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Open AccessFeature PaperArticle

A Missense Variant Affecting the C-Terminal Tail of UNC93B1 in Dogs with Exfoliative Cutaneous Lupus Erythematosus (ECLE)

1
Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland
2
Dermfocus, University of Bern, 3001 Bern, Switzerland
3
Division of Clinical Dermatology, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland
4
Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland
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ZNLabs Veterinary Diagnostics, Garden City, ID 83714, USA
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Westvet, Garden City, ID 83714, USA
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AniCura Tierärztliche Spezialisten, 22043 Hamburg, Germany
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Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA
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Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607, USA
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Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California Davis, Davis, CA 95616, USA
11
Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
12
Department of Veterinary and Biomedical Sciences, University of Minnesota, Saint Paul, MN 55108, USA
13
Department of Veterinary Biosciences, University of Helsinki, 00014 Helsinki, Finland
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Department of Medical and Clinical Genetics, University of Helsinki, 00014 Helsinki, Finland
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Folkhälsan Research Center, 00290 Helsinki, Finland
16
University of Pennsylvania, School of Veterinary Medicine, Philadelphia, PA 19104, USA
*
Author to whom correspondence should be addressed.
Genes 2020, 11(2), 159; https://doi.org/10.3390/genes11020159
Received: 20 December 2019 / Revised: 27 January 2020 / Accepted: 31 January 2020 / Published: 3 February 2020
(This article belongs to the Special Issue Molecular Basis of Inherited Diseases in Companion Animals)
Cutaneous lupus erythematosus (CLE) in humans encompasses multiple subtypes that exhibit a wide array of skin lesions and, in some cases, are associated with the development of systemic lupus erythematosus (SLE). We investigated dogs with exfoliative cutaneous lupus erythematosus (ECLE), a dog-specific form of chronic CLE that is inherited as a monogenic autosomal recessive trait. A genome-wide association study (GWAS) with 14 cases and 29 controls confirmed a previously published result that the causative variant maps to chromosome 18. Autozygosity mapping refined the ECLE locus to a 493 kb critical interval. Filtering of whole genome sequence data from two cases against 654 controls revealed a single private protein-changing variant in this critical interval, UNC93B1:c.1438C>A or p.Pro480Thr. The homozygous mutant genotype was exclusively observed in 23 ECLE affected German Shorthaired Pointers and an ECLE affected Vizsla, but absent from 845 controls. UNC93B1 is a transmembrane protein located in the endoplasmic reticulum and endolysosomes, which is required for correct trafficking of several Toll-like receptors (TLRs). The p.Pro480Thr variant is predicted to affect the C-terminal tail of the UNC93B1 that has recently been shown to restrict TLR7 mediated autoimmunity via an interaction with syndecan binding protein (SDCBP). The functional knowledge on UNC93B1 strongly suggests that p.Pro480Thr is causing ECLE in dogs. These dogs therefore represent an interesting spontaneous model for human lupus erythematosus. Our results warrant further investigations of whether genetic variants affecting the C-terminus of UNC93B1 might be involved in specific subsets of CLE or SLE cases in humans and other species.
Keywords: Canis familiaris; dermatology; immunology; animal model; skin; TLR7; toll-like receptor; syndecan binding protein; syntenin-1; systemic lupus erythematosus; SLE; CLE Canis familiaris; dermatology; immunology; animal model; skin; TLR7; toll-like receptor; syndecan binding protein; syntenin-1; systemic lupus erythematosus; SLE; CLE
MDPI and ACS Style

Leeb, T.; Leuthard, F.; Jagannathan, V.; Kiener, S.; Letko, A.; Roosje, P.; Welle, M.M.; Gailbreath, K.L.; Cannon, A.; Linek, M.; Banovic, F.; Olivry, T.; White, S.D.; Batcher, K.; Bannasch, D.; Minor, K.M.; Mickelson, J.R.; Hytönen, M.K.; Lohi, H.; Mauldin, E.A.; Casal, M.L. A Missense Variant Affecting the C-Terminal Tail of UNC93B1 in Dogs with Exfoliative Cutaneous Lupus Erythematosus (ECLE). Genes 2020, 11, 159.

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