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.
Bibliographical noteFunding Information:
Funding: This study was supported by a grant from the Swiss National Science Foundation. HL and MKH are supported by the Academy of Finland.
This study was supported by a grant from the Swiss National Science Foundation. HL and MKH are supported by the Academy of Finland. The authors are grateful to all dog owners who donated samples and shared health and pedigree data of their dogs. We thank Eva Andrist, Nathalie Besuchet Schmutz, Sini Karjalainen, Sabrina Schenk, and Daniela Steiner for expert technical assistance, the Next Generation Sequencing Platform of the University of Bern for performing the high-throughput sequencing experiments, and the Interfaculty Bioinformatics Unit of the University of Bern for providing high performance computing infrastructure. We thank the Dog Biomedical Variant Database Consortium (Gus Aguirre, Catherine Andr?, Danika Bannasch, Doreen Becker, Brian Davis, Cord Dr?gem?ller, Kari Ekenstedt, Kiterie Faller, Oliver Forman, Steve Friedenberg, Eva Furrow, Urs Giger, Christophe Hitte, Marjo Hyt?nen, Vidhya Jagannathan, Tosso Leeb, Hannes Lohi, Cathryn Mellersh, Jim Mickelson, Leonardo Murgiano, Anita Oberbauer, Sheila Schmutz, Jeffrey Schoenebeck, Kim Summers, Frank van Steenbeek, Claire Wade) for sharing whole genome sequencing data from control dogs. We also acknowledge all researchers who deposited dog or wolf whole genome sequencing data into public databases.
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
- Animal model
- Canis familiaris
- Syndecan binding protein
- Systemic lupus erythematosus
- Toll-like receptor