FREE SHIPPING over $40
OVER 10000 FIVE-STAR REVIEWS
5% OFF ALL SUBSCRIPTIONS
100% HAPPINESS GUARANTEE
Analyze Diet
0
Genes2020; 11(1); doi: 10.3390/genes11010082

Genome-Wide Association Study and Subsequent Exclusion of ATCAY as a Candidate Gene Involved in Equine Neuroaxonal Dystrophy Using Two Animal Models.

Abstract: Equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (eNAD/EDM) is an inherited neurodegenerative disorder of unknown etiology. Clinical signs of neurological deficits develop within the first year of life in vitamin E (vitE) deficient horses. A genome-wide association study (GWAS) was carried out using 670,000 SNP markers in 27 case and 42 control Quarter Horses. Two markers, encompassing a 2.5 Mb region on ECA7, were associated with the phenotype (p = 2.05 × 10-7 and 4.72 × 10-6). Within this region, caytaxin (ATCAY) was identified as a candidate gene due to its known role in Cayman Ataxia and ataxic/dystonic phenotypes in mouse models. Whole-genome sequence data in four eNAD/EDM and five unaffected horses identified 199 associated variants within the ECA7 region. MassARRAY® genotyping was performed on these variants within the GWAS population. The three variants within ATCAY were not concordant with the disease phenotype. No difference in expression or alternative splicing was identified using qRT-PCR in brainstem across the ATCAY transcript. Atcayji-hes mice were then used to conduct functional analysis in a second animal model. Histologic lesions were not identified in the central nervous system of Atcayji-hes mice. Additionally, supplementation of homozygous Atcayji-hes mice with 600 IU/day of dl-α-tocopheryl acetate (vitE) during gestation, lactation, and adulthood did not improve the phenotype. ATCAY has therefore been excluded as a candidate gene for eNAD/EDM.
Get Full Text
Publication Date: 2020-01-10 PubMed ID: 31936863PubMed Central: PMC7016928DOI: 10.3390/genes11010082Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
LinkedInCopy
  • Journal Article
  • Research Support
  • N.I.H.
  • Extramural
  • Research Support
  • Non-U.S. Gov't
  • Research Support
  • U.S. Gov't
  • Non-P.H.S.

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research examined a common, inherited disorder in horses called equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (eNAD/EDM), aiming to identify a genomic marker related to the disease. The study concluded that a potential candidate gene, ATCAY, did not show any link to the disorder in any of their models.

Background

  • The study focuses on equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (eNAD/EDM), a degenerative neurological disease commonly observed in horses.
  • This ailment generally manifests in vitamin E deficient horses during their first year of life. The exact cause or genetic factors related to this disease are still unknown.

Methods

  • The researchers conducted a Genome-Wide Association Study (GWAS), a common method used to identify potential genetic markers for diseases. This involved studying 670,000 Single Nucleotide Polymorphism (SNP) markers in 27 horses with the disease (case) and 42 healthy horses (control).
  • The study identified two SNP markers spanning a 2.5 Mb region on ECA7 associated with the disorder. This region contained a gene known as ATCAY, recognized for its role in causing Cayman Ataxia and ataxic/dystonic phenotypes in mice, making it a potential candidate gene linked to eNAD/EDM.

Findings

  • From sequencing the entire genome of four ailing and five healthy horses, researchers found 199 associated genetic variants in the ECA7 region.
  • However, when conducting genotyping on these variants within the GWAS population via the MassARRAY technique, none of the three genetic variants within ATCAY displayed concordance with the disease phenotype, suggesting that the gene might not be linked with the disorder.
  • Further analysis using quantitative reverse transcription PCR (qRT-PCR) did not reveal any difference in the expression levels or alternate splicing across the ATCAY transcript in both healthy and affected horses.

Further Analysis

  • They pursued further examination by utilizing ATCAY knockout mice, but found no histological lesions in the central nervous system that typically characterize the disease.
  • Additionally, vitamin E supplementation in homozygous ATCAY mice throughout various life stages (gestation, lactation, and adulthood) showed no improvement in the phenotype.

Conclusion

  • Based on the observations from two different animal models – horse and mice, the study excluded ATCAY as a candidate gene being involved in equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy.

Cite This Article

APA
Hales EN, Esparza C, Peng S, Dahlgren AR, Peterson JM, Miller AD, Finno CJ. (2020). Genome-Wide Association Study and Subsequent Exclusion of ATCAY as a Candidate Gene Involved in Equine Neuroaxonal Dystrophy Using Two Animal Models. Genes (Basel), 11(1). https://doi.org/10.3390/genes11010082

Publication

Genes
ISSN: 2073-4425
NlmUniqueID: 101551097
Country: Switzerland
Language: English
Volume: 11
Issue: 1

Researcher Affiliations

Hales, Erin N
  • Department of Population, Health and Reproduction, University of California, Davis School of Veterinary Medicine, Davis, CA 95616, USA.
Esparza, Christina
  • Department of Population, Health and Reproduction, University of California, Davis School of Veterinary Medicine, Davis, CA 95616, USA.
Peng, Sichong
  • Department of Population, Health and Reproduction, University of California, Davis School of Veterinary Medicine, Davis, CA 95616, USA.
Dahlgren, Anna R
  • Department of Population, Health and Reproduction, University of California, Davis School of Veterinary Medicine, Davis, CA 95616, USA.
Peterson, Janel M
  • Department of Population, Health and Reproduction, University of California, Davis School of Veterinary Medicine, Davis, CA 95616, USA.
Miller, Andrew D
  • Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY 14853, USA.
Finno, Carrie J
  • Department of Population, Health and Reproduction, University of California, Davis School of Veterinary Medicine, Davis, CA 95616, USA.

MeSH Terms

  • Animals
  • Disease Models, Animal
  • Female
  • Genome-Wide Association Study
  • Homozygote
  • Horse Diseases / genetics
  • Horses / genetics
  • Male
  • Mice
  • Mice, Inbred C3H
  • Mice, Knockout
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neuroaxonal Dystrophies / genetics
  • Neuroaxonal Dystrophies / veterinary
  • Phenotype
  • Vitamin E
  • Vitamin E Deficiency

Grant Funding

  • 5K01OD015134 / NIH HHS
  • L40 TR001136 / NIH HHS

Conflict of Interest Statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

References

This article includes 41 references
  1. Brown CM, Stowe HD, Trapp AL, Derksen FJ, Clement SF. Equine degenerative myeloencephalopathy: A vitamin E deficiency that may be familial.. J. Vet. Intern. Med. 1987;1:45–50.
    doi: 10.1111/j.1939-1676.1987.tb01985.xpubmed: 3506620google scholar: lookup
  2. Finno CJ, Famula T, Aleman M, Higgins RJ, Madigan JE, Bannasch DL. Pedigree analysis and exclusion of alpha-tocopherol transfer protein (TTPA) as a candidate gene for neuroaxonal dystrophy in the American quarter horse.. J. Vet. Intern. Med. 2013;27:177–185.
    doi: 10.1111/jvim.12015pmc: PMC4557866pubmed: 23186252google scholar: lookup
  3. Aleman M, Finno CJ, Higgins RJ, Puschner B, Gericota B, Gohil K, LeCouteur RA, Madigan JE. Evaluation of epidemiological, clinical, and pathological features of neuroaxonal dystrophy in Quarter Horses.. J. Am. Vet. Med. Assoc. 2011;239:823–833.
    doi: 10.2460/javma.239.6.823pubmed: 21916766google scholar: lookup
  4. Finno CJ, Higgins RJ, Aleman M, Ofri R, Hollingsworth SR, Bannasch DL, Reilly CM, Madigan JE. Equine degenerative myeloencephalopathy in Lusitano horses.. J. Vet. Intern. Med. 2011;25:1439–1446.
    doi: 10.1111/j.1939-1676.2011.00817.xpubmed: 22092640google scholar: lookup
  5. Mayhew IG, de Lahunta A, Whitlock R, Geary JC. Equine degenerative myeloencephalopathy.. J. Am. Vet. Med. Assoc. 1977;170:195–201.
    pubmed: 833044
  6. Finno CJ, Valberg SJ, Shivers J, D’Almeida E, Armién AG. Evidence of the primary afferent tracts undergoing neurodegeneration in horses with equine degenerative myeloencephalopathy based on calretinin immunohistochemical localization.. Vet. Pathol. 2016;53:77–86.
    doi: 10.1177/0300985815598787pmc: PMC4831571pubmed: 26253880google scholar: lookup
  7. Burns EN, Finno CJ. Equine degenerative myeloencephalopathy: Prevalence, impact, and management.. Vet. Med. Res. Reports. 2018;9:63–67.
    doi: 10.2147/VMRR.S148542pmc: PMC6135079pubmed: 30234005google scholar: lookup
  8. Ouahchi K, Arita M, Kayden H, Hentati F, Hamida MB, Sokol R, Arai H, Inoue K, Mandel JL, Koenig M. Ataxia with isolated vitamin E deficiency is caused by mutations in the α–tocopherol transfer protein.. Nat. Genet. 1995;9:141–145.
    doi: 10.1038/ng0295-141pubmed: 7719340google scholar: lookup
  9. Finno CJ, Aleman M, Higgins RJ, Madigan JE, Bannasch DL. Risk of false positive genetic associations in complex traits with underlying population structure: A case study.. Vet. J. 2014;202:543–549.
    doi: 10.1016/j.tvjl.2014.09.013pmc: PMC4337777pubmed: 25278384google scholar: lookup
  10. Schaefer RJ, Schubert M, Bailey E, Bannasch DL, Barrey E, Bar-Gal GK, Brem G, Brooks SA, Distl O, Fries R. Developing a 670k genotyping array to tag ~2M SNPs across 24 horse breeds.. BMC Genomics. 2017;18:1–18.
    doi: 10.1186/s12864-017-3943-8pmc: PMC5530493pubmed: 28750625google scholar: lookup
  11. Zhou X, Stephens M. Genome-wide efficient mixed-model analysis for association studies.. Nat. Genet. 2012;44:821–824.
    doi: 10.1038/ng.2310pmc: PMC3386377pubmed: 22706312google scholar: lookup
  12. Bomar JM, Benke PJ, Slattery EL, Puttagunta R, Taylor LP, Seong E, Nystuen A, Chen W, Albin RL, Patel PD. Mutations in a novel gene encoding a CRAL-TRIO domain cause human Cayman ataxia and ataxia/dystonia in the jittery mouse.. Nat. Genet. 2003;35:264–269.
    doi: 10.1038/ng1255pubmed: 14556008google scholar: lookup
  13. Kapfhamer D, Sweet HO, Sufalko D, Warren S, Johnson KR, Burmeister M. The neurological mouse mutations jittery and hesitant are allelic and map to the region of mouse Chromosome 10 homologous to 19p13.3.. Genomics. 1996;35:533–538.
    doi: 10.1006/geno.1996.0394pubmed: 8812488google scholar: lookup
  14. Aoyama T, Hata S, Nakao T, Tanigawa Y, Oka C, Kawaichi M. Cayman ataxia protein caytaxin is transported by kinesin along neurites through binding to kinesin light chains.. J. Cell Sci. 2009;122:4177–4185.
    doi: 10.1242/jcs.048579pubmed: 19861499google scholar: lookup
  15. Pan CQ, Low BC. Functional plasticity of the BNIP-2 and Cdc42GAP Homology (BCH) domain in cell signaling and cell dynamics.. FEBS Lett. 2012;586:2674–2691.
    doi: 10.1016/j.febslet.2012.04.023pubmed: 22710163google scholar: lookup
  16. Sikora KM, Nosavanh LM, Kantheti P, Burmeister M, Hortsch M. Expression of caytaxin protein in cayman ataxia mouse models correlates with phenotype severity.. PLoS One. 2012;7:1–12.
    doi: 10.1371/journal.pone.0050570pmc: PMC3511541pubmed: 23226316google scholar: lookup
  17. Luna-Cancalon K, Sikora KM, Pappas SS, Singh V, Wulff H, Paulson HL, Burmeister M, Shakkottai VG. Alterations in cerebellar physiology are associated with a stiff-legged gait in Atcayji-hes mice.. Neurobiol. Dis. 2014;67:140–148.
    doi: 10.1016/j.nbd.2014.03.020pmc: PMC4059535pubmed: 24727095google scholar: lookup
  18. Lakes EH, Allen KD. Gait analysis methods for rodent models of arthritic disorders: Reviews and recommendations.. Osteoarthr. Cartil. 2016;24:1837–1849.
    doi: 10.1016/j.joca.2016.03.008pmc: PMC5026889pubmed: 26995111google scholar: lookup
  19. Cummings BJ, Engesser-cesar C, Anderson AJ. Adaptation of a ladder beam walking task to assess locomotor recovery in mice following spinal cord injury Adaptation of a ladder beam walking task to assess locomotor recovery in mice.. Brain. 2007;177:232–241.
    pmc: PMC1892162pubmed: 17197044
  20. Chang CC, Chow CC, Tellier LCAM, Vattikuti S, Purcell SM, Lee JJ. Second-generation PLINK: Rising to the challenge of larger and richer datasets.. Gigascience. 2015;4:1–16.
    doi: 10.1186/s13742-015-0047-8pmc: PMC4342193pubmed: 25722852google scholar: lookup
  21. Beeson SK, Schaefer RJ, Mason VC, McCue ME. Robust remapping of equine SNP array coordinates to Eq쪳.. Anim. Genet. 2018;50:114–115.
    doi: 10.1111/age.12745pmc: PMC6349531pubmed: 30421446google scholar: lookup
  22. Turner SD. qqman: An R package for visualizing GWAS results using Q-Q and manhattan plots.. Am. J. Hum. Genet. 2014.
    doi: 10.1101/005165google scholar: lookup
  23. Vuckovic D, Gasparini P, Soranzo N, Iotchkova V. MultiMeta: An R package for meta-analyzing multi-phenotype genome-wide association studies.. Bioinformatics. 2015;31:2754–2756.
    doi: 10.1093/bioinformatics/btv222pmc: PMC4528637pubmed: 25908790google scholar: lookup
  24. Mi H, Muruganujan A, Ebert D, Huang X, Thomas PD. PANTHER version 14: More genomes, a new PANTHER GO-slim and improvements in enrichment analysis tools.. Nucleic Acids Res. 2019;47:D419–D426.
    doi: 10.1093/nar/gky1038pmc: PMC6323939pubmed: 30407594google scholar: lookup
  25. Manley G. Animal models of dystonia: Lessons from a mutant Rat.. Neurobiol. Dis. 2013;71:233–236.
    pmc: PMC3171987pubmed: 21081162
  26. Li H, Durbin R. Fast and accurate long-read alignment with Burrows-Wheeler transform.. Bioinformatics. 2010;26:589–595.
    doi: 10.1093/bioinformatics/btp698pmc: PMC2828108pubmed: 20080505google scholar: lookup
  27. Marth G, Garrison E. Haplotype-based variant detection from short-read sequencing.. arXiv. 20121207.3907.
  28. Cingolani P, Patel VM, Coon M, Nguyen T, Land SJ, Ruden DM, Lu X. Using Drosophila melanogaster as a model for genotoxic chemical mutational studies with a new program, SnpSift.. Front. Genet. 2012;3:1–9.
    doi: 10.3389/fgene.2012.00035pmc: PMC3304048pubmed: 22435069google scholar: lookup
  29. Cingolani P, Platts A, Wang LL, Coon M, Nguyen T, Wang L, Land SJ, Ruden DM, Lu X. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff.. Fly (Austin). 2012;6:80–92.
    doi: 10.4161/fly.19695pmc: PMC3679285pubmed: 22728672google scholar: lookup
  30. Untergasser A, Nijveen H, Rao X, Bisseling T, Geurts R, Leunissen JAM. Primer3Plus, an enhanced web interface to Primer3.. Nucleic Acids Res. 2007;35:71–74.
    doi: 10.1093/nar/gkm306pmc: PMC1933133pubmed: 17485472google scholar: lookup
  31. Finno CJ, Bordbari MH, Valberg SJ, Lee D, Herron J, Hines K, Monsour T, Scott E, Bannasch DL, Mickelson J. Transcriptome profiling of equine vitamin E deficient neuroaxonal dystrophy identifies upregulation of liver X receptor target genes.. Free Radic. Biol. Med. 2016;101:261–271.
    doi: 10.1016/j.freeradbiomed.2016.10.009pmc: PMC5154892pubmed: 27751910google scholar: lookup
  32. Finno CJ, Bordbari MH, Gianino G, Ming-Whitfield B, Burns E, Merkel J, Britton M, Durbin-Johnson B, Sloma EA, McMackin M. An innate immune response and altered nuclear receptor activation defines the spinal cord transcriptome during alpha-tocopherol deficiency in Ttpa-null mice.. Free Radic. Biol. Med. 2018;120:289–302.
    doi: 10.1016/j.freeradbiomed.2018.02.037pmc: PMC5940542pubmed: 29526809google scholar: lookup
  33. Hayakawa Y, Itoh M, Yamada A, Mitsuda T, Nakagawa T. Expression and localization of Cayman ataxia-related protein, Caytaxin, is regulated in a developmental- and spatial-dependent manner.. Brain Res. 2007.
    doi: 10.1016/j.brainres.2006.10.068pubmed: 17157273google scholar: lookup
  34. Beare JE, Morehouse JR, DeVries WH, Enzmann GU, Burke DA, Magnuson DSK, Whittemore SR. Gait analysis in normal and spinal contused mice using the TreadScan system.. J. Neurotrauma. 2009;26:2045–2056.
    doi: 10.1089/neu.2009.0914pmc: PMC2813489pubmed: 19886808google scholar: lookup
  35. Finno CJ, Estell KE, Katzman S, Winfield L, Rendahl A, Textor J, Bannasch DL, Puschner B. Blood and cerebrospinal fluid α-tocopherol and selenium concentrations in neonatal foals with neuroaxonal dystrophy.. J. Vet. Intern. Med. 2015;29:1667–1675.
    doi: 10.1111/jvim.13618pmc: PMC4831564pubmed: 26391904google scholar: lookup
  36. Sun J, Pan CQ, Chew TW, Liang F, Burmeister M, Low BC. BNIP-H recruits the cholinergic machinery to neurite terminals to promote acetylcholine signaling and neuritogenesis.. Dev. Cell. 2015;34:555–568.
    doi: 10.1016/j.devcel.2015.08.006pubmed: 26343454google scholar: lookup
  37. Ito-Smith KM. Characterization of Caytaxin Protein in Animal Models of cerebellar dysfunction.. PhD Thesis. University of Michigan; Ann Arbor, MI, USA: 2012.
  38. Gago S, Overton NLD, Ben-Ghazzi N, Novak-Frazer L, Read ND, Denning DW, Bowyer P. Lung colonization by Aspergillus fumigatus is controlled by ZNF77.. Nat. Commun. 2018;9:3835.
    doi: 10.1038/s41467-018-06148-7pmc: PMC6147781pubmed: 30237437google scholar: lookup
  39. Pei Z, Jia Z, Watkins PA. The second member of the human and murine “Bubblegum” family is a testis- and brainstem-specific Acyl-CoA synthetase.. J. Biol. Chem. 2006;281:6632–6641.
    doi: 10.1074/jbc.M511558200pubmed: 16371355google scholar: lookup
  40. Sisó S, Ferrer I, Pumarola M. Abnormal synaptic protein expression in two Arabian horses with equine degenerative myeloencephalopathy.. Vet. J. 2003;166:238–243.
    doi: 10.1016/S1090-0233(02)00302-7pubmed: 14550734google scholar: lookup
  41. Finno CJ, Kaese HJ, Miller AD, Gianino G, Divers T, Valberg SJ. Pigment retinopathy in warmblood horses with equine degenerative myeloencephalopathy and equine motor neuron disease.. Vet. Ophthalmol. 2017;20:304–309.
    doi: 10.1111/vop.12417pmc: PMC5292316pubmed: 27491953google scholar: lookup

Citations

This article has been cited 1 times.
  1. Tanaka M, Fujikawa R, Sekiguchi T, Hernandez J, Johnson OT, Tanaka D, Kumafuji K, Serikawa T, Hoang Trung H, Hattori K, Mashimo T, Kuwamura M, Gestwicki JE, Kuramoto T. A missense mutation in the Hspa8 gene encoding heat shock cognate protein 70 causes neuroaxonal dystrophy in rats. Front Neurosci 2024;18:1263724.
    doi: 10.3389/fnins.2024.1263724pubmed: 38384479google scholar: lookup
Subscribe to our newsletter
Join 99,727 horse owners like you who receive our email updates on horse health and nutrition.