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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.

A 4-month-old female Irish Terrier presented with a well demarcated ulcerative and crusting lesion in the right ear canal. Histological analysis revealed epidermal hyperplasia with severe acantholysis affecting all suprabasal layers of the epidermis, which prompted a presumptive diagnosis of canine Darier disease. The lesion was successfully treated by repeated laser ablation of the affected epidermis. Over the course of three years, the dog additionally developed three dermal nodules of up to 4 cm in diameter that were excised and healed without complications. Histology of the excised tissue revealed multiple infundibular cysts extending from the upper dermis to the subcutis. The cysts were lined by squamous epithelium, which presented with abundant acantholysis of suprabasal keratinocytes. Infundibular cysts represent a novel finding not previously reported in Darier patients. Whole genome sequencing of the affected dog was performed, and the functional candidate genes for Darier disease (ATP2A2) and Hailey-Hailey disease (ATP2C1) were investigated. The analysis revealed a heterozygous SINE insertion into the ATP2A2 gene, at the end of intron 14, close to the boundary of exon 15. Analysis of the ATP2A2 mRNA from skin of the affected dog demonstrated a splicing defect and marked allelic imbalance, suggesting nonsense-mediated decay of the resulting aberrant transcripts. As Darier disease in humans is caused by haploinsufficiency of ATP2A2, our genetic findings are in agreement with the clinical and histopathological data and support the diagnosis of canine Darier disease.

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Hereditary nasal parakeratosis (HNPK), an inherited monogenic autosomal recessive skin disorder, leads to crusts and fissures on the nasal planum of Labrador Retrievers. We performed a genome-wide association study (GWAS) using 13 HNPK cases and 23 controls. We obtained a single strong association signal on chromosome 2 (praw = 4.4×10−14). The analysis of shared haplotypes among the 13 cases defined a critical interval of 1.6 Mb with 25 predicted genes. We re-sequenced the genome of one case at 38× coverage and detected 3 non-synonymous variants in the critical interval with respect to the reference genome assembly. We genotyped these variants in larger cohorts of dogs and only one was perfectly associated with the HNPK phenotype in a cohort of more than 500 dogs. This candidate causative variant is a missense variant in the SUV39H2 gene encoding a histone 3 lysine 9 (H3K9) methyltransferase, which mediates chromatin silencing. The variant c.972T>G is predicted to change an evolutionary conserved asparagine into a lysine in the catalytically active domain of the enzyme (p.N324K). We further studied the histopathological alterations in the epidermis in vivo. Our data suggest that the HNPK phenotype is not caused by hyperproliferation, but rather delayed terminal differentiation of keratinocytes. Thus, our data provide evidence that SUV39H2 is involved in the epigenetic regulation of keratinocyte differentiation ensuring proper stratification and tight sealing of the mammalian epidermis. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a chronic or chronically relapsing human and canine skin disease that is known to affect the quality of life (QoL) of affected individuals. Several studies have been conducted to develop disease-specific questionnaires and assess QoL in parents of children with AD and in the children themselves. The severity of canine AD is however currently evaluated using only clinical and pruritus scores. Measurement of the QoL of affected dogs and their owners could therefore provide a new tool for assessing disease severity and treatment efficacy. Ninety-eight owners of AD-affected dogs were asked to complete two questionnaires aiming to evaluate the QoL of affected dogs and their owners on one hand and the relationship between them and their dog on the other hand. Statistical analyses were carried out in order to assess the validity of the questionnaires and to select relevant questions for future studies. These analyses resulted in the selection of 13 questions that could be used in further studies aiming at determining the QoL of affected animals and their owners. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the reproducibility of serum testing for total thyroxine (T4) in three German laboratories., Materials and Methods: Serum was taken from 53 dogs with suspected hypothyroidism and divided into five aliquots. Three aliquots of each sample were marked with different names and sent to one laboratory (two aliquots simultaneously and one aliquot 1-3 days later). The remaining aliquots were sent to two other laboratories. Laboratory 1 used an enzyme immunoassay for T4 measurements, whereas laboratories 2 and 3 used a chemiluminescence immunoassay. The agreement between the three laboratories (values within or below the reference interval) was determined using the Cohen's Kappa test. The intra- and interassay variability was calculated for each laboratory and the agreement between samples submitted to the same laboratory was also determined using the Cohen's Kappa test., Results: For n = 23/41 patients tested simultaneously in the three laboratories, all three values were either uniformly below, within or above the respective reference interval. The Cohen's Kappa value for intra- and interassay agreement was 1.0 in laboratory 2 (n = 15, complete agreement), 0.33 in laboratory 1 (n = 16) and 0.37 (intra-) and 0.19 (interassay agreement) in laboratory 3 (n = 16, low agreement). There was a low agreement between laboratories 1 and 2 and between laboratories 1 and 3 (κ = 0.30 and 0.25, respectively), while a high agreement was determined between laboratories 2 and 3 (κ = 0.68). The intrassay variability of laboratories 1, 2 and 3 was 13.6%, 5.0% and 10.4%, the interassay variability 17.2%, 5.1% and 17.4%, respectively., Conclusion and Clinical Relevance: The differences in the measurement of thyroxine concentrations of the same serum sample in different laboratories and at different time points in the same laboratory underline the high relevance of interpreting laboratory results in context with the clinical signs of hypothyroidism as well as other laboratory values such as TSH concentration.