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Equine veterinary journal2020; 53(2); 316-323; doi: 10.1111/evj.13318

Whole-genome sequencing identifies missense mutation in GRM6 as the likely cause of congenital stationary night blindness in a Tennessee Walking Horse.

Abstract: The only known genetic cause of congenital stationary night blindness (CSNB) in horses is a 1378 bp insertion in TRPM1. However, an affected Tennessee Walking Horse was found to have no copies of this variant. Objective: To identify the genetic cause for CSNB in an affected Tennessee Walking Horse. Methods: Case report detailing a whole-genome sequencing (WGS) approach to identify a causal variant. Methods: A complete ophthalmic exam, including an electroretinogram (ERG), was performed on suspected CSNB-affected horse. WGS data were generated from the case and compared with data from seven other breeds (n = 29). One hundred candidate genes were evaluated for coding variants homozygous in the case and absent in all other horses. Protein modelling was used to assess the functional effects of the identified variant. A random cohort of 90 unrelated Tennessee Walking Horses and 273 horses from additional breeds were screened to estimate allele frequency of the GRM6 variant. Results: ERG results were consistent with CSNB. WGS analysis identified a missense mutation in metabotropic glutamate receptor 6 (GRM6) (c.533C>T p.Thr178Met). This single nucleotide polymorphism (SNP) is predicted to be deleterious and protein modelling supports impaired binding of the neurotransmitter glutamate. This variant was not detected in 273 horses from three additional breeds. The estimated allele frequency in Tennessee Walking Horses is 10%. Conclusions: Limited phenotype information for controls and no additional cases with which to replicate this finding. Conclusions: We identified a likely causal recessive missense variant in GRM6. Based on protein modelling, this variant alters GRM6 binding, and thus signalling from the retinal rod cell to the ON-bipolar cell, impairing vision in low light conditions. Given the 10% population allele frequency, it is likely that additional affected horses exist in this breed and further work is needed to identify and examine these animals.
© 2020 EVJ Ltd.
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Publication Date: 2020-08-03 PubMed ID: 32654228DOI: 10.1111/evj.13318Google Scholar: Lookup
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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.

The research study describes how whole-genome sequencing helped identify a likely genetic cause, a missense mutation in GRM6, of congenital stationary night blindness in a Tennessee Walking Horse. This was different from the previously known genetic cause associated with a 1378 bp insertion in TRPM1.

Methodology:

The research used a methodical approach with the following steps:

  • A complete ophthalmic exam, inclusive of an electroretinogram (ERG), was performed on the supposedly CSNB-affected horse. The ERG results confirmed the condition of CSNB.
  • Whole-Genome Sequencing (WGS) was performed on the affected horse. The resultant data were contrasted with data from other horses encompassing seven different breeds.
  • From this analysis, potentially significant genes which may carry the causal variant were evaluated. Here, the researchers focused on coding variants that were homozygous in the affected horse and absent from all the other horses.
  • Protein modelling was undertaken to examine the potential functional effects of the identified variant.
  • The identified GRM6 variant was screened in a sizable cohort of 90 unrelated Tennessee Walking Horses and 273 horses from additional breeds. This helped to estimate the allele frequency of the GRM6 variant.

Findings:

The findings of the research unfolded as such:

  • The WGS and ERG analyses identified a missense mutation in the metabotropic glutamate receptor 6 (GRM6) (c.533C>T p.Thr178Met) as the likely cause of CSNB in the affected horse.
  • This specific SNP was suggested to be damaging, as protein modelling indicated that this mutation hampers the binding of the neurotransmitter glutamate.
  • The estimated frequency of the GRM6 allele was found to be 10% specifically within the Tennessee Walking Horses, and it was unseen in 273 horses from three unrelated breeds.

Conclusion:

The conclusion of the study centered around the following points:

  • The research highlighted a likely causal recessive missense variant in GRM6 as the cause of CSNB.
  • This variant is believed to disrupt GRM6 binding and subsequently the signalling from the retinal rod cell to the ON-bipolar cell, which then worsens vision in low light conditions.
  • Considering the 10% population allele frequency, the researchers suggested that additional affected horses likely exist in this breed.
  • However, it was also noted that limited phenotype information for controls and no additional cases with which to replicate this finding were present, hence further research is required to identify and examine these animals.

Cite This Article

APA
Hack YL, Crabtree EE, Avila F, Sutton RB, Grahn R, Oh A, Gilger B, Bellone RR. (2020). Whole-genome sequencing identifies missense mutation in GRM6 as the likely cause of congenital stationary night blindness in a Tennessee Walking Horse. Equine Vet J, 53(2), 316-323. https://doi.org/10.1111/evj.13318

Publication

Equine veterinary journal
ISSN: 2042-3306
NlmUniqueID: 0173320
Country: United States
Language: English
Volume: 53
Issue: 2
Pages: 316-323

Researcher Affiliations

Hack, Yael L
  • Veterinary Genetics Laboratory, School of Veterinary Medicine, University of California, Davis, California, USA.
Crabtree, Elizabeth E
  • College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, USA.
Avila, Felipe
  • Veterinary Genetics Laboratory, School of Veterinary Medicine, University of California, Davis, California, USA.
Sutton, Roger B
  • Cell Physiology and Molecular Biophysics, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas, USA.
Grahn, Robert
  • Veterinary Genetics Laboratory, School of Veterinary Medicine, University of California, Davis, California, USA.
Oh, Annie
  • College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, USA.
Gilger, Brian
  • College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, USA.
Bellone, Rebecca R
  • Veterinary Genetics Laboratory, School of Veterinary Medicine, University of California, Davis, California, USA.
  • Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, California, USA.

MeSH Terms

  • Animals
  • Eye Diseases, Hereditary / genetics
  • Eye Diseases, Hereditary / veterinary
  • Genetic Diseases, X-Linked
  • Horse Diseases / genetics
  • Horses
  • Mutation, Missense
  • Myopia
  • Night Blindness / genetics
  • Night Blindness / veterinary
  • Receptors, Glutamate / genetics
  • Tennessee

Grant Funding

  • 16-12 / UC Davis Center for Equine Health
  • North Carolina State University's College of Veterinary Medicine
  • School of Veterinary Medicine at the University of California, Davis

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Citations

This article has been cited 6 times.
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