SMA-Causing Missense Mutations in Display a Wide Range of Phenotypes When Modeled in

English version České info

Spinal Muscular Atrophy (SMA) is a prevalent childhood neuromuscular disease, which in its most common form causes death by the age of two. One in fifty Americans is a carrier for SMA, making this genetic disease a serious health concern. SMA is caused by loss of function mutations in the survival motor neuron 1 (SMN1) gene. SMN is an essential protein and has a well-characterized function in the assembly of small nuclear ribonucleoproteins (snRNPs), which are core components of the spliceosome. To elucidate the phenotypic consequences of disrupting specific SMN protein interactions, we have generated a series of SMA-causing point mutations, modeled in Drosophila melanogaster. Using this system, we have shown that key aspects of SMN structure and function are conserved between humans and flies. Intragenic complementation analyses reveal the potential for dominant negative interactions between wild-type and mutant SMN subunits, highlighting the essential nature of the YG box in formation of higher-order SMN multimers. These results provide a basis for future studies investigating therapy targeted at restoration of functional SMN oligomers.

Vyšlo v časopise: SMA-Causing Missense Mutations in Display a Wide Range of Phenotypes When Modeled in. PLoS Genet 10(8): e32767. doi:10.1371/journal.pgen.1004489
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004489

Souhrn

Zdroje

1. PearnJ (1980) Classification of spinal muscular atrophies. Lancet 1: 919–922.

2. TizianoFD, MelkiJ, SimardLR (2013) Solving the puzzle of spinal muscular atrophy: what are the missing pieces? Am J Med Genet A 161A: 2836–2845.

3. LefebvreS, BurglenL, ReboulletS, ClermontO, BurletP, et al. (1995) Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80: 155–165.

4. BurghesAH, BeattieCE (2009) Spinal muscular atrophy: why do low levels of survival motor neuron protein make motor neurons sick? Nat Rev Neurosci 10: 597–609.

5. FischerU, EnglbrechtC, ChariA (2011) Biogenesis of spliceosomal small nuclear ribonucleoproteins. Wiley Interdiscip Rev RNA 2: 718–731.

6. MateraAG, WangZ (2014) A day in the life of the spliceosome. Nat Rev Mol Cell Biol 15: 108–121.

7. ShababiM, LorsonCL, Rudnik-SchonebornSS (2014) Spinal muscular atrophy: a motor neuron disorder or a multi-organ disease? J Anat 224: 15–28.

8. GouletBB, KotharyR, ParksRJ (2013) At the “junction” of spinal muscular atrophy pathogenesis: the role of neuromuscular junction dysfunction in SMA disease progression. Curr Mol Med 13: 1160–1174.

9. FalliniC, BassellGJ, RossollW (2012) Spinal muscular atrophy: the role of SMN in axonal mRNA regulation. Brain Res 1462: 81–92.

10. PraveenK, WenY, GrayKM, Van DuyneGD, MateraAG (2014) Point mutations in fruitfly Survival Motor Neuron (Smn) recapitulate the full range of phenotypic severity observed in human SMA patients. PLoS Genet in revision

11. HamiltonG, GillingwaterTH (2013) Spinal muscular atrophy: going beyond the motor neuron. Trends Mol Med 19: 40–50.

12. GolicKG (2013) RNA-guided nucleases: a new era for engineering the genomes of model and nonmodel organisms. Genetics 195: 303–308.

13. GogliottiRG, QuinlanKA, BarlowCB, HeierCR, HeckmanCJ, et al. (2012) Motor neuron rescue in spinal muscular atrophy mice demonstrates that sensory-motor defects are a consequence, not a cause, of motor neuron dysfunction. J Neurosci 32: 3818–3829.

14. ParkGH, Maeno-HikichiY, AwanoT, LandmesserLT, MonaniUR (2010) Reduced survival of motor neuron (SMN) protein in motor neuronal progenitors functions cell autonomously to cause spinal muscular atrophy in model mice expressing the human centromeric (SMN2) gene. J Neurosci 30: 12005–12019.

15. Paez-ColasanteX, SeabergB, MartinezTL, KongL, SumnerCJ, et al. (2013) Improvement of neuromuscular synaptic phenotypes without enhanced survival and motor function in severe spinal muscular atrophy mice selectively rescued in motor neurons. PLoS One 8: e75866.

16. FrugierT, TizianoFD, Cifuentes-DiazC, MiniouP, RoblotN, et al. (2000) Nuclear targeting defect of SMN lacking the C-terminus in a mouse model of spinal muscular atrophy. Hum Mol Genet 9: 849–858.

17. HuaY, SahashiK, RigoF, HungG, HorevG, et al. (2011) Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model. Nature 478: 123–126.

18. MentisGZ, BlivisD, LiuW, DrobacE, CrowderME, et al. (2011) Early functional impairment of sensory-motor connectivity in a mouse model of spinal muscular atrophy. Neuron 69: 453–467.

19. ImlachWL, BeckES, ChoiBJ, LottiF, PellizzoniL, et al. (2012) SMN is required for sensory-motor circuit function in Drosophila. Cell 151: 427–439.

20. HayhurstM, WagnerAK, CerlettiM, WagersAJ, RubinLL (2012) A cell-autonomous defect in skeletal muscle satellite cells expressing low levels of survival of motor neuron protein. Dev Biol 368: 323–334.

21. SahashiK, LingKK, HuaY, WilkinsonJE, NomakuchiT, et al. (2013) Pathological impact of SMN2 mis-splicing in adult SMA mice. EMBO Mol Med 5: 1586–1601.

22. BoyerJG, MurrayLM, ScottK, De RepentignyY, RenaudJM, et al. (2013) Early onset muscle weakness and disruption of muscle proteins in mouse models of spinal muscular atrophy. Skelet Muscle 3: 24.

23. WalkerMP, RajendraTK, SaievaL, FuentesJL, PellizzoniL, et al. (2008) SMN complex localizes to the sarcomeric Z-disc and is a proteolytic target of calpain. Hum Mol Genet 17: 3399–3410.

24. RajendraTK, GonsalvezGB, WalkerMP, ShpargelKB, SalzHK, et al. (2007) A Drosophila melanogaster model of spinal muscular atrophy reveals a function for SMN in striated muscle. J Cell Biol 176: 831–841.

25. ZhangZ, LottiF, DittmarK, YounisI, WanL, et al. (2008) SMN deficiency causes tissue-specific perturbations in the repertoire of snRNAs and widespread defects in splicing. Cell 133: 585–600.

26. LottiF, ImlachWL, SaievaL, BeckES, Hao leT, et al. (2012) An SMN-dependent U12 splicing event essential for motor circuit function. Cell 151: 440–454.

27. BaumerD, LeeS, NicholsonG, DaviesJL, ParkinsonNJ, et al. (2009) Alternative splicing events are a late feature of pathology in a mouse model of spinal muscular atrophy. PLoS Genet 5: e1000773.

28. PraveenK, WenY, MateraAG (2012) A Drosophila model of spinal muscular atrophy uncouples snRNP biogenesis functions of survival motor neuron from locomotion and viability defects. Cell Rep 1: 624–631.

29. GarciaEL, LuZ, MeersMP, PraveenK, MateraAG (2013) Developmental arrest of Drosophila survival motor neuron (Smn) mutants accounts for differences in expression of minor intron-containing genes. RNA 19: 1510–1516.

30. SchrankB, GotzR, GunnersenJM, UreJM, ToykaKV, et al. (1997) Inactivation of the survival motor neuron gene, a candidate gene for human spinal muscular atrophy, leads to massive cell death in early mouse embryos. Proc Natl Acad Sci U S A 94: 9920–9925.

31. ChanYB, Miguel-AliagaI, FranksC, ThomasN, TrulzschB, et al. (2003) Neuromuscular defects in a Drosophila survival motor neuron gene mutant. Hum Mol Genet 12: 1367–1376.

32. WinklerC, EggertC, GradlD, MeisterG, GiegerichM, et al. (2005) Reduced U snRNP assembly causes motor axon degeneration in an animal model for spinal muscular atrophy. Genes Dev 19: 2320–2330.

33. ShpargelKB, PraveenK, RajendraTK, MateraAG (2009) Gemin3 is an essential gene required for larval motor function and pupation in Drosophila. Mol Biol Cell 20: 90–101.

34. Bosch-MarceM, WeeCD, MartinezTL, LipkesCE, ChoeDW, et al. (2011) Increased IGF-1 in muscle modulates the phenotype of severe SMA mice. Hum Mol Genet 20: 1844–1853.

35. JodelkaFM, EbertAD, DuelliDM, HastingsML (2010) A feedback loop regulates splicing of the spinal muscular atrophy-modifying gene, SMN2. Hum Mol Genet 19: 4906–4917.

36. RuggiuM, McGovernVL, LottiF, SaievaL, LiDK, et al. (2012) A role for SMN exon 7 splicing in the selective vulnerability of motor neurons in spinal muscular atrophy. Mol Cell Biol 32: 126–138.

37. BrownJB, BoleyN, EismanR, MayGE, StoiberMH, et al. (2014) Diversity and dynamics of the Drosophila transcriptome. Nature

38. BischofJ, MaedaRK, HedigerM, KarchF, BaslerK (2007) An optimized transgenesis system for Drosophila using germ-line-specific phiC31 integrases. Proc Natl Acad Sci U S A 104: 3312–3317.

39. ChangHC, DimlichDN, YokokuraT, MukherjeeA, KankelMW, et al. (2008) Modeling spinal muscular atrophy in Drosophila. PLoS One 3: e3209.

40. LorsonCL, StrasswimmerJ, YaoJM, BalejaJD, HahnenE, et al. (1998) SMN oligomerization defect correlates with spinal muscular atrophy severity. Nat Genet 19: 63–66.

41. PellizzoniL, CharrouxB, DreyfussG (1999) SMN mutants of spinal muscular atrophy patients are defective in binding to snRNP proteins. Proc Natl Acad Sci U S A 96: 11167–11172.

42. ShpargelKB, MateraAG (2005) Gemin proteins are required for efficient assembly of Sm-class ribonucleoproteins. Proc Natl Acad Sci U S A 102: 17372–17377.

43. BurnettBG, MunozE, TandonA, KwonDY, SumnerCJ, et al. (2009) Regulation of SMN protein stability. Mol Cell Biol 29: 1107–1115.

44. MartinR, GuptaK, NinanNS, PerryK, Van DuyneGD (2012) The survival motor neuron protein forms soluble glycine zipper oligomers. Structure 20: 1929–1939.

45. KroissM, SchultzJ, WiesnerJ, ChariA, SickmannA, et al. (2008) Evolution of an RNP assembly system: a minimal SMN complex facilitates formation of UsnRNPs in Drosophila melanogaster. Proc Natl Acad Sci U S A 105: 10045–10050.

46. CauchiRJ, Sanchez-PulidoL, LiuJL (2010) Drosophila SMN complex proteins Gemin2, Gemin3, and Gemin5 are components of U bodies. Exp Cell Res 316: 2354–2364.

47. OgawaC, UsuiK, AokiM, ItoF, ItohM, et al. (2007) Gemin2 plays an important role in stabilizing the survival of motor neuron complex. J Biol Chem 282: 11122–11134.

48. ZhangR, SoBR, LiP, YongJ, GlisovicT, et al. (2011) Structure of a key intermediate of the SMN complex reveals Gemin2's crucial function in snRNP assembly. Cell 146: 384–395.

49. SunY, GrimmlerM, SchwarzerV, SchoenenF, FischerU, et al. (2005) Molecular and functional analysis of intragenic SMN1 mutations in patients with spinal muscular atrophy. Hum Mutat 25: 64–71.

50. WirthB, HerzM, WetterA, MoskauS, HahnenE, et al. (1999) Quantitative analysis of survival motor neuron copies: identification of subtle SMN1 mutations in patients with spinal muscular atrophy, genotype-phenotype correlation, and implications for genetic counseling. Am J Hum Genet 64: 1340–1356.

51. BrandAH, PerrimonN (1993) Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118: 401–415.

52. YamamotoT, SatoH, LaiPS, NurputraDK, HarahapNI, et al. (2013) Intragenic mutations in SMN1 may contribute more significantly to clinical severity than SMN2 copy numbers in some spinal muscular atrophy (SMA) patients. Brain Dev

53. WirthB (2000) An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA). Hum Mutat 15: 228–237.

54. HahnenE, SchonlingJ, Rudnik-SchonebornS, RaschkeH, ZerresK, et al. (1997) Missense mutations in exon 6 of the survival motor neuron gene in patients with spinal muscular atrophy (SMA). Hum Mol Genet 6: 821–825.

55. KotaniT, SutomoR, SasongkoTH, SadewaAH, Gunadi, etal (2007) A novel mutation at the N-terminal of SMN Tudor domain inhibits its interaction with target proteins. J Neurol 254: 624–630.

56. CuscoI, BarceloMJ, del RioE, BaigetM, TizzanoEF (2004) Detection of novel mutations in the SMN Tudor domain in type I SMA patients. Neurology 63: 146–149.

57. GonsalvezGB, RajendraTK, TianL, MateraAG (2006) The Sm-protein methyltransferase, dart5, is essential for germ-cell specification and maintenance. Curr Biol 16: 1077–1089.

58. GonsalvezGB, TianL, OspinaJK, BoisvertFM, LamondAI, et al. (2007) Two distinct arginine methyltransferases are required for biogenesis of Sm-class ribonucleoproteins. J Cell Biol 178: 733–740.

59. GonsalvezGB, PraveenK, HicksAJ, TianL, MateraAG (2008) Sm protein methylation is dispensable for snRNP assembly in Drosophila melanogaster. RNA 14: 878–887.