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Home / Equine Research Bank / Genes (Basel) / Genome-Wide Association Study and Subsequent Exclusion of AT...
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.
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Publication Date: 2020-01-10 PubMed ID: 31936863PubMed Central: PMC7016928DOI: 10.3390/genes11010082Google Scholar: Lookup
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  • 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.

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