Characterization of C9orf72 haplotypes to evaluate the effects of normal and pathological variations on its expression and splicing
Autoři:
Israel Ben-Dor aff001; Crystal Pacut aff002; Yuval Nevo aff003; Eva L. Feldman aff002; Benjamin E. Reubinoff aff001
Působiště autorů:
The Hadassah Human Embryonic Stem Cell Research Center, The Goldyne Savad Institute of Gene Therapy, Hadassah Medical Center, Jerusalem, Israel
aff001; Department of Neurology, University of Michigan Medical School, Ann Arbor, MI, United States of America
aff002; Computation Center, Hebrew University–Hadassah Medical School, Jerusalem, Israel
aff003
Vyšlo v časopise:
Characterization of C9orf72 haplotypes to evaluate the effects of normal and pathological variations on its expression and splicing. PLoS Genet 17(3): e1009445. doi:10.1371/journal.pgen.1009445
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1009445
Souhrn
Expansion of the hexanucleotide repeat (HR) in the first intron of the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in Caucasians. All C9orf72-ALS/FTD patients share a common risk (R) haplotype. To study C9orf72 expression and splicing from the mutant R allele compared to the complementary normal allele in ALS/FTD patients, we initially created a detailed molecular map of the single nucleotide polymorphism (SNP) signature and the HR length of the various C9orf72 haplotypes in Caucasians. We leveraged this map to determine the allelic origin of transcripts per patient, and decipher the effects of pathological and normal HR lengths on C9orf72 expression and splicing. In C9orf72 ALS patients’ cells, the HR expanded allele, compared to non-R allele, was associated with decreased levels of a downstream initiated transcript variant and increased levels of transcripts initiated upstream of the HR. HR expanded R alleles correlated with high levels of unspliced intron 1 and activation of cryptic donor splice sites along intron 1. Retention of intron 1 was associated with sequential intron 2 retention. The SNP signature of C9orf72 haplotypes described here enables allele-specific analysis of transcriptional products and may pave the way to allele-specific therapeutic strategies.
Klíčová slova:
Alleles – Fibroblasts – Gene mapping – Haplotypes – Heterozygosity – Introns – Polymerase chain reaction – Single nucleotide polymorphisms
Zdroje
1. Andersen PM (2000) Genetic factors in the early diagnosis of ALS. Amyotroph Lateral Scler Other Motor Neuron Disord 1 Suppl 1: S31–42. doi: 10.1080/14660820052415899 11464924
2. Borroni B, Grassi M, Bianchi M, Bruni AC, Maletta RG, et al. (2014) Estimating the inheritance of frontotemporal lobar degeneration in the Italian population. J Alzheimers Dis 41: 371–376. doi: 10.3233/JAD-130128 23719513
3. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, et al. (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72: 245–256. doi: 10.1016/j.neuron.2011.09.011 21944778
4. Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, et al. (2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72: 257–268. doi: 10.1016/j.neuron.2011.09.010 21944779
5. Majounie E, Renton AE, Mok K, Dopper EG, Waite A, et al. (2012) Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol 11: 323–330. doi: 10.1016/S1474-4422(12)70043-1 22406228
6. Beck J, Poulter M, Hensman D, Rohrer JD, Mahoney CJ, et al. (2013) Large C9orf72 hexanucleotide repeat expansions are seen in multiple neurodegenerative syndromes and are more frequent than expected in the UK population. Am J Hum Genet 92: 345–353. doi: 10.1016/j.ajhg.2013.01.011 23434116
7. van der Zee J, Gijselinck I, Dillen L, Van Langenhove T, Theuns J, et al. (2013) A pan-European study of the C9orf72 repeat associated with FTLD: geographic prevalence, genomic instability, and intermediate repeats. Hum Mutat 34: 363–373. doi: 10.1002/humu.22244 23111906
8. Gami P, Murray C, Schottlaender L, Bettencourt C, De Pablo Fernandez E, et al. (2015) A 30-unit hexanucleotide repeat expansion in C9orf72 induces pathological lesions with dipeptide-repeat proteins and RNA foci, but not TDP-43 inclusions and clinical disease. Acta Neuropathol 130: 599–601. doi: 10.1007/s00401-015-1473-5 26347457
9. Cooper-Knock J, Walsh MJ, Higginbottom A, Robin Highley J, Dickman MJ, et al. (2014) Sequestration of multiple RNA recognition motif-containing proteins by C9orf72 repeat expansions. Brain 137: 2040–2051. doi: 10.1093/brain/awu120 24866055
10. Ash PE, Bieniek KF, Gendron TF, Caulfield T, Lin WL, et al. (2013) Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 77: 639–646. doi: 10.1016/j.neuron.2013.02.004 23415312
11. Bauer PO (2016) Methylation of C9orf72 expansion reduces RNA foci formation and dipeptide-repeat proteins expression in cells. Neurosci Lett 612: 204–209. doi: 10.1016/j.neulet.2015.12.018 26690922
12. Cohen-Hadad Y, Altarescu G, Eldar-Geva T, Levi-Lahad E, Zhang M, et al. (2016) Marked Differences in C9orf72 Methylation Status and Isoform Expression between C9/ALS Human Embryonic and Induced Pluripotent Stem Cells. Stem Cell Reports 7: 927–940. doi: 10.1016/j.stemcr.2016.09.011 27773700
13. Liu EY, Russ J, Wu K, Neal D, Suh E, et al. (2014) C9orf72 hypermethylation protects against repeat expansion-associated pathology in ALS/FTD. Acta Neuropathol 128: 525–541. doi: 10.1007/s00401-014-1286-y 24806409
14. Xi Z, Zinman L, Moreno D, Schymick J, Liang Y, et al. (2013) Hypermethylation of the CpG island near the G4C2 repeat in ALS with a C9orf72 expansion. Am J Hum Genet 92: 981–989. doi: 10.1016/j.ajhg.2013.04.017 23731538
15. Xi Z, Rainero I, Rubino E, Pinessi L, Bruni AC, et al. (2014) Hypermethylation of the CpG-island near the C9orf72 G(4)C(2)-repeat expansion in FTLD patients. Hum Mol Genet 23: 5630–5637. doi: 10.1093/hmg/ddu279 24908669
16. Xi Z, Zhang M, Bruni AC, Maletta RG, Colao R, et al. (2015) The C9orf72 repeat expansion itself is methylated in ALS and FTLD patients. Acta Neuropathol 129: 715–727. doi: 10.1007/s00401-015-1401-8 25716178
17. Frick P, Sellier C, Mackenzie IRA, Cheng CY, Tahraoui-Bories J, et al. (2018) Novel antibodies reveal presynaptic localization of C9orf72 protein and reduced protein levels in C9orf72 mutation carriers. Acta Neuropathol Commun 6: 72. doi: 10.1186/s40478-018-0579-0 30075745
18. Waite AJ, Baumer D, East S, Neal J, Morris HR, et al. (2014) Reduced C9orf72 protein levels in frontal cortex of amyotrophic lateral sclerosis and frontotemporal degeneration brain with the C9ORF72 hexanucleotide repeat expansion. Neurobiol Aging 35: 1779 e1775–1779 e1713. doi: 10.1016/j.neurobiolaging.2014.01.016 24559645
19. Gao FB, Almeida S, Lopez-Gonzalez R (2017) Dysregulated molecular pathways in amyotrophic lateral sclerosis-frontotemporal dementia spectrum disorder. EMBO J 36: 2931–2950. doi: 10.15252/embj.201797568 28916614
20. Zhu Q, Jiang J, Gendron TF, McAlonis-Downes M, Jiang L, et al. (2020) Reduced C9ORF72 function exacerbates gain of toxicity from ALS/FTD-causing repeat expansion in C9orf72. Nat Neurosci 23: 615–624. doi: 10.1038/s41593-020-0619-5 32284607
21. Sareen D, ORourke JG, Meera P, Muhammad AK, Grant S, et al. (2013) Targeting RNA foci in iPSC-derived motor neurons from ALS patients with a C9ORF72 repeat expansion. Sci Transl Med 5: 208ra149. doi: 10.1126/scitranslmed.3007529 24154603
22. Laaksovirta H, Peuralinna T, Schymick JC, Scholz SW, Lai SL, et al. (2010) Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study. Lancet Neurol 9: 978–985. doi: 10.1016/S1474-4422(10)70184-8 20801718
23. Mok K, Traynor BJ, Schymick J, Tienari PJ, Laaksovirta H, et al. (2012) Chromosome 9 ALS and FTD locus is probably derived from a single founder. Neurobiol Aging 33: 209 e203–208. doi: 10.1016/j.neurobiolaging.2011.08.005 21925771
24. Konno T, Shiga A, Tsujino A, Sugai A, Kato T, et al. (2013) Japanese amyotrophic lateral sclerosis patients with GGGGCC hexanucleotide repeat expansion in C9ORF72. J Neurol Neurosurg Psychiatry 84: 398–401. doi: 10.1136/jnnp-2012-302272 23012445
25. Goldstein O, Gana-Weisz M, Nefussy B, Vainer B, Nayshool O, et al. (2018) High frequency of C9orf72 hexanucleotide repeat expansion in amyotrophic lateral sclerosis patients from two founder populations sharing the same risk haplotype. Neurobiol Aging 64: 160 e161–160 e167. doi: 10.1016/j.neurobiolaging.2017.12.015 29352617
26. Smith BN, Newhouse S, Shatunov A, Vance C, Topp S, et al. (2013) The C9ORF72 expansion mutation is a common cause of ALS+/-FTD in Europe and has a single founder. Eur J Hum Genet 21: 102–108. doi: 10.1038/ejhg.2012.98 22692064
27. O’Rourke JG, Bogdanik L, Yanez A, Lall D, Wolf AJ, et al. (2016) C9orf72 is required for proper macrophage and microglial function in mice. Science 351: 1324–1329. doi: 10.1126/science.aaf1064 26989253
28. Shi Y, Lin S, Staats KA, Li Y, Chang WH, et al. (2018) Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons. Nat Med 24: 313–325. doi: 10.1038/nm.4490 29400714
29. Sivadasan R, Hornburg D, Drepper C, Frank N, Jablonka S, et al. (2016) C9ORF72 interaction with cofilin modulates actin dynamics in motor neurons. Nat Neurosci 19: 1610–1618. doi: 10.1038/nn.4407 27723745
30. Cali CP, Patino M, Tai YK, Ho WY, McLean CA, et al. (2019) C9orf72 intermediate repeats are associated with corticobasal degeneration, increased C9orf72 expression and disruption of autophagy. Acta Neuropathol. doi: 10.1007/s00401-019-02045-5 31327044
31. Cao P, Wang QJ, Zhu XT, Zhou H, Li R, et al. (2011) Quantitative determination of allele frequency in pooled DNA by using sequencing method. J Chromatogr B Analyt Technol Biomed Life Sci 879: 527–532. doi: 10.1016/j.jchromb.2011.01.014 21277843
32. Nurpeisov V, Hurwitz SJ, Sharma PL (2003) Fluorescent dye terminator sequencing methods for quantitative determination of replication fitness of human immunodeficiency virus type 1 containing the codon 74 and 184 mutations in reverse transcriptase. J Clin Microbiol 41: 3306–3311. doi: 10.1128/jcm.41.7.3306-3311.2003 12843079
33. Ye X, McLeod S, Elfick D, Dekkers JC, Lamont SJ (2006) Rapid identification of single nucleotide polymorphisms and estimation of allele frequencies using sequence traces from DNA pools. Poult Sci 85: 1165–1168. doi: 10.1093/ps/85.7.1165 16830855
34. Haeusler AR, Donnelly CJ, Periz G, Simko EA, Shaw PG, et al. (2014) C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature 507: 195–200. doi: 10.1038/nature13124 24598541
35. Sznajder LJ, Thomas JD, Carrell EM, Reid T, McFarland KN, et al. (2018) Intron retention induced by microsatellite expansions as a disease biomarker. Proc Natl Acad Sci U S A 115: 4234–4239. doi: 10.1073/pnas.1716617115 29610297
36. Tran H, Almeida S, Moore J, Gendron TF, Chalasani U, et al. (2015) Differential Toxicity of Nuclear RNA Foci versus Dipeptide Repeat Proteins in a Drosophila Model of C9ORF72 FTD/ALS. Neuron 87: 1207–1214. doi: 10.1016/j.neuron.2015.09.015 26402604
37. Birger A, Ben-Dor I, Ottolenghi M, Turetsky T, Gil Y, et al. (2019) Human iPSC-derived astrocytes from ALS patients with mutated C9ORF72 show increased oxidative stress and neurotoxicity. EBioMedicine 50: 274–289. doi: 10.1016/j.ebiom.2019.11.026 31787569
38. Chen Y, Lin Z, Chen X, Cao B, Wei Q, et al. (2016) Large C9orf72 repeat expansions are seen in Chinese patients with sporadic amyotrophic lateral sclerosis. Neurobiol Aging 38: 217 e215–217 e222. doi: 10.1016/j.neurobiolaging.2015.11.016 26725464
39. He J, Tang L, Benyamin B, Shah S, Hemani G, et al. (2015) C9orf72 hexanucleotide repeat expansions in Chinese sporadic amyotrophic lateral sclerosis. Neurobiol Aging 36: 2660 e2661–2668. doi: 10.1016/j.neurobiolaging.2015.06.002 26142124
40. Shamim U, Ambawat S, Singh J, Thomas A, Pradeep-Chandra-Reddy C, et al. (2020) C9orf72 hexanucleotide repeat expansion in Indian patients with ALS: a common founder and its geographical predilection. Neurobiol Aging 88: 156 e151–156 e159. doi: 10.1016/j.neurobiolaging.2019.12.024 32035847
41. Kelkar YD, Tyekucheva S, Chiaromonte F, Makova KD (2008) The genome-wide determinants of human and chimpanzee microsatellite evolution. Genome Res 18: 30–38. doi: 10.1101/gr.7113408 18032720
42. Sun JX, Helgason A, Masson G, Ebenesersdottir SS, Li H, et al. (2012) A direct characterization of human mutation based on microsatellites. Nat Genet 44: 1161–1165. doi: 10.1038/ng.2398 22922873
43. Almeida S, Gascon E, Tran H, Chou HJ, Gendron TF, et al. (2013) Modeling key pathological features of frontotemporal dementia with C9ORF72 repeat expansion in iPSC-derived human neurons. Acta Neuropathol 126: 385–399. doi: 10.1007/s00401-013-1149-y 23836290
44. Suh E, Lee EB, Neal D, Wood EM, Toledo JB, et al. (2015) Semi-automated quantification of C9orf72 expansion size reveals inverse correlation between hexanucleotide repeat number and disease duration in frontotemporal degeneration. Acta Neuropathol 130: 363–372. doi: 10.1007/s00401-015-1445-9 26022924
45. van Blitterswijk M, DeJesus-Hernandez M, Niemantsverdriet E, Murray ME, Heckman MG, et al. (2013) Association between repeat sizes and clinical and pathological characteristics in carriers of C9ORF72 repeat expansions (Xpansize-72): a cross-sectional cohort study. Lancet Neurol 12: 978–988. doi: 10.1016/S1474-4422(13)70210-2 24011653
46. Bruun GH, Doktor TK, Borch-Jensen J, Masuda A, Krainer AR, et al. (2016) Global identification of hnRNP A1 binding sites for SSO-based splicing modulation. BMC Biol 14: 54. doi: 10.1186/s12915-016-0279-9 27380775
47. Fairbrother WG, Yeh RF, Sharp PA, Burge CB (2002) Predictive identification of exonic splicing enhancers in human genes. Science 297: 1007–1013. doi: 10.1126/science.1073774 12114529
48. Jiang J, Zhu Q, Gendron TF, Saberi S, McAlonis-Downes M, et al. (2016) Gain of Toxicity from ALS/FTD-Linked Repeat Expansions in C9ORF72 Is Alleviated by Antisense Oligonucleotides Targeting GGGGCC-Containing RNAs. Neuron 90: 535–550. doi: 10.1016/j.neuron.2016.04.006 27112497
49. Lagier-Tourenne C, Baughn M, Rigo F, Sun S, Liu P, et al. (2013) Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration. Proc Natl Acad Sci U S A 110: E4530–4539. doi: 10.1073/pnas.1318835110 24170860
50. Kim SW, Taggart AJ, Heintzelman C, Cygan KJ, Hull CG, et al. (2017) Widespread intra-dependencies in the removal of introns from human transcripts. Nucleic Acids Res 45: 9503–9513. doi: 10.1093/nar/gkx661 28934498
51. Donnelly CJ, Zhang PW, Pham JT, Haeusler AR, Mistry NA, et al. (2013) RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention. Neuron 80: 415–428. doi: 10.1016/j.neuron.2013.10.015 24139042
52. Krishnan G, Zhang Y, Gu Y, Kankel MW, Gao FB, et al. (2020) CRISPR deletion of the C9ORF72 promoter in ALS/FTD patient motor neurons abolishes production of dipeptide repeat proteins and rescues neurodegeneration. Acta Neuropathol. doi: 10.1007/s00401-020-02154-6 32266467
53. Burberry A, Suzuki N, Wang JY, Moccia R, Mordes DA, et al. (2016) Loss-of-function mutations in the C9ORF72 mouse ortholog cause fatal autoimmune disease. Sci Transl Med 8: 347ra393. doi: 10.1126/scitranslmed.aaf6038 27412785
54. Sullivan PM, Zhou X, Robins AM, Paushter DH, Kim D, et al. (2016) The ALS/FTLD associated protein C9orf72 associates with SMCR8 and WDR41 to regulate the autophagy-lysosome pathway. Acta Neuropathol Commun 4: 51. doi: 10.1186/s40478-016-0324-5 27193190
55. Vourc’h P, Wurmser F, Brulard C, Mouzat K, Kassem S, et al. (2021) Genes containing hexanucleotide repeats resembling C9ORF72 and expressed in the central nervous system are frequent in the human genome. Neurobiol Aging 97: 148 e141–148 e147. doi: 10.1016/j.neurobiolaging.2020.07.027 32843153
56. Carroll JB, Warby SC, Southwell AL, Doty CN, Greenlee S, et al. (2011) Potent and selective antisense oligonucleotides targeting single-nucleotide polymorphisms in the Huntington disease gene / allele-specific silencing of mutant huntingtin. Mol Ther 19: 2178–2185. doi: 10.1038/mt.2011.201 21971427
57. Kay C, Collins JA, Caron NS, Agostinho LA, Findlay-Black H, et al. (2019) A Comprehensive Haplotype-Targeting Strategy for Allele-Specific HTT Suppression in Huntington Disease. Am J Hum Genet 105: 1112–1125. doi: 10.1016/j.ajhg.2019.10.011 31708117
58. Skotte NH, Southwell AL, Ostergaard ME, Carroll JB, Warby SC, et al. (2014) Allele-specific suppression of mutant huntingtin using antisense oligonucleotides: providing a therapeutic option for all Huntington disease patients. PLoS One 9: e107434. doi: 10.1371/journal.pone.0107434 25207939
59. Akimoto C, Volk AE, van Blitterswijk M, Van den Broeck M, Leblond CS, et al. (2014) A blinded international study on the reliability of genetic testing for GGGGCC-repeat expansions in C9orf72 reveals marked differences in results among 14 laboratories. J Med Genet 51: 419–424. doi: 10.1136/jmedgenet-2014-102360 24706941
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