepeatexpansionreduces C9ORF72transcriptvariant1expressioninlymphoblastcell linesofexpandedrepeatscarriersandinfrontalcortexsamples fromunrelatedFTLD-TDPpatientscarryingexpandedrepeats (DeJesus-Hernandezetal.,2011).Thehexanucleotiderepeti- tionspresentintheC9ORF72transcriptcanformG-tetradunits, calledG-quartets,whereGbasesarerearrangedinacyclicpatternwitheighthydrogenbonds(Frattaetal.,2012).Thepres- enceofRNAG-quadruplexeshasbeenfoundindifferentorgan- ismsandhasbeenobservedinvitroandinvivo(Kikinetal., 2008;Xuetal.,2010b).TranscriptsareenrichedinRNAG- quadruplexesstructuresinthe5′UTR,3′UTRandinthefirst exon(EddyandMaizels,2008;Huppertetal.,2008).Recently amolecularmechanismwasdescribedbywhichtheDNAand RNAG-quadruplexesinC9ORF72createstructuresthatpro- motetheformationofRNA/DNAhybrids(R-loops)(Haeusler etal.,2014).ThepathologicalmechanisminvolvingC9ORF72 geneoritsfunctionarenotclear,evenifseveralstudiesshowed adecreaseinthemRNAlevelsofsomeC9ORF72variantsin ALS,whichsuggestsaloss-of-functionmechanism(DeJesus- Hernandezetal.,2011;Rentonetal.,2011;Gijselincketal.,2012; Morietal.,2013b).Moreover,theaberranttranscriptscontaining TABLE8|ListofmutationsinC9ORF72andtheircharacteristicphenotypes. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by degeneration of the fronto temporal lobes and abnormal protein inclusions. It exhibits a broad clinicopathological spectrum and has been linked to mutations in seven different genes. We will provide a picture, which connects the products of these genes, albeit diverse in nature and function, in a network. Despite the paucity of information available for some of these genes, we believe that RNA processing and post-transcriptional regulation of gene expression might constitute a common theme in the network. Recent studies have unraveled the role of mutations affecting the functions of RNA binding proteins and regulation of microRNAs. This review will combine all the recent findings on genes involved in the pathogenesis of FTD, highlighting the importance of a common network of interactions in order to study and decipher the heterogeneous clinical manifestations associated with FTD. This approach could be helpful for the research of potential therapeutic strategies.
    Full-text · Article · Mar 2015 · Frontiers in Molecular Neuroscience
  • Source
    • "Since the initial discoveries, many more diseases have been identified that are caused by repeat expansions, most of which are trinucleotide repeats, although several diseases are caused by repeats of larger units. Examples include SCA10 caused by an ATTCT expansion (Matsuura et al., 2000) and the recently identified G 4 C 2 repeat expansion in the c9orf72 gene, which is the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (DeJesus-Hernandez et al., 2011; Renton et al., 2011) (Table 1). In addition, it has recently been recognized that different sized expansions can in some cases result in different disease phenotypes. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Abstract The expansion of repeated sequences is the cause of over 30 inherited genetic diseases, including Huntington disease, myotonic dystrophy (types 1 and 2), fragile X syndrome, many spinocerebellar ataxias, and some cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Repeat expansions are dynamic, and disease inheritance and progression are influenced by the size and the rate of expansion. Thus, an understanding of the various cellular mechanisms that cooperate to control or promote repeat expansions is of interest to human health. In addition, the study of repeat expansion and contraction mechanisms has provided insight into how repair pathways operate in the context of structure-forming DNA, as well as insights into non-canonical roles for repair proteins. Here we review the mechanisms of repeat instability, with a special emphasis on the knowledge gained from the various model systems that have been developed to study this topic. We cover the repair pathways and proteins that operate to maintain genome stability, or in some cases cause instability, and the cross-talk and interactions between them.
    Full-text · Article · Jan 2015 · Critical Reviews in Biochemistry and Molecular Biology
  • Source
    • "However, no genomic DNA was available from other family members to study the patterns of segregation and anticipation, and no other FALS cases possessed this expansion. Tandem repeats are frequently associated with neurodegenerative diseases, such as Huntington's disease and spinocerebellar ataxias and have recently been shown to be the most common mutation found in ALS, FTD and ALS/FTD, with the identification of hexanucleotide repeat expansions in the first intron of the C9orf72 gene, located on chromosome 9p21 accounting for 18–55% of FALS cases according to geographic location , being most prevalent in Western Europe [16] [17] [18]. Tri-nucleotide expansions in the NIPA1 [19] and ATXN2 [20] genes also confer risk of ALS. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease causing loss of motor neurons in the spinal cord, brain stem and cerebral cortex. Mutations in the Valosin containing protein (VCP) gene have recently been identified in Familial ALS (FALS) patients, accounting for ~1% of all FALS cases. In order to study the frequency of VCP mutations in UK FALS patients, we have screened the exons known to harbour mutations together with 3' and 5' UTR sequences. No coding changes were identified in this UK cohort and no common polymorphisms were associated with FALS. However, we identified an imperfect hexanucleotide expansion (8 repeats), c.-221_-220insCTGCCACTGCCACTGCCG, in the 5'UTR of a FALS case and a 7-repeat hexanucleotide repeat in a Sporadic ALS case (SALS) that were not present in 219 UK controls. Subsequent screening of sequence data from 1844 controls (1000 genomes Phase 3) revealed the presence of the 7-repeat (0.3%) and a single individual with an 8-repeat containing a homogeneous insert [CTGCCG]3 but no individuals with the heterogeneous insert found in FALS ([CTGCCA]2[CTGCCG]). Two novel single base pair substitutions, c.-360G>C and c.2421+94C>T, were found in FALS cases in the 5' and 3' UTRs respectively. The hexanucleotide expansion and c.-360G>C were predicted to be pathogenic and were found in FALS cases harbouring C9orf72 expansions. The SALS case with a 7 repeat lacked a C9orf72 expansion. We conclude that VCP mutations are not a major cause of FALS in the UK population although novel rare variations in the 5' UTR of the VCP gene may be pathogenic. Copyright © 2015 Elsevier B.V. All rights reserved.
    Full-text · Article · Jan 2015 · Journal of the Neurological Sciences
Show more