Description:
AMYOTROPHIC LATERAL SCLEROSIS 1; ALS1
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Repository
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NINDS Repository
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| Subcollection |
Motor Neuron Disease |
| Quantity |
3 µg |
| Quantitation Method |
Please see our FAQ |
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Biopsy Source
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Peripheral vein
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Sample Source
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DNA from LCL
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Race
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White
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Subject Type
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family with at least 3 members, including 1 proband, not a trio
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Ethnicity
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Not Hispanic/Latino
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Ethnicity
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WELSH
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Country of Origin
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USA
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Family Member
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4
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Family History
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Y
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Relation to Proband
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proband
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Species
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Homo sapiens
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Common Name
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Human
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| Gene |
C9ORF72 |
| Chromosomal Location |
9p21 |
| Allelic Variant 1 |
614260.0001; FRONTOTEMPORAL DEMENTIA AND/OR AMYOTROPHIC LATERAL SCLEROSIS |
| Identified Mutation |
(GGGGCC)n EXPANSION; DeJesus-Hernandez et al. (2011) identified a polymorphic hexanucleotide repeat (GGGGCC) located between the noncoding exons 1a and 1b of the C9ORF72 gene. The maximum size of the repeat in healthy controls was 23 units, whereas it was expanded in members of a large family with frontotemporal dementia and/or anyotrophic lateral sclerosis mapping to chromosome 9p21 (FTDALS; 105550) (Boxer et al., 2011). Affected individuals had expanded repeat units ranging from 700 to 1,600. Further analysis identified this expanded hexanucleotide repeat in 16 (61.5%) of a series of 26 families with the disorder, as well as in 11.7% of familial FTD and 23.5% of familial ALS from 3 patient series. Sporadic cases with the expansion were also identified. Overall, 75 (10.4%) of 722 unrelated patients with FTD, ALS, or both were found to carry an expanded GGGGCC repeat, and DeJesus-Hernandez et al. (2011) concluded that it is the most common genetic abnormality in FTD/ALS. Longer repeats were associated with the A allele at SNP rs3849942, which marked a disease haplotype. The expanded repeat is located in the promoter region of C9ORF72 transcript variant 1 and in intron 1 of transcript variants 2 and 3. Tissue from affected individuals showed reduced or absent mRNA levels of C9ORF72 variants 1 and 3 compared to nonrepeat carriers, 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.
Simultaneously and independently, Renton et al. (2011) identified the GGGGCC expanded repeat as a cause of FTD/ALS in families reported by Pearson et al. (2011) and Mok et al. (2011). The expanded repeat was also found in 46.4% of Finnish familial ALS cases and in 21% of sporadic cases. PCR assays showed that Finnish controls had between 0 and 22 repeats. FISH studies showed that the expansion in a family from Wales (Pearson et al., 2011) was at least 250 repeats. In addition, an expanded repeat was found in 102 (38.1%) of 268 familial ALS probands of European origin. Real-time RT-PCR analysis of expression in frontal cortex tissue from patients and controls did not detect conclusive changes in RNA levels and produced inconsistent results. Nevertheless, Renton et al. (2011) postulated that a disruption in RNA metabolism likely underlies this disorder.
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| Hendricks E, Quihuis AM, Hung ST, Chang J, Dorjsuren N, Der B, Staats KA, Shi Y, Sta Maria NS, Jacobs RE, Ichida JK, The C9ORF72 repeat expansion alters neurodevelopment Cell reports42:112983 2023 |
| PubMed ID: 37590144 |
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| Lai JD, Berlind JE, Fricklas G, Lie C, Urenda JP, Lam K, Sta Maria N, Jacobs R, Yu V, Zhao Z, Ichida JK, KCNJ2 inhibition mitigates mechanical injury in a human brain organoid model of traumatic brain injury Cell stem cell31:519-536.e8 2023 |
| PubMed ID: 38579683 |
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| Lee S, Jun YW, Linares GR, Butler B, Yuva-Adyemir Y, Moore J, Krishnan G, Ruiz-Juarez B, Santana M, Pons M, Silverman N, Weng Z, Ichida JK, Gao FB, Downregulation of Hsp90 and the antimicrobial peptide Mtk suppresses poly(GR)-induced neurotoxicity in C9ORF72-ALS/FTD Neuron111:1381-1390.e6 2022 |
| PubMed ID: 36931278 |
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| Liu Y, Huang Z, Liu H, Ji Z, Arora A, Cai D, Wang H, Liu M, Simko EAJ, Zhang Y, Periz G, Liu Z, Wang J, DNA-initiated epigenetic cascades driven by C9orf72 hexanucleotide repeat Neuron111:1205-1221.e9 2022 |
| PubMed ID: 36822200 |
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| Linares GR, Li Y, Chang WH, Rubin-Sigler J, Mendonca S, Hong S, Eoh Y, Guo W, Huang YH, Chang J, Tu S, Dorjsuren N, Santana M, Hung ST, Yu J, Perez J, Chickering M, Cheng TY, Huang CC, Lee SJ, Deng HJ, Bach KT, Gray K, Subramanyam V, Rosenfeld J, Alworth SV, Goodarzi H, Ichida JK, SYF2 suppression mitigates neurodegeneration in models of diverse forms of ALS Cell stem cell30:171-187.e14 2021 |
| PubMed ID: 36736291 |
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| Renton AE, Majounie E, Waite A, Simón-Sánchez J, Rollinson S, Gibbs JR, Schymick JC, Laaksovirta H, van Swieten JC, Myllykangas L, Kalimo H, Paetau A, Abramzon Y, Remes AM, Kaganovich A, Scholz SW, Duckworth J, Ding J, Harmer DW, Hernandez DG, Johnson JO, Mok K, Ryten M, Trabzuni D, Guerreiro RJ, Orrell RW, Neal J, Murray A, Pearson J, Jansen IE, Sondervan D, Seelaar H, Blake D, Young K, Halliwell N, Callister JB, Toulson G, Richardson A, Gerhard A, Snowden J, Mann D, Neary D, Nalls MA, Peuralinna T, Jansson L, Isoviita VM, Kaivorinne AL, Hölttä-Vuori M, Ikonen E, Sulkava R, Benatar M, Wuu J, Chiò A, Restagno G, Borghero G, Sabatelli M, ITALSGEN Consortium M, Heckerman D, Rogaeva E, Zinman L, Rothstein JD, Sendtner M, Drepper C, Eichler EE, Alkan C, Abdullaev Z, Pack SD, Dutra A, Pak E, Hardy J, Singleton A, Williams NM, Heutink P, Pickering-Brown S, Morris HR, Tienari PJ, Traynor BJ, A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD Neuron72:257-68 2011 |
| PubMed ID: 21944779 |
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