#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

FRA2A Is a CGG Repeat Expansion Associated with Silencing of


Some human genetic diseases are caused by dynamic mutations, or expansions of a short repeated sequence in the genome that can be unstably passed on from generation to generation. A subset of these dynamic mutations known as fragile sites can be seen as a break or gap on the chromosome when cells are cultured under specific conditions. To date eight folate-sensitive fragile sites (FSFS) have been characterized, and all are due to CGG-repeat expansions within the 5′ UTR or promoter region of the respective gene. When the repeat expands in size, it becomes hypermethylated and the adjacent gene or genes are transcriptionally silenced. For at least four of the eight known fragile sites this silencing of the associated gene(s) lead to intellectual disability syndromes such as fragile X. In this work we describe molecular characterization of an autosomal FSFS called FRA2A on chromosome 2. As the molecular cause of FRA2A, we identify an expansion of a CGG repeat which subsequently results in silencing of the neighbouring gene AFF3. This gene is one of the four autosomal paralogss of the AFF2/FMR2 gene which, when mutated, is the cause of the FRAXE syndrome. We find that FRA2A expression is associated with highly variable developmental anomalies in the three FRA2A families studied.


Vyšlo v časopise: FRA2A Is a CGG Repeat Expansion Associated with Silencing of. PLoS Genet 10(4): e32767. doi:10.1371/journal.pgen.1004242
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004242

Souhrn

Some human genetic diseases are caused by dynamic mutations, or expansions of a short repeated sequence in the genome that can be unstably passed on from generation to generation. A subset of these dynamic mutations known as fragile sites can be seen as a break or gap on the chromosome when cells are cultured under specific conditions. To date eight folate-sensitive fragile sites (FSFS) have been characterized, and all are due to CGG-repeat expansions within the 5′ UTR or promoter region of the respective gene. When the repeat expands in size, it becomes hypermethylated and the adjacent gene or genes are transcriptionally silenced. For at least four of the eight known fragile sites this silencing of the associated gene(s) lead to intellectual disability syndromes such as fragile X. In this work we describe molecular characterization of an autosomal FSFS called FRA2A on chromosome 2. As the molecular cause of FRA2A, we identify an expansion of a CGG repeat which subsequently results in silencing of the neighbouring gene AFF3. This gene is one of the four autosomal paralogss of the AFF2/FMR2 gene which, when mutated, is the cause of the FRAXE syndrome. We find that FRA2A expression is associated with highly variable developmental anomalies in the three FRA2A families studied.


Zdroje

1. WojciechowskaM, KrzyzosiakWJ (2011) CAG repeat RNA as an auxiliary toxic agent in polyglutamine disorders. RNA Biol 8: 565–571.

2. Costa LimaMA, PimentelMM (2004) Dynamic mutation and human disorders: the spinocerebellar ataxias. Int J Mol Med 13: 3.

3. RudnickiDD, MargolisRL, PearsonCE, KrzyzosiakWJ (2012) Diced triplets expose neurons to RISC. Plos Genet 8: e1002545.

4. PearsonCE, Nichol EdamuraK, ClearyJD (2005) Repeat instability: mechanisms of dynamic mutations. Nat Rev Genet 6: 729–742.

5. KumariD, UsdinK (2009) Chromatin remodeling in the noncoding repeat expansion diseases. J Biol Chem 284: 5.

6. McMurrayC (2010) Mechanisms of trinucleotide repeat instability during human development. Nat Rev Genet 11: 786–799.

7. Dudek RW (2006) High-yield cell and molecular biology. Philadelphia; Baltimore; New York: Lippincott Williams & Wilkins.

8. LicatalosiDD, DarnellRB (2006) Splicing regulation in neurologic disease. Neuron 52: 93–101.

9. PierettiM, ZhangFP, FuYH, WarrenST, OostraBA, et al. (1991) Absence of expression of the FMR-1 gene in fragile X syndrome. Cell 66: 817–822.

10. TrottierY, LutzY, StevaninG, ImbertG, DevysD, et al. (1996) Polyglutamine expansion as a pathological epitope in Huntington's disease and four dominant cerebellar ataxias. Nature 378: 403–406.

11. LinYaW, JH (2011) Transcription-induced DNA toxicity at trinucleotide repeats. Cell Cycle 10: 611–618.

12. RichardsRI (2001) Fragile and unstable chromosomes in cancer: causes and consequences. Trends Genet 17: 339–345.

13. RichardsRI (2001) Dynamic mutations: a decade of unstable expanded repeats in human genetic disease. Hum Mol Genet 10: 2187–2194.

14. ZuT, GibbensB, DotyNS, Gomes-PereiraM, HuguetA, et al. (2011) Non-ATG-initiated translation directed by microsatellite expansions. Proc Natl Acad Sci U S A 108: 260–265.

15. PearsonCE (2011) Repeat associated non-ATG translation initiation: one DNA, two transcripts, seven reading frames, potentially nine toxic entities!. PLoS Genet 7: e1002018.

16. BenítezJ (1999) Clinical and genetic implications of dynamic mutations in neuropediatric practice. Rev Neurol 28: 4.

17. La SpadaAR, TaylorJP (2010) Repeat expansion disease: progress and puzzles in disease pathogenesis. Nat Rev Genet 11: 13.

18. KatoM (2006) A new paradigm for West syndrome based on molecular and cell biology. Epilepsy Res 70 Suppl 1: S87–95.

19. DebackerK, KooyRF (2007) Fragile sites and human disease. Hum Mol Genet 16: R150–158.

20. VerkerkAJMH, PierettiM, SutcliffeJS, FuY-H, KuhlDPA, et al. (1991) Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65: 905–914.

21. KnightSJL, FlanneryAV, HirstMC, CampbellL, ChristodoulouZ, et al. (1993) Trinucleotide repeat amplification and hypermethylation of a CpG island in FRAXE mental retardation. Cell 74: 127–134.

22. ParrishJE, OostraBA, VerkerkAJMH, RichardsCS, ReynoldsJ, et al. (1994) Isolation of a GCC repeat showing expansion in FRAXF, a fragile site distal to FRAXA and FRAXE. Nat Genet 8: 229–235.

23. NancarrowJK, KremerE, HolmanK, EyreH, DoggettNA, et al. (1994) Implications of FRA16A structure for the mechanism of chromosomal fragile site genesis. Science 264: 1938–1941.

24. JonesC, PennyL, MattinaT, YuS, BakerE, et al. (1995) Association of a chromosome deletion syndrome with a fragile site within the proto-oncogene CBL2. Nature 376: 145–149.

25. SarafidouT, KahlC, Martinez-GarayI, MangelsdorfM, GeskS, et al. (2004) Folate-sensitive fragile site FRA10A is due to an expansion of a CGG repeat in a novel gene, FRA10AC1, encoding a nuclear protein. Genomics 84: 69–81.

26. WinnepenninckxB, DebackerK, RamsayJ, SmeetsD, SmitsA, et al. (2007) CGG repeat expansion in the DIP2B gene is associated with the fragile site FRA12A on chromosome 12q13.1. Am J Hum Genet 80: 221–231.

27. DebackerK, WinnepenninckxB, LongmanC, ColganJ, TolmieJ, et al. (2007) The molecular basis of the folate-sensitive fragile site FRA11A at 11q13. Cytogenet Genome Res 119: 9–14.

28. PierettiM, ZhangF, FuY-H, WarrenST, OostraBA, et al. (1991) Absence of expression of the FMR-1 gene in fragile X syndrome. Cell 66: 817–822.

29. Kooy RF (2009) Fragile sites and human disease. Encyclopedia of Life Sciences. Chichester, UK: John Wiley & Sons, Ltd. pp. DOI:10.1002/9780470015902.a9780470021457.

30. TukunA, RendaY, TopcuM, TuncaliT, BokesoyI (2000) Mental retardation with rare fragile site expressed at 2q11. Brain Dev 22: 498–500.

31. MurthyDS, TeebiAS, SundareshanTS, al-AwadiSA (1990) Familial fragile secondary constriction on chromosome 2 (2q11) with unusual features and psychomotor retadation. Indian Pediatr 57: 257–260.

32. AnnerénG, GustavsonKH (1981) A fragile secondary constriction on chromosome 2 in five patients with different clinical features. Hereditas 95: 63–67.

33. MaC, StaudtL (1996) LAF-4 encodes a lymphoid nuclear protein with transactivation potential that is homologous to AF-4, the gene fused to MLL in t(4;11) leukemias. Blood 87: 734–745.

34. KodziusR, KojimaM, NishiyoriH, NakamuraM, FukudaS, et al. (2006) CAGE: cap analysis of gene expression. Nat Methods 3: 211–222.

35. TostJ, GutIG (2007) DNA methylation analysis by pyrosequencing. Nat Protocols 2: 2265–2275.

36. IllingworthR, KerrA, DesousaD, JorgensenH, EllisP, et al. (2008) A novel CpG island set identifies tissue-specific methylation at developmental gene loci. PLoS Biol 6: e22.

37. LancasterMA, RennerM, MartinCA, WenzelD, BicknellLS, et al. (2013) Cerebral organoids model human brain development and microcephaly. Nature 501: 373–379.

38. de GraaffE, RouillardP, WillemsPJ, SmitsAPT, RousseauF, et al. (1995) Hotspot for deletions in the CGG repeat region of FMR1 in fragile X patients. Hum Mol Genet 4: 45–49.

39. AxfordMM, Lopez-CastelA, NakamoriM, ThorntonCA, PearsonCE (2011) Replacement of the myotonic dystrophy type 1 CTG repeat with ‘non-CTG repeat’ insertions in specific tissues. J Med Genet 48: 438–443.

40. GronskovK, HjalgrimH, BjeragerMO, Brondum-NielsenK (1997) Deletion of all CGG repeats plus flanking sequences in FMR1 does not abolish gene expression. Am J Hum Genet 61: 961–967.

41. TakiT, KanoH, TaniwakiM, SakoM, YanagisawaM, et al. (1999) AF5q31, a newly identified AF4-related gene, is fused to MLL in infant acute lymphoblastic leukemia with ins(5;11) (q31;q13q23). Proc Natl Acad Sci USA 96: 14535–14540.

42. LiaoX, MaC, TraskB, MassaH, GilbertD, et al. (1996) LAF4 maps to mouse chromosome 1 and human chromosome 2q11.2-q12. Mamm Genome 7: 467–468.

43. MelkoM, DouguetD, BensaidM, ZongaroS, VerheggenC, et al. (2011) Functional characterization of the AFF (AF4/FMR2) family of RNA-binding proteins: insights into the molecular pathology of FRAXE intellectual disability. Hum Mol Genet 20: 1873–1885.

44. BritanovaO, LukyanovS, GrussP, TarabykinV (2002) The mouse Laf4 gene: Exon/intron organization, cDNA sequence, alternative splicing, and expression during central nervous system development. Genomics 80: 31–37.

45. GéczJ, OostraBA, HockeyA, CarbonellP, TurnerG, et al. (1997) FMR2 expression in families with FRAXE mental retardation. Hum Mol Genet 6: 435–441.

46. ChakrabartiL, BristulfJ, FossGS, DaviesKE (1998) Expression of the murine homologue of FMR2 in mouse brain and during development. Hum Mol Genet 7: 441–448.

47. MondalK, RamachandranD, PatelVC, HagenKR, BoseP, et al. (2012) Excess variants in AFF2 detected by massively parallel sequencing of males with autism spectrum disorder. Hum Mol Genet 21: 4356–4364.

48. GuY, NelsonDL (2003) FMR2 function: insight from a mouse knockout model. Cytogenet Genome Res 100: 129–139.

49. DaviesKE, OliverPL, JonesEL, JeansA, ClarkJ, et al. (2003) Functional studies of Af4 in the robotic mouse. Am J Hum Genet 73 Suppl: A86.

50. Steichen-GersdorfE, GassnerI, Superti-FurgaA, UllmannR, StrickerS, et al. (2008) Triangular tibia with fibular aplasia associated with a microdeletion on 2q11.2 encompassing LAF4. Clin Genet 74: 560–565.

51. WillemsenR, BontekoeCJ, SeverijnenLA, OostraBA (2002) Timing of the absence of FMR1 expression in full mutation chorionic villi. Hum Genet 110: 601–605.

52. Ruiz-HerreraA, GarciaF, GiulottoE, AttoliniC, EgozcueJ, et al. (2005) Evolutionary breakpoints are co-localized with fragile sites and intrachromosomal telomeric sequences in primates. Cytogenet Genome Res 108: 234–247.

53. Ruiz-HerreraA, CastresanaJ, RobinsonTJ (2006) Is mammalian chromosomal evolution driven by regions of genome fragility? Genome Biol 7: R115.

54. O'RahillyR, MullerF (1987) Developmental stages in human embryos: revised and new measurements. Cells Tissues Organs 192: 73–84.

55. Bullen P, Wilson D, editors(1997) The Carnegie Staging of Human Embryos: a Practical Guide. Oxford: Bios Scientific Publishers. 27–50 p.

56. ChongSS, PackSD, RoschkeAV, TanigamiA, CarrozzoR, et al. (1997) A revision of the lissencephaly and Miller-Dieker syndrome critical regions in chromosome 17p13.3. Hum Mol Genet 6: 147–155.

57. NolinSL, BrownWT, GlicksmanA, HouckGEJr, GarganoAD, et al. (2003) Expansion of the fragile X CGG repeat in females with premutation or intermediate alleles. Am J Hum Genet 72: 454–464.

58. RaingerJ, BenganiH, CampbellL, AndersonE, SokhiK, et al. (2012) Miller (Genee-Wiedemann) syndrome represents a clinically and biochemically distinct subgroup of postaxial acrofacial dysostosis associated with partial deficiency of DHODH. Hum Mol Genet 21: 3969–3983.

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2014 Číslo 4
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Získaná hemofilie - Povědomí o nemoci a její diagnostika
nový kurz

Eozinofilní granulomatóza s polyangiitidou
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#