Frontotemporal Degeneration and Amyotrophic Lateral Sclerosis (C9orf72)
| Dred_ID | RD00056 |
| OMIM ID | 105550 |
| Disease name | Frontotemporal Degeneration and Amyotrophic Lateral Sclerosis |
| Alternative names | FTD and ALS |
| Category | Genetic diseases, Neuronal diseases, Rare diseases, Mental diseases |
| Phenotype | OMIM: Frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis (ALS) is an autosomal dominant neurodegenerative disorder characterized by adult onset of one or both of these features in an affected individual, with significant intrafamilial variation. The disorder is genetically and pathologically heterogeneous (summary by Vance et al., 2006). Patients with C9ORF72 repeat expansions tend to show a lower age of onset, shorter survival, bulbar symptom onset, increased incidence of neurodegenerative disease in relatives, and a propensity toward psychosis or hallucinations compared to patients with other forms of ALS and/or FTD (summary by Harms et al., 2013). Patients with C9ORF72 repeat expansions also show psychiatric disturbances that may predate the onset of dementia (Meisler et al., 2013; Gomez-Tortosa et al., 2013). For a general phenotypic description of frontotemporal dementia, also known as frontotemporal lobar degeneration (FTLD), see 600274. For a general discussion of motor neuron disease (MND), see amyotrophic lateral sclerosis-1. |
| Miscellaneouse | OMIM: onset in adulthood rapidly progressive patients can have als, ftd, or both intrafamilial variability |
| Prevalence | N/A [source: MalaCards] |
| Inheritance | Autosomal dominant |
| Anticipation | Yes |
| Evidence | Strong |
| Gene symbol | C9orf72 |
| Alias symbols | ALSFTD; FTDALS |
| Gene name | chromosome 9 open reading frame 72 |
| Gene map locus | 9p21.2; chr9:27,535,640-27,573,866(-) |
| Ensembl Gene ID | ENSG00000147894 |
| Gene expression and Gene Ontology | BioGPS |
| Protein expression | Human Protein Atlas |
| Gene sequence | Sequence |
| Variation | ClinVar, dbSNP |
| Gene conservation | Gene Conservation from UCSC Genome Browser |
| Gene Description | The protein encoded by this gene plays an important role in the regulation of endosomal trafficking, and has been shown to interact with Rab proteins that are involved in autophagy and endocytic transport. Expansion of a GGGGCC repeat from 2-22 copies to 700-1600 copies in the intronic sequence between alternate 5' exons in transcripts from this gene is associated with 9p-linked ALS (amyotrophic lateral sclerosis) and FTD (frontotemporal dementia) (PMID: 21944778, 21944779). Studies suggest that hexanucleotide expansions could result in the selective stabilization of repeat-containing pre-mRNA, and the accumulation of insoluble dipeptide repeat protein aggregates that could be pathogenic in FTD-ALS patients (PMID: 23393093). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2016] |
| Repeat unit | GGGGCC |
| Normal repeat copies | 2-19 |
| Pathogenic repeat copies | ≥250 |
| Gene | C9ORF72 |
| Repeat location | intron |
| Chromosome locus | chr9:27573526-27573546 (-) |
| Repeat conservation | Repeat Conservation from UCSC Genome Browser |
| Toxic cause | RNA |
| Possible toxicity | Both DeJesus-Hernandez et al. (2011) and Renton et al. (2011) concluded that it is the most common genetic abnormality in FTD/ALS. The expanded repeat is located in the promoter region of C9ORF72 transcript variant 1 and in intron 1 of transcript variants 2 and 3. In the study of DeJesus-Hernandez et al. (2011), transcript-specific cDNA amplified from frozen frontal cortex brain tissue from an affected individual showed absence of the variant 1 transcribed from the mutant RNA, whereas transcription of variants 2 and 3 was normal. mRNA expression analysis of variant 1 was decreased to about 50% in lymphoblast cells from a patient and in frontal cortex samples from other patients. These findings were consistent with a loss-of-function mechanism. However, protein levels of these variants were similar to controls, and analysis of patient frontal cortex and spinal cord tissue showed that the transcribed expanded GGGGCC repeat formed nuclear RNA foci, suggesting a gain-of-function mechanism. |
| Pathway annotation | Reactome, KEGG |
| PMID | 24248382 |
| Authors | Zu T, Liu Y, Bañez-Coronel M, Reid T, Pletnikova O, Lewis J, Miller TM, Harms MB, Falchook AE, Subramony SH, Ostrow LW, Rothstein JD, Troncoso JC, Ranum LP |
| Title | RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia |
| Journal | Proc Natl Acad Sci USA. 110(51):E4968-77 |
| Year | 2013 |
| PMID | 24598541 |
| Authors | Haeusler AR, Donnelly CJ, Periz G, Simko EA, Shaw PG, Kim MS, Maragakis NJ, Troncoso JC, Pandey A, Sattler R, Rothstein JD, Wang J |
| Title | C9orf72 nucleotide repeat structures initiate molecular cascades of disease |
| Journal | Nature. 507(7491):195-200 |
| Year | 2014 |