Fine-mapping and mutation analysis of TRPM1: a candidate gene for leopard complex (LP) spotting and congenital stationary night blindness in horses.
Abstract: Leopard Complex spotting occurs in several breeds of horses and is caused by an incompletely dominant allele (LP). Homozygosity for LP is also associated with congenital stationary night blindness (CSNB) in Appaloosa horses. Previously, LP was mapped to a 6 cm region on ECA1 containing the candidate gene TRPM1 (Transient Receptor Potential Cation Channel, Subfamily M, Member 1) and decreased expression of this gene, measured by qRT-PCR, was identified as the likely cause of both spotting and ocular phenotypes. This study describes investigations for a mutation causing or associated with the Leopard Complex and CSNB phenotype in horses. Re-sequencing of the gene and associated splice sites within the 105 624 bp genomic region of TRPM1 led to the discovery of 18 SNPs. Most of the SNPs did not have a predictive value for the presence of LP. However, one SNP (ECA1:108,249,293 C>T) found within intron 11 had a strong (P < 0.0005), but not complete, association with LP and CSNB and thus is a good marker but unlikely to be causative. To further localize the association, 70 SNPs spanning over two Mb including the TRPM1 gene were genotyped in 192 horses from three different breeds segregating for LP. A single 173 kb haplotype associated with LP and CSNB (ECA1: 108,197,355- 108,370,150) was identified. Illumina sequencing of 300 kb surrounding this haplotype revealed 57 SNP variants. Based on their localization within expressed sequences or regions of high sequence conservation across mammals, six of these SNPs were considered to be the most likely candidate mutations. While the precise function of TRPM1 remains to be elucidated, this work solidifies its functional role in both pigmentation and night vision. Further, this work has identified several potential regulatory elements of the TRPM1 gene that should be investigated further in this and other species.
Publication Date: 2010-03-29 PubMed ID: 20353955DOI: 10.1093/bfgp/elq002Google Scholar: Lookup
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- Journal Article
- Research Support
- N.I.H.
- Extramural
- Research Support
- Non-U.S. Gov't
Summary
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This research focuses on investigating the role of a specific gene TRPM1, in causing Leopard Complex spotting and congenital stationary night blindness in horses. The study identified several Single Nucleotide Polymorphisms (SNPs) located in and around the gene that are likely connected with these conditions.
Overview of the research
- The study was centred on the gene TRPM1 (Transient Receptor Potential Cation Channel, Subfamily M, Member 1), which was previously identified as a candidate gene for Leopard Complex (LP) spotting and congenital stationary night blindness (CSNB) in horses.
- LP spotting is a common physical trait observed in several horse breeds and is linked to an allele, while CSNB is an eye disease commonly found in Appaloosa horses, known to share the link with LP.
- Prior to this study, LP was narrowed down to a 6 cm region on a chromosome, involving the TRPM1 gene. It was suggested that decreased activity or expression of this gene could be the trigger for LP spotting and CSNB.
The TRPM1 gene and LP spotting
- To better understand the connection, the researchers re-sequenced the TRPM1 gene and its associated splice sites, discovering 18 SNPs (single nucleotide polymorphisms).
- These SNPs are essentially variations in a single nucleotide, the basic structural unit of DNA, which can exhibit variations amongst individuals of a species.
- However, most of these SNPs did not have any predictive value for LP, meaning they weren’t significantly associated with LP spotting or CSNB.
Identifying the most likely candidate mutations
- One SNP in intron 11 was found to be strongly associated with LP and CSNB, marking it as a good genetic marker for these conditions, but it was deemed unlikely to be the cause.
- In order to narrow down the association, further genotyping of 70 SNPs spanning over the TRPM1 gene was performed in horses from three different breeds. A single 173 kb haplotype associated with LP and CSNB was identified.
- Sequencing of the surrounding region revealed several more SNP variants. Based on the analysis of where these variants are located and the function of those locations, six SNPs were singled out as the most prospective candidate mutations for the disorder.
Future implications
- The functional role of the TRPM1 gene in pigmentation and night vision in horses needs further exploration.
- Future studies would also need to focus on understanding the potential regulatory elements of the TRPM1 gene, as this study identified several elements that may provide more insights into the role of this gene in these conditions.
Cite This Article
APA
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.
(2010).
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, 9(3), 193-207.
https://doi.org/10.1093/bfgp/elq002 Publication
Researcher Affiliations
- Department of Biology, University of Tampa, Tampa, FL 33611, USA. rbellone@ut.edu
MeSH Terms
- Animals
- Base Sequence
- Chromosome Mapping
- DNA Mutational Analysis
- Exons
- Genetic Predisposition to Disease
- Horse Diseases / congenital
- Horse Diseases / genetics
- Horse Diseases / pathology
- Horses
- Molecular Sequence Data
- Night Blindness / congenital
- Night Blindness / genetics
- Night Blindness / veterinary
- Polymorphism, Single Nucleotide
- Promoter Regions, Genetic
- TRPM Cation Channels / genetics
Citations
This article has been cited 14 times.- Derks MFL, Steensma M. Review: Balancing Selection for Deleterious Alleles in Livestock.. Front Genet 2021;12:761728.
- Shen CH, Hsieh CC, Jiang KY, Lin CY, Chiang NJ, Li TW, Yen CT, Chen WJ, Hwang DY, Chen LT. AUY922 induces retinal toxicity through attenuating TRPM1.. J Biomed Sci 2021 Jul 23;28(1):55.
- Orhan E, Neuillé M, de Sousa Dias M, Pugliese T, Michiels C, Condroyer C, Antonio A, Sahel JA, Audo I, Zeitz C. A New Mouse Model for Complete Congenital Stationary Night Blindness Due to Gpr179 Deficiency.. Int J Mol Sci 2021 Apr 23;22(9).
- Seberg HE, Van Otterloo E, Loftus SK, Liu H, Bonde G, Sompallae R, Gildea DE, Santana JF, Manak JR, Pavan WJ, Williams T, Cornell RA. TFAP2 paralogs regulate melanocyte differentiation in parallel with MITF.. PLoS Genet 2017 Mar;13(3):e1006636.
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- Scott ML, John EE, Bellone RR, Ching JC, Loewen ME, Sandmeyer LS, Grahn BH, Forsyth GW. 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 2016 Jun 21;12(1):121.
- Jun J, Cho YS, Hu H, Kim HM, Jho S, Gadhvi P, Park KM, Lim J, Paek WK, Han K, Manica A, Edwards JS, Bhak J. Whole genome sequence and analysis of the Marwari horse breed and its genetic origin.. BMC Genomics 2014;15 Suppl 9(Suppl 9):S4.
- Ludwig A, Reissmann M, Benecke N, Bellone R, Sandoval-Castellanos E, Cieslak M, Fortes GG, Morales-Muñiz A, Hofreiter M, Pruvost M. Twenty-five thousand years of fluctuating selection on leopard complex spotting and congenital night blindness in horses.. Philos Trans R Soc Lond B Biol Sci 2015 Jan 19;370(1660):20130386.
- 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.
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- Dhingra A, Fina ME, Neinstein A, Ramsey DJ, Xu Y, Fishman GA, Alexander KR, Qian H, Peachey NS, Gregg RG, Vardi N. Autoantibodies in melanoma-associated retinopathy target TRPM1 cation channels of retinal ON bipolar cells.. J Neurosci 2011 Mar 16;31(11):3962-7.
- Webb AA, Cullen CL. Coat color and coat color pattern-related neurologic and neuro-ophthalmic diseases.. Can Vet J 2010 Jun;51(6):653-7.
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