Redundant contribution of a Transient Receptor Potential cation channel Member 1 exon 11 single nucleotide polymorphism to equine congenital stationary night blindness.
Abstract: Congenital stationary night-blindness (CSNB) is a recessive autosomal defect in low-light vision in Appaloosa and other horse breeds. This condition has been mapped by linkage analysis to a gene coding for the Transient Receptor Potential cation channel Member 1 (TRPM1). TRPM1 is normally expressed in the ON-bipolar cells of the inner nuclear layer of the retina. Down-regulation of TRPM1 expression in CSNB results from a transposon-like insertion in intron 1 of the TRPM1 gene. Stop transcription signals in this transposon significantly reduce TRPM1 primary transcript levels in CSNB horses. This study describes additional contributions by a second mutation of the TRPM1 gene, the ECA1 108,249,293 C > T SNP, to down-regulation of transcription of the TRPM1 gene in night-blind horses. This TRPM1 SNP introduces a consensus binding site for neuro-oncological ventral antigen 1 (Nova-1) protein in the primary transcript. Nova-1 binding disrupts normal splicing signals, producing unstable, non-functional mRNA transcripts. Results: Retinal bipolar cells express both TRPM1 and Nova-1 proteins. In vitro addition of Nova-1 protein retards electrophoretic migration of TRPM1 RNA containing the ECA1 108,249,293 C > T SNP. Up-regulating Nova-1 expression in primary cultures of choroidal melanocytes carrying the intron 11 SNP caused an average log 2-fold reduction of ~6 (64-fold) of TRPM1 mRNA expression. Conclusions: These finding suggest that the equine TRPM1 SNP can act independently to reduce survival of TRPM1 mRNA escaping the intron 1 transcriptional stop signals in CSNB horses. Coexistence and co-inheritance of two independent TRPM1 mutations across 1000 equine generations suggests a selective advantage for the apparently deleterious CSNB trait.
Publication Date: 2016-06-21 PubMed ID: 27329127PubMed Central: PMC4915136DOI: 10.1186/s12917-016-0745-1Google 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.
- Journal Article
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 looks into how congenital stationary night-blindness (CSNB) in horses is influenced by two mutations in the Transient Receptor Potential cation channel Member 1 (TRPM1) gene. The study discovered that a specific TRPM1 single nucleotide polymorphism (SNP), when bound with neuro-oncological ventral antigen 1 (Nova-1) protein, can independently down-regulate TRPM1 gene transcription and limit proper mRNA transcripts, thus negating the detrimental effects of another mutation within the same gene.
Background of the Research
- The focus of the research is congenital stationary night-blindness (CSNB), a condition seen in certain horse breeds that affects their vision under low-light situations. This condition is linked to a gene referred to as the Transient Receptor Potential cation channel Member 1 (TRPM1).
- This gene is typically expressed within ON-bipolar cells in the retina’s inner nuclear layer. In CSNB horses, the expression of this gene is impeded by a transposon-like insertion found in intron 1 of the TRPM1 gene. Transcription stop signals within this transposon reduce the levels of the primary TRPM1 transcript in such horses.
Findings of the Research
- The TRPM1 gene exhibits an additional mutation in the form of a single nucleotide polymorphism (SNP), specified as ECA1 108,249,293 C > T. This mutation also contributes to the down-regulation of TRPM1 gene transcription.
- This specific SNP introduces a new consensus binding site for the neuro-oncological ventral antigen 1 (Nova-1) protein. Once this protein binds, it disrupts the normal splicing signals, leading to the creation of non-functional and unstable mRNA transcripts.
- Experimental evidence showed that both Nova-1 and TRPM1 proteins are expressed in the retinal bipolar cells. When Nova-1 protein was added in vitro, it impeded the electrophoretic movement of TRPM1 RNA carrying the aforementioned SNP.
- Augmented Nova-1 expression in choroidal melanocyte primary cultures that carried the intron 11 SNP caused a notable reduction (approximately 64-fold) in TRPM1 mRNA expression.
- The study concludes that this specific equine TRPM1 SNP can independently decrease TRPM1 mRNA survival, thereby limiting the negative impact of the intron 1 transcriptional stop signals in CSNB horses.
Implications of the Research
- The results suggest a co-inheritance and co-existence pattern of these two independent TRPM1 mutations over approximately 1000 equine generations. This discovery implies that there could be a potential selective advantage for the seemingly detrimental CSNB trait.
Cite This Article
APA
Scott ML, John EE, Bellone RR, Ching JC, Loewen ME, Sandmeyer LS, Grahn BH, Forsyth GW.
(2016).
Redundant contribution of a Transient Receptor Potential cation channel Member 1 exon 11 single nucleotide polymorphism to equine congenital stationary night blindness.
BMC Vet Res, 12(1), 121.
https://doi.org/10.1186/s12917-016-0745-1 Publication
Researcher Affiliations
- Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK, S7N 5B4, Canada.
- Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK, S7N 5B4, Canada.
- Department of Biology, University of Tampa, Tampa, FL, 33606, USA.
- Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK, S7N 5B4, Canada.
- Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK, S7N 5B4, Canada.
- Small Animal Clinical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Canada.
- Small Animal Clinical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Canada.
- Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK, S7N 5B4, Canada. george.forsyth@usask.ca.
MeSH Terms
- Animals
- Binding Sites
- Cells, Cultured
- Exons
- Eye Diseases, Hereditary / genetics
- Eye Diseases, Hereditary / veterinary
- Genetic Diseases, X-Linked / genetics
- Genetic Diseases, X-Linked / veterinary
- Horse Diseases / genetics
- Horses
- Myopia / genetics
- Myopia / veterinary
- Nerve Tissue Proteins / genetics
- Neuro-Oncological Ventral Antigen
- Night Blindness / genetics
- Night Blindness / veterinary
- Polymorphism, Single Nucleotide
- RNA / metabolism
- RNA-Binding Proteins / genetics
- TRPM Cation Channels / genetics
References
This article includes 17 references
- Bellone RR, Brooks SA, Sandmeyer L, Murphy BA, Forsyth G, Archer S, Bailey E, Grahn B. Differential gene expression of TRPM1, the potential cause of congenital stationary night blindness and coat spotting patterns (LP) in the Appaloosa horse (Equus caballus).. Genetics 2008 Aug;179(4):1861-70.
- Koike C, Numata T, Ueda H, Mori Y, Furukawa T. TRPM1: a vertebrate TRP channel responsible for retinal ON bipolar function.. Cell Calcium 2010 Aug-Sep;48(2-3):95-101.
- Morgans CW, Brown RL, Duvoisin RM. TRPM1: the endpoint of the mGluR6 signal transduction cascade in retinal ON-bipolar cells.. Bioessays 2010 Jul;32(7):609-14.
- Oancea E, Vriens J, Brauchi S, Jun J, Splawski I, Clapham DE. TRPM1 forms ion channels associated with melanin content in melanocytes.. Sci Signal 2009 May 12;2(70):ra21.
- Sandmeyer LS, Breaux CB, Archer S, Grahn BH. Clinical and electroretinographic characteristics of congenital stationary night blindness in the Appaloosa and the association with the leopard complex.. Vet Ophthalmol 2007 Nov-Dec;10(6):368-75.
- Bellone RR, Forsyth G, Leeb T, Archer S, Sigurdsson S, Imsland F, Mauceli E, Engensteiner M, Bailey E, Sandmeyer L, Grahn B, Lindblad-Toh K, Wade CM. Fine-mapping and mutation analysis of TRPM1: a candidate gene for leopard complex (LP) spotting and congenital stationary night blindness in horses.. Brief Funct Genomics 2010 May;9(3):193-207.
- Bellone RR, Archer S, Wade CM, Cuka-Lawson C, Haase B, Leeb T, Forsyth GW, Sandmeyer LS, Grahn BH. Association analysis of candidate SNPs in TRPM1 with leopard complex spotting (LP) and congenital stationary night blindness (CSNB) in horses.. Anim Genet 2010;41:207.
- Bellone RR, Holl H, Setaluri V, Devi S, Maddodi N, Archer S, Sandmeyer L, Ludwig A, Foerster D, Pruvost M, Reissmann M, Bortfeldt R, Adelson DL, Lim SL, Nelson J, Haase B, Engensteiner M, Leeb T, Forsyth G, Mienaltowski MJ, Mahadevan P, Hofreiter M, Paijmans JL, Gonzalez-Fortes G, Grahn B, Brooks SA. Evidence for a retroviral insertion in TRPM1 as the cause of congenital stationary night blindness and leopard complex spotting in the horse.. PLoS One 2013;8(10):e78280.
- Buckanovich RJ, Posner JB, Darnell RB. Nova, the paraneoplastic Ri antigen, is homologous to an RNA-binding protein and is specifically expressed in the developing motor system.. Neuron 1993 Oct;11(4):657-72.
- Buckanovich RJ, Darnell RB. The neuronal RNA binding protein Nova-1 recognizes specific RNA targets in vitro and in vivo.. Mol Cell Biol 1997 Jun;17(6):3194-201.
- Yasumoto K, Yokoyama K, Shibata K, Tomita Y, Shibahara S. Microphthalmia-associated transcription factor as a regulator for melanocyte-specific transcription of the human tyrosinase gene.. Mol Cell Biol 1994 Dec;14(12):8058-70.
- Graham FL, van der Eb AJ. A new technique for the assay of infectivity of human adenovirus 5 DNA.. Virology 1973 Apr;52(2):456-67.
- Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.. Methods 2001 Dec;25(4):402-8.
- Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method.. Nat Protoc 2008;3(6):1101-8.
- Watanabe K, Takeda K, Yasumoto K, Udono T, Saito H, Ikeda K, Takasaka T, Takahashi K, Kobayashi T, Tachibana M, Shibahara S. Identification of a distal enhancer for the melanocyte-specific promoter of the MITF gene.. Pigment Cell Res 2002 Jun;15(3):201-11.
- Miller AJ, Du J, Rowan S, Hershey CL, Widlund HR, Fisher DE. Transcriptional regulation of the melanoma prognostic marker melastatin (TRPM1) by MITF in melanocytes and melanoma.. Cancer Res 2004 Jan 15;64(2):509-16.
- Pruvost M, Bellone R, Benecke N, Sandoval-Castellanos E, Cieslak M, Kuznetsova T, Morales-Muñiz A, O'Connor T, Reissmann M, Hofreiter M, Ludwig A. Genotypes of predomestic horses match phenotypes painted in Paleolithic works of cave art.. Proc Natl Acad Sci U S A 2011 Nov 15;108(46):18626-30.
Citations
This article has been cited 1 times.- Beyene SS, Ling T, Ristevski B, Chen M. A novel riboswitch classification based on imbalanced sequences achieved by machine learning.. PLoS Comput Biol 2020 Jul;16(7):e1007760.
Use Nutrition Calculator
Check if your horse's diet meets their nutrition requirements with our easy-to-use tool Check your horse's diet with our easy-to-use tool
Talk to a Nutritionist
Discuss your horse's feeding plan with our experts over a free phone consultation Discuss your horse's diet over a phone consultation
Submit Diet Evaluation
Get a customized feeding plan for your horse formulated by our equine nutritionists Get a custom feeding plan formulated by our nutritionists
