TSEN54 missense variant in Standard Schnauzers with leukodystrophy

English version

Autoři: Theresa Störk ^aff001; Jasmin Nessler ^aff002; Linda Anderegg ^aff003; Enrice Hünerfauth ^aff002; Isabelle Schmutz ^aff003; Vidhya Jagannathan ^aff003; Kaisa Kyöstilä ^aff004; Hannes Lohi ^aff004; Wolfgang Baumgärtner ^aff001; Andrea Tipold ^aff002; Tosso Leeb ^aff003
Působiště autorů: Department of Pathology, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany ^aff001; Department for Small Animal Medicine and Surgery, University of Veterinary Medicine Hannover, Foundation, Hannover, Germany ^aff002; Institute of Genetics, Vetsuisse Faculty, University of Bern, Switzerland ^aff003; Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland ^aff004; Folkhälsan Research Center, Helsinki, Finland ^aff005; Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland ^aff006
Vyšlo v časopise: TSEN54 missense variant in Standard Schnauzers with leukodystrophy. PLoS Genet 15(10): e1008411. doi:10.1371/journal.pgen.1008411
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1008411

Souhrn

We report a hereditary leukodystrophy in Standard Schnauzer puppies. Clinical signs occurred shortly after birth or started at an age of under 4 weeks and included apathy, dysphoric vocalization, hypermetric ataxia, intension tremor, head tilt, circling, proprioceptive deficits, seizures and ventral strabismus consistent with a diffuse intracranial lesion. Magnetic resonance imaging revealed a diffuse white matter disease without mass effect. Macroscopically, the cerebral white matter showed a gelatinous texture in the centrum semiovale. A mild hydrocephalus internus was noted. Histopathologically, a severe multifocal reduction of myelin formation and moderate diffuse edema without inflammation was detected leading to the diagnosis of leukodystrophy. Combined linkage analysis and homozygosity mapping in two related families delineated critical intervals of approximately 29 Mb. The comparison of whole genome sequence data of one affected Standard Schnauzer to 221 control genomes revealed a single private homozygous protein changing variant in the critical intervals, TSEN54:c.371G>A or p.(Gly124Asp). TSEN54 encodes the tRNA splicing endonuclease subunit 54. In humans, several variants in TSEN54 were reported to cause different types of pontocerebellar hypoplasia. The genotypes at the c.371G>A variant were perfectly associated with the leukodystrophy phenotype in 12 affected Standard Schnauzers and almost 1000 control dogs from different breeds. These results suggest that TSEN54:c.371G>A causes the leukodystrophy. The identification of a candidate causative variant enables genetic testing so that the unintentional breeding of affected Standard Schnauzers can be avoided in the future. Our findings extend the known genotype-phenotype correlation for TSEN54 variants.

Klíčová slova:

Mammalian genomics – Pets and companion animals – Dogs – Central nervous system – Magnetic resonance imaging – Veterinary medicine – Variant genotypes – Cerebrum

Zdroje

1. Vanderver A, Prust M, Tonduti D, Mochel F, Hussey HM, Helman G, et al. Case definition and classification of leukodystrophies and leukoencephalopathies. Mol Genet Metab. 2015;114: 494–500. doi: 10.1016/j.ymgme.2015.01.006 25649058

2. Summers BA, Cummings, John F., de Lahunta, Alexander. Veterinary Neuropathology: St Louis; Mosby; 1995.

3. Steenweg ME, Vanderver A, Blaser S, Bizzi A, de Koning TJ, Mancini GM, et al. Magnetic resonance imaging pattern recognition in hypomyelinating disorders. Brain. 2010;133: 2971–2982. doi: 10.1093/brain/awq257 20881161

4. Schiffmann R, van der Knaap MS. Invited article: an MRI-based approach to the diagnosis of white matter disorders. Neurology. 2009;72: 750–759. doi: 10.1212/01.wnl.0000343049.00540.c8 19237705

5. Lynch DS, Rodrigues Brandão de Paiva A, Zhang WJ, Bugiardini E, Freua F, Tavares Lucato L, et al. Clinical and genetic characterization of leukoencephalopathies in adults. Brain. 2017;140: 1204–1211. doi: 10.1093/brain/awx045 28334938

6. Gamble DA, Chrisman CL. A leukoencephalomyelopathy of rottweiler dogs. Vet Pathol. 1984;21: 274–280. doi: 10.1177/030098588402100302 6730216

7. Hirschvogel K, Matiasek K, Flatz K, Drögemüller M, Drögemüller C, Reiner B, et al. Magnetic resonance imaging and genetic investigation of a case of Rottweiler leukoencephalomyelopathy. BMC Vet Res. 2013;9: 57. doi: 10.1186/1746-6148-9-57 23531239

8. Lucot KL, Dickinson PJ, Finno CJ, Mansour TA, Letko A, Minor KM, et al. A missense mutation in the vacuolar protein sorting 11 (VPS11) gene is associated with neuroaxonal dystrophy in Rottweiler dogs. G3 (Bethesda). 2018;8: 2773–2780.

9. Minor KM, Letko A, Becker D, Drögemüller M, Mandigers PJJ, Bellekom SR, et al. Canine NAPEPLD-associated models of human myelin disorders. Sci Rep. 2018;8: 5818. doi: 10.1038/s41598-018-23938-7 29643404

10. Wenger DA, Victoria T, Rafi MA, Luzi P, Vanier MT, Vite C, et al. Globoid cell leukodystrophy in cairn and West Highland white terriers. J Hered. 1999;90: 138–142. doi: 10.1093/jhered/90.1.138 9987921

11. Monaldi A, Martínez Munera AM. Globoid leukodystrophy in a West Highland terrier. / Leucodistrofia de células globoides en un westy. Argos—Informativo Veterinario. 2014;158: 38–41.

12. Fletcher JL, Williamson P, Horan D, Taylor RM. Clinical signs and neuropathologic abnormalities in working Australian Kelpies with globoid cell leukodystrophy (Krabbe disease). J Am Vet Med Assoc. 2010;237: 682–688. doi: 10.2460/javma.237.6.682 20839990

13. Bjerkås I. Hereditary ‘Cavitating’ leucodystrophy in Dalmatian dogs. Acta Neuropathol. 1977;40: 163. doi: 10.1007/bf00688706

14. Van Poucke M, Martlé V, Van Brantegem L, Ducatelle R, Van Ham L, Bhatti S, et al. A canine orthologue of the human GFAP c.716G>A (p.Arg239His) variant causes Alexander disease in a Labrador retriever. Eur J Hum Genet. 2016;24: 852–856. doi: 10.1038/ejhg.2015.223 26486469

15. Cummings J, de Lahunta A. Hereditary myelopathy of Afghan hounds, a myelinolytic disease. Acta Neuropathol. 1978;42: 173–181. doi: 10.1007/bf00690354 676666

16. Gross B, Garcia-Tapia D, Riedesel E, Ellinwood NM, Jens JK. Normal canine brain maturation at magnetic resonance imaging. Vet Radiol Ultrasound. 2010;51: 361–373. doi: 10.1111/j.1740-8261.2010.01681.x 20806866

17. Griffiths IR, Duncan ID, McCulloch M, Harvey MJ. Shaking pups: a disorder of central myelination in the Spaniel dog. Part 1. Clinical, genetic and light-microscopical observations. J Neurol Sci. 1981;50: 423–433. doi: 10.1016/0022-510x(81)90154-4 7196438

18. Mar S, Noetzel M. Axonal damage in leukodystrophies. Pediatr Neurol. 2010;42:239–242. doi: 10.1016/j.pediatrneurol.2009.08.011 20304325

19. Matzner U, Hartmann D, Lüllmann-Rauch R, Coenen R, Rothert F, Månsson JE, et al. Bone marrow stem cell-based gene transfer in a mouse model for metachromatic leukodystrophy: effects on visceral and nervous system disease manifestations. Gene Ther. 2002;9:53–63. doi: 10.1038/sj.gt.3301593 11850723

20. Moreno-López B, González-Forero D. Nitric oxide and synaptic dynamics in the adult brain: physiopathological aspects. Rev Neurosci. 2006;17: 309–357. 16878402

21. Tsunoda I, Fujinami RS. Inside-Out versus Outside-In models for virus induced demyelination: axonal damage triggering demyelination. Springer Semin Immunopathol. 2002;24: 105–125. doi: 10.1007/s00281-002-0105-z 12503060

22. Vandevelde M, Braund KG, Walker TL, Kornegay JN. Dysmyelination of the central nervous system in the Chow-Chow dog. Acta Neuropathol. 1978;42: 211–215. doi: 10.1007/bf00690359 676669

23. Kornegay JN, Goodwin MA, Spyridakis LK. Hypomyelination in Weimaraner dogs. Acta Neuropathol. 1987;72: 394–401. doi: 10.1007/bf00687272 3577694

24. Gielen E, Baron W, Vandeven M, Steels P, Hoekstra D, Ameloot M. Rafts in oligodendrocytes: evidence and structure-function relationship. Glia. 2006;54: 499–512. doi: 10.1002/glia.20406 16927294

25. Kuhlmann T, Remington L, Maruschak B, Owens T, Brück W. Nogo-A is a reliable oligodendroglial marker in adult human and mouse CNS and in demyelinated lesions. J Neuropathol Exp Neurol. 2007;66: 238–246. doi: 10.1097/01.jnen.0000248559.83573.71 17356385

26. Cozzi F, Vite CH, Wenger DA, Victoria T, Haskins ME. MRI and electrophysiological abnormalities in a case of canine globoid cell leucodystrophy." J Small Anim Pract. 1998;39: 401–405. doi: 10.1111/j.1748-5827.1998.tb03741.x 9741878

27. Mariani CL, Clemmons RM, Graham JP, Phillips LA, Chrisman CL. Magnetic resonance imaging of spongy degeneration of the central nervous system in a Labrador Retriever. Vet Radiol Ultrasound. 2001;42: 285–290. doi: 10.1111/j.1740-8261.2001.tb00941.x 11499701

28. Abelson J, Trotta CR, Li H. tRNA splicing. J Biol Chem. 1998;273: 12685–12688. doi: 10.1074/jbc.273.21.12685 9582290

29. Paushkin SV, Patel M, Furia BS, Peltz SW, Trotta CR. Identification of a human endonuclease complex reveals a link between tRNA splicing and pre-mRNA 3' end formation. Cell. 2004;117: 311–321. doi: 10.1016/s0092-8674(04)00342-3 15109492

30. Budde BS, Namavar Y, Barth PG, Poll-The BT, Nurnberg G, Becker C, et al. tRNA splicing endonuclease mutations cause pontocerebellar hypoplasia. Nat Genet. 2008;40: 1113–1118. doi: 10.1038/ng.204 18711368

31. Namavar Y, Barth PG, Kasher PR, van Ruissen F, Brockmann K, Bernert G, et al. Clinical, neuroradiological and genetic findings in pontocerebellar hypoplasia. Brain. 2011;134(Pt 1): 143–156. doi: 10.1093/brain/awq287 20952379

32. Namavar Y, Chitayat D, Barth PG, van Ruissen F, de Wissel MB, Poll-The BT, et al. TSEN54 mutations cause pontocerebellar hypoplasia type 5. Eur J Hum Genet. 2011;19: 724–726. doi: 10.1038/ejhg.2011.8 21368912

33. Patel MS, Becker LE, Toi A, Armstrong DL, Chitayat D. Severe, fetal-onset form of olivopontocerebellar hypoplasia in three sibs: PCH type 5? Am J Med Genet A. 2006;140: 594–603. doi: 10.1002/ajmg.a.31095 16470708

34. Albrecht S, Schneider MC, Belmont J, Armstrong DL. Fatal infantile encephalopathy with olivopontocerebellar hypoplasia and micrencephaly. Report of three siblings. Acta Neuropathol. 1993;85: 394–399. doi: 10.1007/bf00334450 8480512

35. Hashimoto K, Takeuchi Y, Kida Y, Hasegawa H, Kantake M, Sasaki A, et al. Three siblings of fatal infantile encephalopathy with olivopontocerebellar hypoplasia and microcephaly. Brain Dev. 1998;20: 169–174. doi: 10.1016/s0387-7604(98)00014-x 9628193

36. Battini R, D’Arrigo S, Cassandrini D, Guzzetta A, Fiorillo C, Pantaleoni C, et al. Novel mutations in TSEN54 in pontocerebellar hypoplasia type 2. J Child Neurol. 2014 Apr;29: 520–525. doi: 10.1177/0883073812470002 23307886

37. Kasher PR, Namavar Y, van Tijn P, Fluiter K, Sizarov A, Kamermans M, et al. Impairment of the tRNA-splicing endonuclease subunit 54 (tsen54) gene causes neurological abnormalities and larval death in zebrafish models of pontocerebellar hypoplasia. Hum Mol Genet. 2011;20: 1574–1584. doi: 10.1093/hmg/ddr034 21273289

38. Seehusen F, Baumgartner W. Axonal pathology and loss precede demyelination and accompany chronic lesions in a spontaneously occurring animal model of multiple sclerosis. Brain Pathol. 2010;20: 551–559. doi: 10.1111/j.1750-3639.2009.00332.x 19775292

39. Haverkamp AK, Lehmbecker A, Spitzbarth I, Widagdo W, Haagmans BL, Segalés J, et al. Experimental infection of dromedaries with Middle East respiratory syndrome-Coronavirus is accompanied by massive ciliary loss and depletion of the cell surface receptor dipeptidyl peptidase 4. Sci Rep. 2018;8: 9778. doi: 10.1038/s41598-018-28109-2 29950581

40. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81: 559–575. doi: 10.1086/519795 17701901

41. Abecasis GR, Cherny SS, Cookson WO, Cardon LR. Merlin—rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet. 2002;30: 97–101. doi: 10.1038/ng786 11731797

42. Bauer A, Jagannathan V, Högler S, Richter B, McEwan NA, Thomas A, et al. MKLN1 splicing defect in dogs with lethal acrodermatitis. PLoS Genet. 2018;14: e1007264. doi: 10.1371/journal.pgen.1007264 29565995

43. Cingolani P, Platts A, Wang le L, Coon M, Nguyen T, Wang L, et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly. 2012;6: 80–92. doi: 10.4161/fly.19695 22728672

44. Bai B, Zhao WM, Tang BX, Wang YQ, Wang L, Zhang Z, et al. DoGSD: the dog and wolf genome SNP database. Nucleic Acids Res. 2015;43(Database issue): D777–783. doi: 10.1093/nar/gku1174 25404132