Canine Hereditary Ataxia in Old English Sheepdogs and Gordon Setters Is Associated with a Defect in the Autophagy Gene Encoding


Old English Sheepdogs and Gordon Setters suffer from a juvenile onset, autosomal recessive form of canine hereditary ataxia primarily affecting the Purkinje neuron of the cerebellar cortex. The clinical and histological characteristics are analogous to hereditary ataxias in humans. Linkage and genome-wide association studies on a cohort of related Old English Sheepdogs identified a region on CFA4 strongly associated with the disease phenotype. Targeted sequence capture and next generation sequencing of the region identified an A to C single nucleotide polymorphism (SNP) located at position 113 in exon 1 of an autophagy gene, RAB24, that segregated with the phenotype. Genotyping of six additional breeds of dogs affected with hereditary ataxia identified the same polymorphism in affected Gordon Setters that segregated perfectly with phenotype. The other breeds tested did not have the polymorphism. Genome-wide SNP genotyping of Gordon Setters identified a 1.9 MB region with an identical haplotype to affected Old English Sheepdogs. Histopathology, immunohistochemistry and ultrastructural evaluation of the brains of affected dogs from both breeds identified dramatic Purkinje neuron loss with axonal spheroids, accumulation of autophagosomes, ubiquitin positive inclusions and a diffuse increase in cytoplasmic neuronal ubiquitin staining. These findings recapitulate the changes reported in mice with induced neuron-specific autophagy defects. Taken together, our results suggest that a defect in RAB24, a gene associated with autophagy, is highly associated with and may contribute to canine hereditary ataxia in Old English Sheepdogs and Gordon Setters. This finding suggests that detailed investigation of autophagy pathways should be undertaken in human hereditary ataxia.


Vyšlo v časopise: Canine Hereditary Ataxia in Old English Sheepdogs and Gordon Setters Is Associated with a Defect in the Autophagy Gene Encoding. PLoS Genet 10(2): e32767. doi:10.1371/journal.pgen.1003991
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003991

Souhrn

Old English Sheepdogs and Gordon Setters suffer from a juvenile onset, autosomal recessive form of canine hereditary ataxia primarily affecting the Purkinje neuron of the cerebellar cortex. The clinical and histological characteristics are analogous to hereditary ataxias in humans. Linkage and genome-wide association studies on a cohort of related Old English Sheepdogs identified a region on CFA4 strongly associated with the disease phenotype. Targeted sequence capture and next generation sequencing of the region identified an A to C single nucleotide polymorphism (SNP) located at position 113 in exon 1 of an autophagy gene, RAB24, that segregated with the phenotype. Genotyping of six additional breeds of dogs affected with hereditary ataxia identified the same polymorphism in affected Gordon Setters that segregated perfectly with phenotype. The other breeds tested did not have the polymorphism. Genome-wide SNP genotyping of Gordon Setters identified a 1.9 MB region with an identical haplotype to affected Old English Sheepdogs. Histopathology, immunohistochemistry and ultrastructural evaluation of the brains of affected dogs from both breeds identified dramatic Purkinje neuron loss with axonal spheroids, accumulation of autophagosomes, ubiquitin positive inclusions and a diffuse increase in cytoplasmic neuronal ubiquitin staining. These findings recapitulate the changes reported in mice with induced neuron-specific autophagy defects. Taken together, our results suggest that a defect in RAB24, a gene associated with autophagy, is highly associated with and may contribute to canine hereditary ataxia in Old English Sheepdogs and Gordon Setters. This finding suggests that detailed investigation of autophagy pathways should be undertaken in human hereditary ataxia.


Zdroje

1. KlockgetherT (2011) PaulsonH (2011) Milestones in ataxia. Mov Disord 26: 1134–1141.

2. KlockgetherT (2012) Sporadic adult-onset ataxia of unknown etiology. Handb Clin Neurol 103: 253–262.

3. HershesonJ, HaworthA (2012) HouldenH (2012) The inherited ataxias: Genetic heterogeneity, mutation databases, and future directions in research and clinical diagnostics. Hum Mutat 33: 1324–1332.

4. Bird TD (2013) Hereditary Ataxia Overview. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, editors. GeneReviews. Seattle: University of Washington.

5. SeidelK, SiswantoS, BruntER, den DunnenW, KorfHW, et al. (2012) Brain pathology of spinocerebellar ataxias. Acta Neuropathol 124: 1–21.

6. KoeppenAH (2005) The pathogenesis of spinocerebellar ataxia. Cerebellum 4: 62–73.

7. FrontaliM (2001) Spinocerebellar ataxia type 6: Channelopathy or glutamine repeat disorder? Brain Res Bull 56: 227–231.

8. van SwietenJC, BrusseE, de GraafBM, KriegerE, van de GraafR, et al. (2003) A mutation in the fibroblast growth factor 14 gene is associated with autosomal dominant cerebellar ataxia [corrected]. Am J Hum Genet 72: 191–199.

9. IkedaY, DickKA, WeatherspoonMR, GincelD, ArmbrustKR, et al. (2006) Spectrin mutations cause spinocerebellar ataxia type 5. Nat Genet 38: 184–190.

10. de LahuntaA (1990) Abiotrophy in domestic animals: A review. Can J Vet Res 54: 65–76.

11. UrkasemsinG, LinderKE, BellJS, de LahuntaA, OlbyNJ (2012) Mapping of Purkinje neuron loss and polyglucosan body accumulation in hereditary cerebellar degeneration in scottish terriers. Vet Pathol 49: 852–859.

12. TatalickLM, MarksSL, BaszlerTV (1993) Cerebellar abiotrophy characterized by granular cell loss in a brittany. Vet Pathol 30: 385–388.

13. CoatesJR, O'BrienDP, KlineKL, StortsRW, JohnsonGC, et al. (2002) Neonatal cerebellar ataxia in coton de tulear dogs. J Vet Intern Med 16: 680–689.

14. SandyJR, SlocombeRE, MittenRW, JedwabD (2002) Cerebellar abiotrophy in a family of border collie dogs. Vet Pathol 39: 736–738.

15. TipoldA, FatzerR, JaggyA, MooreP, VandeveldeM (2000) Presumed immune-mediated cerebellar granuloprival degeneration in the coton de tulear breed. J Neuroimmunol 110: 130–133.

16. CantileC, SalvadoriC, ModenatoM, ArispiciM, FatzerR (2002) Cerebellar granuloprival degeneration in an italian hound. J Vet Med A Physiol Pathol Clin Med 49: 523–525.

17. FlegelT, MatiasekK, HenkeD, GrevelV (2007) Cerebellar cortical degeneration with selective granule cell loss in bavarian mountain dogs. J Small Anim Pract 48: 462–465.

18. CoatesJR, CarmichaelKP, SheltonGD, O'BrienDP, JohnsonGS (1996) Preliminary characterization of a cerebellar ataxia in jack russell terriers. J Vet Int Med 10: 176.

19. CorkLC, TroncosoJC, PriceDL (1981) Canine inherited ataxia. Ann Neurol 9: 492–498.

20. SteinbergHS, Van WinkleT, BellJS, de LahuntaA (2000) Cerebellar degeneration in Old English Sheepdogs. J Am Vet Med Assoc 217: 1162–1165.

21. UrkasemsinG, LinderKE, BellJS, de LahuntaA, OlbyNJ (2010) Hereditary cerebellar degeneration in scottish terriers. J Vet Intern Med 24: 565–570.

22. HigginsRJ, LeCouteurRA, KornegayJN, CoatesJR (1998) Late-onset progressive spinocerebellar degeneration in brittany spaniel dogs. Acta Neuropathol 96: 97–101.

23. KyostilaK, CizinauskasS, SeppäläEH, SuhonenE, JeserevicsJ, et al. (2012) A SEL1L mutation links a canine progressive early-onset cerebellar ataxia to the endoplasmic reticulum-associated protein degradation (ERAD) machinery. PLoS Genet 8: e1002759.

24. FormanOP, De RisioL, StewartJ, MellershCS, BeltranE (2012) Genome-wide mRNA sequencing of a single canine cerebellar cortical degeneration case leads to the identification of a disease associated SPTBN2 mutation. BMC Genet 13: 55.

25. ZengR, FariasFH, JohnsonGS, McKaySD, SchnabelRD, et al. (2011) A truncated retrotransposon disrupts the GRM1 coding sequence in coton de tulear dogs with bandera's neonatal ataxia. J Vet Intern Med 25: 267–272.

26. de LahuntaA, FennerWR, IndrieriRJ, MellickPW, GardnerS, et al. (1980) Hereditary cerebellar cortical abiotrophy in the gordon setter. J Am Vet Med Assoc 177: 538–541.

27. SteinbergHS, TroncosoJC, CorkLC, PriceDL (1981) Clinical features of inherited cerebellar degeneration in gordon setters. J Am Vet Med Assoc 179: 886–890.

28. ThamesRA, ThamesRA, RobertsonID, FlegelT, HenkeD, O'BrienDP, et al. (2010) Development of a morphometric magnetic resonance image parameter suitable for distinguishing between normal dogs and dogs with cerebellar atrophy. Vet Radiol Ultrasound 51: 246–253.

29. TiemeyerMJ, SingerHS, TroncosoJC, CorkLC, CoyleJT, et al. (1984) Synaptic neurochemical alterations associated with neuronal degeneration in an inherited cerebellar ataxia of gordon setters. J Neuropathol Exp Neurol 43: 580–591.

30. TroncosoJC, CorkLC, PriceDL (1985) Canine inherited ataxia: Ultrastructural observations. J Neuropathol Exp Neurol 44: 165–175.

31. ClarkLA, TsaiKL, SteinerJM, WilliamsDA, GuerraT, et al. (2004) Chromosome-specific microsatellite multiplex sets for linkage studies in the domestic dog. Genomics 84: 550–554.

32. ThompsonEA (2000) MCMC estimation of multi-locus genome sharing and multipoint gene location scores. International Statistical Review 68: 53–73.

33. PurcellS, NealeB, Todd-BrownK, ThomasL, FerreiraMA, et al. (2007) PLINK: A tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81: 559–575.

34. LairdNM, HorvathS, XuX (2000) Implementing a unified approach to family-based tests of association. Genet Epidemiol 19 Suppl 1: S36–42.

35. McKennaA, HannaM, BanksE, SivachenkoA, CibulskisK, et al. (2010) The genome analysis toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20: 1297–1303.

36. PerilleAL, BaerK, JosephRJ, CarrilloJM, AverillDR (1991) Postnatal cerebellar cortical degeneration in labrador retriever puppies. Can Vet J 32: 619–621.

37. BildfellRJ, MitchellSK, de LahuntaA (1995) Cerebellar cortical degeneration in a labrador retriever. Can Vet J 36: 570–572.

38. AdzhubeiIA, SchmidtS, PeshkinL, RamenskyVE, GerasimovaA, et al. (2010) A method and server for predicting damaging missense mutations. Nat Methods 7: 248–249.

39. KumarP, HenikoffS, NgPC (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4: 1073–1081.

40. ZerialM (2001) McBrideH (2001) Rab proteins as membrane organizers. Nat Rev Mol Cell Biol 2: 107–117.40.

41. ChuaCE, GanBQ, TangBL (2011) Involvement of members of the rab family and related small GTPases in autophagosome formation and maturation. Cell Mol Life Sci 68: 3349–3358.

42. VonholdtBM, PollingerJP, LohmuellerKE, HanE, ParkerHG, et al. (2010) Genome-wide SNP and haplotype analyses reveal a rich history underlying dog domestication. Nature 464: 898–902.

43. ParkerHG (2012) Genomic analyses of modern dog breeds. Mamm Genome 23: 19–27.

44. OlkkonenVM, DupreeP, KillischI, LütckeA, ZerialM, et al. (1993) Molecular cloning and subcellular localization of three GTP-binding proteins of the rab subfamily. J Cell Sci 106: 1249–1261.

45. ErdmanRA, ShellenbergerKE, OvermeyerJH, MalteseWA (2000) Rab24 is an atypical member of the rab GTPase family. Deficient GTPase activity, GDP dissociation inhibitor interaction, and prenylation of Rab24 expressed in cultured cells. J Biol Chem 275: 3848–3856.

46. MunafoDB, ColomboMI (2002) Induction of autophagy causes dramatic changes in the subcellular distribution of GFP-Rab24. Traffic 3: 472–482.

47. ParkerHG, KimLV, SutterNB, CarlsonS, LorentzenTD, et al. (2004) Genetic structure of the purebred domestic dog. Science 304: 1160–1164.

48. Lindblad-TohK, WadeCM, MikkelsenTS, KarlssonEK, JaffeDB, et al. (2005) Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature 438: 803–819.

49. GoldsteinO, ZangerlB, Pearce-KellingS, SidjaninDJ, KijasJW, et al. (2006) Linkage disequilibrium mapping in domestic dog breeds narrows the progressive rod-cone degeneration interval and identifies ancestral disease-transmitting chromosome. Genomics 88: 541–550.

50. Pereira-LealJB (2000) SeabraMC (2000) The mammalian rab family of small GTPases: Definition of family and subfamily sequence motifs suggests a mechanism for functional specificity in the ras superfamily. J Mol Biol 301: 1077–1087.

51. BehrendsC, SowaME, GygiSP, HarperJW (2010) Network organization of the human autophagy system. Nature 466: 68–76.

52. EgamiY, Kiryu-SeoS, YoshimoriT, KiyamaH (2005) Induced expressions of Rab24 GTPase and LC3 in nerve-injured motor neurons. Biochem Biophys Res Commun 337: 1206–1213.

53. MalteseWA, SouleG, GunningW, CalomeniE, AlexanderB (2002) Mutant Rab24 GTPase is targeted to nuclear inclusions. BMC Cell Biol 3: 25.

54. MilitelloRD, MunafóDB, BerónW, LópezLA, MonierS, et al. (2013) Rab24 is required for normal cell division. Traffic 14: 502–18.

55. DumasJJ, ZhuZ, ConnollyJL, LambrightDG (1999) Structural basis of activation and GTP hydrolysis in rab proteins. Structure 7: 413–423.

56. WestbroekW, TuchmanM, TinloyB, De WeverO, VilbouxT, et al. (2008) A novel missense mutation (G43S) in the switch I region of Rab27A causing Griscelli syndrome. Mol Genet Metab 94: 248–254.

57. VerhoevenK, De JongheP, CoenK, VerpoortenN, Auer-GrumbachM, et al. (2003) Mutations in the small GTP-ase late endosomal protein RAB7 cause Charcot-Marie-Tooth type 2B neuropathy. Am J Hum Genet 72: 722–727.

58. BingolB, ShengM (2011) Deconstruction for reconstruction: The role of proteolysis in neural plasticity and disease. Neuron 69: 22–32.

59. HegdeAN, UpadhyaSC (2011) Role of ubiquitin-proteasome-mediated proteolysis in nervous system disease. Biochim Biophys Acta 1809: 128–140.

60. RileyBE, KaiserSE, ShalerTA, NgAC, HaraT, et al. (2010) Ubiquitin accumulation in autophagy-deficient mice is dependent on the Nrf2-mediated stress response pathway: A potential role for protein aggregation in autophagic substrate selection. J Cell Biol 191: 537–552.

61. KraftC, KijanskaM, KalieE, SiergiejukE, LeeSS, et al. (2012) Binding of the Atg1/ULK1 kinase to the ubiquitin-like protein Atg8 regulates autophagy. EMBO J 31: 3691–3703.

62. KomatsuM, UenoT, WaguriS, UchiyamaY, KominamiE, et al. (2007) Constitutive autophagy: Vital role in clearance of unfavorable proteins in neurons. Cell Death Differ 14: 887–894.

63. KomatsuM, KominamiE, TanakaK (2006) Autophagy and neurodegeneration. Autophagy 2: 315–317.

64. KomatsuM, WaguriS, UenoT, IwataJ, MurataS, et al. (2005) Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol 169(3): 425–434.

65. KomatsuM, WaguriS, ChibaT, MurataS, IwataJ, et al. (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441: 880–884.

66. YuWH, CuervoAM, KumarA, PeterhoffCM, SchmidtSD, et al. (2005) Macroautophagy–a novel beta-amyloid peptide-generating pathway activated in alzheimer's disease. J Cell Biol 171: 87–98.

67. IharaY, Morishima-KawashimaM, NixonR (2012) The ubiquitin-proteasome system and the autophagic-lysosomal system in alzheimer disease. Cold Spring Harb Perspect Med 2(8): 10.1101/cshperspect.a006361

68. de VriesRL, PrzedborskiS (2013) Mitophagy and parkinson's disease: Be eaten to stay healthy. Mol Cell Neurosci 55: 37–43.

69. HaraT, NakamuraK, MatsuiM, YamamotoA, NakaharaY, et al. (2006) Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441: 885–889.

70. SpielmanRS, McGinnisRE, EwensWJ (1993) Transmission test for linkage disequilibrium: The insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 52: 506–516.

71. NingZ, CoxAJ, MullikinJC (2001) SSAHA: A fast search method for large DNA databases. Genome Res 11: 1725–1729.

72. LiH, DurbinR (2009) Fast and accurate short read alignment with burrows-wheeler transform. Bioinformatics 25: 1754–1760.

73. RobinsonJT, ThorvaldsdóttirH, WincklerW, GuttmanM, LanderES, et al. (2011) Integrative genomics viewer. Nat Biotechnol 29: 24–26.

74. RozenS, SkaletskyH (2000) Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol 132: 365–386.

75. YeJ, CoulourisG, ZaretskayaI, CutcutacheI, RozenS, et al. (2012) Primer-BLAST: A tool to design target-specific primers for polymerase chain reaction. BMC Bioinformatics 13: 134-2105-13-134.

76. MarshallOJ (2004) PerlPrimer: Cross-platform, graphical primer design for standard, bisulphite and real-time PCR. Bioinformatics 20: 2471–2472.

77. BrinkhofB, SpeeB, RothuizenJ, PenningLC (2006) Development and evaluation of canine reference genes for accurate quantification of gene expression. Anal Biochem 356: 36–43.

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2014 Číslo 2
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Eozinofilní granulomatóza s polyangiitidou
nový kurz
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