C9ORF72 hexanucleotide repeat expansions in patients with ALS from the Coriell Cell Repository.
ABSTRACT Amyotrophic lateral sclerosis (ALS) is a neurologic disorder, characterized by progressive degeneration of both upper and lower motor neurons in the brain and spinal cord. Previous genetic studies have identified mutations in Cu/Zn superoxide dismutase (SOD1), transactive response binding protein 43 (TARDBP), fused in sarcoma (FUS), and valosin containing protein (VCP) genes as being causative of disease.(1) Recently, an expansion of the noncoding GGGGCC hexanucleotide repeat in chromosome 9 open reading frame 72 (C9ORF72) was identified as an important novel genetic defect in patients with ALS without or with frontotemporal dementia (FTD-ALS).(2,3) Here we report the frequency of this new mutation and its associated clinical features in a cohort of patients obtained from the Coriell Cell Repository.
Full-textDOI: · Available from: Nicola Jayne Rutherford, Mar 27, 2014
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ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that results in progressive degeneration of motor neurons, ultimately leading to paralysis and death. Approximately 10% of ALS cases are familial, with the remaining 90% of cases being sporadic. Genetic studies in familial cases of ALS have been extremely informative in determining the causative mutations behind ALS, especially as the same mutations identified in familial ALS can also cause sporadic disease. However, the cause of ALS in approximately 30% of familial cases and in the majority of sporadic cases remains unknown. Sporadic ALS cases represent an underutilized resource for genetic information about ALS; therefore, we undertook a targeted sequencing approach of 169 known and candidate ALS disease genes in 242 sporadic ALS cases and 129 matched controls to try to identify novel variants linked to ALS. We found a significant enrichment in novel and rare variants in cases versus controls, indicating that we are likely identifying disease associated mutations. This study highlights the utility of next generation sequencing techniques combined with functional studies and rare variant analysis tools to provide insight into the genetic etiology of a heterogeneous sporadic disease.PLoS Genetics 10/2014; 10(10):e1004704. DOI:10.1371/journal.pgen.1004704 · 8.17 Impact Factor
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ABSTRACT: The discovery that a hexanucleotide repeat expansion in C9orf72 is the most numerous genetic variant of both amyotrophic lateral sclerosis and frontotemporal dementia has opened a rapidly growing field, which may provide long hoped for advances in the understanding and treatment of these devastating diseases. In this review we describe the various phenotypes, clinical and pathological, associated with expansion of C9orf72, which go beyond amyotrophic lateral sclerosis and frontotemporal dementia to include neurodegeneration more broadly. Next we take a step back and summarize the current understanding of the C9orf72 expansion and its protein products at a molecular level. Three mechanisms are prominent: toxicity mediated directly by RNA transcribed from the repeat; toxicity mediated by dipeptide repeat proteins translated from the repeat sequence; and haploinsufficiency resulting from reduced transcription of the C9orf72 exonic sequence. A series of exciting advances have recently described how dipeptide repeat proteins might interfere with the normal role of the nucleolus in maturation of RNA binding proteins and in production of ribosomes. Importantly, these mechanisms are unlikely to be mutually exclusive. We draw attention to the fact that clinical and pathological similarities to other genetic variants without a repeat expansion must not be overlooked in ascribing a pathogenic mechanism to C9orf72-disease. Finally, with a view to impact on patient care, we discuss current practice with respect to genetic screening in patients with and without a family history of disease, and the most promising developments towards therapy that have been reported to date.Journal of the American Society for Experimental NeuroTherapeutics 03/2015; 12(2). DOI:10.1007/s13311-015-0342-1 · 3.88 Impact Factor
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ABSTRACT: Recent works have demonstrated an expansion of the GGGGCC hexanucleotide repeat in the first intron of chromosome 9 open reading frame 72 (C9ORF72), encoding an unknown C9ORF72 protein, which was responsible for an unprecedented large proportion of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) cases of European ancestry. C9ORF72 is expressed in most tissues including the brain. Emerging evidence has demonstrated that C9ORF72 mutations could reduce the level of C9ORF72 variant 1, which may influence protein expression and the formation of nuclear RNA foci. The spectrum of mutations is broad and provides new insight into neurological diseases. Clinical manifestations of diseases related with C9ORF72 mutations can vary from FTD, ALS, primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), Huntington disease-like syndrome (HDL syndrome), to Alzheimer's disease. In this article, we will review the brief characterizations of the C9ORF72 gene, the expansion mutations, the related disorders, and their features, followed by a discussion of the deficiency knowledge of C9ORF72 mutations. Based on the possible pathological mechanisms of C9ORF72 mutations in ALS and FTD, we can find new targets for the treatment of C9ORF72 mutation-related diseases. Future studies into the mechanisms, taking into consideration the discovery of those disorders, will significantly accelerate new discoveries in this field, including targeting identification of new therapy.Molecular Neurobiology 02/2014; 49(1):386-398. DOI:10.1007/s12035-013-8528-1. · 5.29 Impact Factor