OMIA 001609-9615 : Exfoliative cutaneous lupus erythematosus in Canis lupus familiaris
UNC93B1 is a 12 transmembrane domain containing protein located in endosomal membranes. It acts as a trafficking chaperone of the intracellular nucleic acid-sensing Toll-like receptors (TLRs) 3, 7 and 9. These TLRs are essential components of the innate immune system and activated when pathogen derived nucleic acids appear in endolysosomes. UNC93B1 mediates the correct trafficking and localization of these TLRs to endolysosomes. Complete loss-of-function of UNC93B1 results in a severe immune deficiency in human patients and the 3d mouse mutant. The molecular mechanisms of the interaction of UNC93B1 with TLRs were studied in detail (Majer et al., 2019). A 33 amino acid sequence motif in the cytoplasmic C-terminal domain of UNC93B1 binds to syndecan binding protein (SDCBP), also called syntenin-1. SDCBP interacts with both UNC93B1 and TLR7. This interaction dampens TLR7 signaling and prevents autoimmune activation of TLR7 by endogenous nucleic acids (Majer et al., 2019). Gene-edited mice expressing a mutant Unc93B1 in which three critical amino acids of this C-terminal domain were altered (530-PKP/AAA-532) developed hallmarks of systemic inflammation and autoimmunity (Majer et al., 2019) similar to what has been observed in Tlr7 overexpressing mice. In summary, the available literature suggests that complete loss of function of UNC93B1 leads to an immune deficiency, while UNC93B1 variants that only affect the C-terminal tail containing the SDCBP binding domain lead to upregulation of TLR7 signaling with subsequent development of systemic autoimmune disease (Majer et al., 2019; Leeb et al., 2020).Clinical features: This is an exfoliating skin disease, with significant scaling and crusting that begin on the face, ears and back. Scaling progresses to involve the entire body. Secondary infections are common. Lesions can be scales, crusts, pustules, papules, erythema, and/or alopecia (Wang et al., 2011, Vroom et al., 1995, Mauldin et al., 2010). Most affected dogs present before 10 months of age, but signs can begin as late as 2.75 years. Dogs that live with this condition for several years may develop lupus nephritis. Many dogs show lameness and a hunched stance due to arthralgia. Dogs can also become infertile, with low sperm counts and abnormal estrous cycles (Wang et al., 2011, Mauldin et al., 2010). Pathology: ECLE is characterized by vacuolar degeneration of basal keratinocytes and multifocal apoptotic basal cells. Exocytosis of lymphocytes into the basal and suprabasal layers of the epidermis and a mild to moderate band-like subepidermal infiltrate composed of lymphocytes, plasma cells and few histiocytes is present (cell rich interface dermatitis). These changes may result in pigmentary incontinence and subepidermal cleft formation. Interface changes are also present in the infundibulum and the outer root sheath of the isthmus and the suprabulbar region of hair follicles. Follicles may undergo subsequent atrophy. Sebaceous glands may be infiltrated with lymphocytes and become absent multifocally. The epidermis is covered by moderate amounts of orthokeratotic laminar keratin which exfoliates (Bryden et al., 2005, Olivry et al., 2018). Mild vacuolar degeneration of basal keratinocytes may be visible in dogs as early as 6 weeks of age and will be fully developed at the age of 4 to 6 months. A generalized peripheral lymphadenomegaly has been reported in one-third of the dogs (Wang et al., 2011). Direct immunofluorescence revealed the deposition along the epidermal basement membrane of IgG in all, and IgM, IgA and C3 in a smaller percentage of the paraffin sections tested. Indirect immunofluorescence testing revealed the existence of circulating anti-follicular IgG and anti-sebaceous gland antibodies in the serum of more than 50% of the dogs (Bryden et al., 2005). Prevalence: This is a rare disease among German shorthaired pointers (Vroom et al., 1995) and related hunting dog breeds.
Leeb et al. (2020) reported that "The homozygous mutant genotype [i.e. homozygous for UNC93B1:c.1438A] was exclusively observed in 23 ECLE affected German Shorthaired Pointers and an ECLE affected Vizsla, but absent from 845 controls." Heterozygous carriers were found in German Shorthaired Pointers, German Longhaired Pointers, and Viszlas (Leeb et al., 2020).Breeds: Braque du Bourbonnais, German Shorthaired Pointer, Vizsla. Associated gene:
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|UNC93B1||unc-93 homolog B1 (C. elegans)||Canis lupus familiaris||18||NC_051822.1 (50746392..50756504)||UNC93B1||Homologene, Ensembl, NCBI gene|
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WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.
Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.
|OMIA Variant ID||Breed(s)||Variant Phenotype||Gene||Allele||Type of Variant||Source of Genetic Variant||Reference Sequence||Chr.||g. or m.||c. or n.||p.||Verbal Description||EVA ID||Inferred EVA rsID||Year Published||PubMed ID(s)||Acknowledgements|
|1157||German Shorthaired Pointer Vizsla||Exfoliative cutaneous lupus erythematosus||UNC93B1||missense||Naturally occurring variant||CanFam3.1||18||g.49834825C>A||c.1438C>A||p.(P480T)||XM_540813.6:c.1438C>A; XP_540813.3:p.(Pro480Thr) (Leeb et al., 2020)||2020||32028618|
Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
|2020||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 (Basel) 11:159, 2020. Pubmed reference: 32028618. DOI: 10.3390/genes11020159.|
|2019||Majer, O., Liu, B., Kreuk, L.S.M., Krogan, N., Barton, G.M. :|
|UNC93B1 recruits syntenin-1 to dampen TLR7 signalling and prevent autoimmunity. Nature 575:366-370, 2019. Pubmed reference: 31546246. DOI: 10.1038/s41586-019-1612-6.|
|2018||Olivry, T., Linder, K.E., Banovic, F. :|
|Cutaneous lupus erythematosus in dogs: a comprehensive review. BMC Vet Res 14:132, 2018. Pubmed reference: 29669547. DOI: 10.1186/s12917-018-1446-8.|
|2017||Banovic, F., Robson, D., Linek, M., Olivry, T. :|
|Therapeutic effectiveness of calcineurin inhibitors in canine vesicular cutaneous lupus erythematosus. Vet Dermatol :, 2017. Pubmed reference: 28439997. DOI: 10.1111/vde.12448.|
|2011||Wang, P., Zangerl, B., Werner, P., Mauldin, E.A., Casal, M.L. :|
|Familial cutaneous lupus erythematosus (CLE) in the German shorthaired pointer maps to CFA18, a canine orthologue to human CLE. Immunogenetics 63:197-207, 2011. Pubmed reference: 21132284. DOI: 10.1007/s00251-010-0499-z.|
|2010||Mauldin, E.A., Morris, D.O., Brown, D.C., Casal, M.L. :|
|Exfoliative cutaneous lupus erythematosus in German shorthaired pointer dogs: disease development, progression and evaluation of three immunomodulatory drugs (ciclosporin, hydroxychloroquine, and adalimumab) in a controlled environment. Vet Dermatol :, 2010. Pubmed reference: 20374572. DOI: 10.1111/j.1365-3164.2010.00867.x.|
|2005||Bryden, S.L., White, S.D., Dunston, S.M., Burrows, A.K., Olivry, T. :|
|Clinical, histopathological and immunological characteristics of exfoliative cutaneous lupus erythematosus in 25 German short-haired pointers. Vet Dermatol 16:239-52, 2005. Pubmed reference: 16101795. DOI: 10.1111/j.1365-3164.2005.00468.x.|
|1995||Vroom, M.W., Theaker, M.J., Rest, J.R., White, S.D. :|
|Lupoid dermatosis in five german short-haired pointers Veterinary Dermatology 6:93-98, 1995.|
|1992||Theaker, A.J., Rest, J.R. :|
|Lupoid dermatosis in a German short-haired pointer. Veterinary Record 131:495, 1992. Pubmed reference: 1471334.|
- Created by Frank Nicholas on 28 Sep 2011
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