Categories: Integument (skin) phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 608204 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2020

Species-specific symbol: ECLE

Species-specific description: Exfoliative cutaneous lupus erythematosus is characterized by scaling and crusting skin lesions that progress over the entire body. In later stages, the disease may also become systemic with the involvement of additional organs.

Inheritance: Wang et al. (2011) confirmed the autosomal recessive inheritance of this disorder in German shorthair pointers.

Mapping: By conducting a GWAS on 13 affected and 21 control German shorthaired pointers, each genotyped with the canine Affymetrix 127 k SNP v2 full set chip (yielding 64,987 informative SNPs for analysis), Wang et al. (2011) mapped this disorder to a 0.5 MB region of chromosome CFA18.

Molecular basis: Leeb et al. (2020): "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 [Wang et al., 2011] 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." 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 (Dog) (VBO_0200221), German Shorthaired Pointer (Dog) (VBO_0200583), Vizsla (Dog) (VBO_0201389).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: