Dataset Information

Evidence for a retroviral insertion in TRPM1 as the cause of congenital stationary night blindness and leopard complex spotting in the horse.

ABSTRACT: Leopard complex spotting is a group of white spotting patterns in horses caused by an incompletely dominant gene (LP) where homozygotes (LP/LP) are also affected with congenital stationary night blindness. Previous studies implicated Transient Receptor Potential Cation Channel, Subfamily M, Member 1 (TRPM1) as the best candidate gene for both CSNB and LP. RNA-Seq data pinpointed a 1378 bp insertion in intron 1 of TRPM1 as the potential cause. This insertion, a long terminal repeat (LTR) of an endogenous retrovirus, was completely associated with LP, testing 511 horses (?(2)=1022.00, p<<0.0005), and CSNB, testing 43 horses (?(2)=43, p<<0.0005). The LTR was shown to disrupt TRPM1 transcription by premature poly-adenylation. Furthermore, while deleterious transposable element insertions should be quickly selected against the identification of this insertion in three ancient DNA samples suggests it has been maintained in the horse gene pool for at least 17,000 years. This study represents the first description of an LTR insertion being associated with both a pigmentation phenotype and an eye disorder.

SUBMITTER: Bellone RR

PROVIDER: S-EPMC3805535 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Evidence for a retroviral insertion in TRPM1 as the cause of congenital stationary night blindness and leopard complex spotting in the horse.

Bellone Rebecca R RR Holl Heather H Setaluri Vijayasaradhi V Devi Sulochana S Maddodi Nityanand N Archer Sheila S Sandmeyer Lynne L Ludwig Arne A Foerster Daniel D Pruvost Melanie M Reissmann Monika M Bortfeldt Ralf R Adelson David L DL Lim Sim Lin SL Nelson Janelle J Haase Bianca B Engensteiner Martina M Leeb Tosso T Forsyth George G Mienaltowski Michael J MJ Mahadevan Padmanabhan P Hofreiter Michael M Paijmans Johanna L A JL Gonzalez-Fortes Gloria G Grahn Bruce B Brooks Samantha A SA

PloS one 20131022 10

Leopard complex spotting is a group of white spotting patterns in horses caused by an incompletely dominant gene (LP) where homozygotes (LP/LP) are also affected with congenital stationary night blindness. Previous studies implicated Transient Receptor Potential Cation Channel, Subfamily M, Member 1 (TRPM1) as the best candidate gene for both CSNB and LP. RNA-Seq data pinpointed a 1378 bp insertion in intron 1 of TRPM1 as the potential cause. This insertion, a long terminal repeat (LTR) of an en ...[more]

PMID: 24167615

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Project description:Importance:Congenital stationary night blindness (CSNB) implies a stable condition, with the major symptom being nyctalopia present at birth. Pediatric clinical presentation and the course of different genetic subtypes of CSNB have not, to our knowledge, been well described in the era of molecular genetic diagnosis. Objective:To describe the presentation and longitudinal clinical characteristics of pediatric patients with molecularly confirmed TRPM1-associated complete CSNB (cCSNB). Design, Setting, Participants:This study was conducted at the University of Iowa from January 1, 1990, to July 1, 2015, and was a retrospective, longitudinal case series of 7 children (5 [71.4%] female) with TRPM1-associated cCSNB followed up for a mean (SD) of 11.1 (2.8) years. Main Outcomes and Measures:History, ophthalmologic examination findings, full-field electroretinogram (ffERG) results, full-field stimulus threshold testing results, Goldmann visual field results, optical coherence tomography results, and molecular genetic results were evaluated. Presenting symptoms and signs, the correlation of refractive error with electroretinography, and clinical evolution were analyzed. Results:Seven patients (5 [71.4%] female) presented early in childhood with strabismus (n = 6 [86%]), myopia (n = 5 [71%]), and/or nystagmus (n = 3 [43%]). The mean (SD) age at presentation was 8 (4) months and for receiving a diagnosis by ffERG was 7.3 years, with molecular diagnosis at 9.7 years. The mean (SD) length of follow-up was 11 (2.8) years. The best-corrected visual acuity at the most recent visit averaged 20/30 in the better-seeing eye (range, 20/20-20/60). The mean (SD) initial refraction was -2.80 (4.42) diopters (D) and the mean refraction at the most recent visit was -8.75 (3.53) D (range, -4.00 to -13.75 D), with the greatest rate of myopic shift before age 5 years. Full-field electroretinogram results were electronegative, consistent with cCSNB, without a significant change in amplitude over time. No patient or parent noted night blindness at presentation; however, subjective nyctalopia was eventually reported in 5 of 7 patients (71%). The full-field stimulus threshold testing results were moderately subnormal (-29.7 [3.8] dB; normal -59.8 [4.0] dB). Goldmann visual field results were significant for full I-4e, but constricted I-2e isopter. Eight different mutations or rare variants in TRPM1 predicted to be pathogenic were detected, with 3 novel variants. Conclusions and Relevance:Children with TRPM1-associated cCSNB presented before school age with progressive myopia as well as strabismus and nystagmus (but not nyctalopia), with stable, electronegative ffERG results, mildly subnormal full-field stimulus threshold testing results, and a constricted I2e isopter on perimetry. These findings suggest that ffERG and cCSNB genetic testing should be considered for children who present with early-onset myopia, especially in the presence of strabismus and/or nystagmus, and that TRPM1-associated cCSNB is a channelopathy that may present without complaints of night blindness in childhood.

Dataset Information

Evidence for a retroviral insertion in TRPM1 as the cause of congenital stationary night blindness and leopard complex spotting in the horse.

Publications

Evidence for a retroviral insertion in TRPM1 as the cause of congenital stationary night blindness and leopard complex spotting in the horse.

Similar Datasets

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