Genetics of inherited skin disorders in dogs

Canine genodermatoses represent a broad spectrum of diseases with diverse phenotypes. Modern genetic technology including whole genome sequencing has expedited the identification of novel genes and greatly simplified the establishment of genetic diagnoses in such heterogeneous disorders. The precise genetic diagnosis of a heritable skin disorder is essential for the appropriate counselling of owners regarding the course of the disease, prognosis and implications for breeding. Understanding the underlying pathophysiology is a prerequisite to developing specific, targeted or individualized therapeutic approaches. This review aims to create a comprehensive overview of canine genodermatoses and their respective genetic aetiology known to date. Raising awareness of genodermatoses in dogs is important and this review may help clinicians to apply modern genetics in daily clinical practice, so that a precise diagnoses can be established in suspected genodermatoses

Canine Epithelial Skin Tumours: Expression of the Stem Cell Markers Lgr5, Lgr6 and Sox9 in Light of New Cancer Stem Cell Theories.

Evidence is accumulating that tumour development is driven by cancer stem cells (CSCs). In order to understand the presence and potential contribution of stem cells (SCs) as tumour-initiating cells in canine cutaneous tumours, we selected three putative SC markers (Lgr5, Lgr6 and Sox9) and investigated their expression pattern, level of protein and mRNA expression, in 43 canine hair follicle (HF) and 18 canine cutaneous epidermal tumours by immunohistochemistry and qRT-PCR, using normal skin samples as controls. Lgr5 protein expression was not detected in epidermal and HF tumours; however, Lgr5 mRNA overexpression was evident in some HF tumours. Sox9 was expressed in several tumour cases, both at the protein and mRNA level. The Lgr6 antibody tested was not suitable for formalin-fixed paraffin-embedded tissue samples, but Lgr6 gene showed higher expression in several samples of both HF and epidermal tumours compared with normal skin. Significantly higher mRNA expression levels of the three SC markers were found in trichoblastomas (TB) compared with basal cell carcinomas (BCC). The present results indicated that canine HF and epidermal tumours might have common tumour-initiating cells. The mRNA expression of the three selected SC markers, especially Lgr5, could be potentially useful in the distinction between canine TB and BCC

SDR9C7 missense variant in a Chihuahua with non-epidermolytic ichthyosis.

Ichthyoses represent a heterogeneous group of cornification disorders that are associated with skin barrier defects. We investigated a 9-month-old Chihuahua showing excessive scale formation. Clinical and histopathological examinations revealed non-epidermolytic ichthyosis and a genetic defect was suspected. We therefore sequenced the genome of the affected dog and compared the data with 564 genetically diverse control genomes. Filtering for private variants identified a homozygous missense variant in SDR9C7, c.454C>T or p.(Arg152Trp). SDR9C7 is a known candidate gene for ichthyosis in humans and encodes the short-chain dehydrogenase/reductase family 9C member 7. The enzyme is involved in the production of a functional corneocyte lipid envelope (CLE), a crucial component of the epidermal barrier. Pathogenic variants in SDR9C7 have been described in human patients with autosomal recessive ichthyosis. We assume that the identified missense variant in the affected Chihuahua of this study impairs the normal enzymatic activity of SDR9C7 and thus prevents the formation of a functioning CLE, resulting in a defective skin barrier. To the best of our knowledge, this is the first report of a spontaneous SDR9C7 variant in domestic animals

Immunohistochemical localization and quantitative assessment of GnRH-, FSH-, and LH-receptor mRNA Expression in canine skin: a powerful tool to study the pathogenesis of side effects after spaying

It has been proposed that gonadotropins and/or gonadotropin releasing hormone (GnRH) could be involved in the pathophysiology of the side effects after spaying in bitches, such as urinary incontinence and an increased production of a woolly undercoat. In order to provide tools to investigate the role of these hormones in dogs we developed immunohistochemical techniques and real-time RT-PCR to study whether GnRH-, LH-, and FSH-receptors exist in canine skin and urinary bladder. Tissue samples from the skin of the flank region and the ventral midline of the urinary bladder from euthanised dogs were examined. We were able to quantify mRNA expression of GnRH-, FSH-, and LH-receptors in canine skin and bladder biopsies with a high primer efficacy. Immunohistochemical studies showed that GnRH-, FSH-, and LH-receptors are expressed in vessel walls, the epidermis, the hair follicle and in sebaceous and sweat glands in canine skin and in transitional epithelium, and smooth muscle tissue in the urinary bladder. Our data provide the fundamentals to examine the distribution of FSH-, LH-, and GnRH-receptors in canine skin and urinary bladder and to assess gene activity at the transcriptional level by real-time RT-PC

Mental health and use of health care services in opioid‑exposed school‑aged children compared to foster children

Given the concerns raised regarding the effects of prenatal exposure to methadone and buprenorphine on the developmental outcomes of the children, this study assessed mental health and use of services in a national sample of school-aged children (N = 78) born to women enrolled in opioid maintenance treatment during pregnancy, compared with a group of foster children (N = 140). The majority of the opioid-exposed children lived with their birth parent(s) at the time of assessment (N = 62), while 16 lived in foster homes. Caregivers completed the Strengths and Difficulties Questionnaire (SDQ) and the Reactive Attachment Disorder scale. Teachers completed the SDQ. Three kinds of services were included in measuring service use: school-based education services, child mental health services, and hospital-based habilitation services. The main finding of the study is that children prenatally exposed to methadone or buprenorphine living with their family of origin had significantly better mental health status than their foster-placed counterparts and that of the comparison group of foster children. In addition, the exposed children living at home had less child welfare involvement, and only half of them were using any of the three services measured. The odds for using services increased significantly in accordance with increasing mental health problems, independent of group affiliation, indicating a need-based access to services. In line with other studies, we found that the odds for using one or more services was 2.3 times greater for boys than for girls. Our results contribute to a more-nuanced understanding of the developmental outcomes of prenatal exposure to methadone and buprenorphine, and factors associated with increased service use in groups of at-risk children.publishedVersio

Independent DSG4 frameshift variants in cats with hair shaft dystrophy

Investigations of hereditary phenotypes in spontaneous mutants may help to better understand the physiological functions of the altered genes. We investigated two unrelated domestic shorthair cats with bulbous swellings of the hair shafts. The clinical, histopathological, and ultrastructural features were similar to those in mice with lanceolate hair phenotype caused by loss-of-function variants in Dsg4 encoding desmoglein 4. We sequenced the genomes from both affected cats and compared the data of each affected cat to 61 control genomes. A search for private homozygous variants in the DSG4 candidate gene revealed independent frameshift variants in each case, c.76del or p.Ile26fsLeu*4 in case no. 1 and c.1777del or p.His593Thrfs*23 in case no. 2. DSG4 is a transmembrane glycoprotein located primarily in the extracellular part of desmosomes, a complex of adhesion molecules responsible for connecting the keratin intermediate filaments of neighbouring epithelial cells. Desmosomes are essential for normal hair shaft formation. Both identified DSG4 variants in the affected cats lead to premature stop codons and truncate major parts of the open-reading frame. We assume that this leads to a complete loss of DSG4 function, resulting in an incorrect formation of the desmosomes and causing the development of defective hair shafts. Together with the knowledge on the effects of DSG4 variants in other species, our data suggest that the identified DSG4 variants cause the hair shaft dystrophy. To the best of our knowledge, this study represents the first report of pathogenic DSG4 variants in domestic animals

Independent DSG4 frameshift variants in cats with hair shaft dystrophy

Investigations of hereditary phenotypes in spontaneous mutants may help to better understand the physiological functions of the altered genes. We investigated two unrelated domestic shorthair cats with bulbous swellings of the hair shafts. The clinical, histopathological, and ultrastructural features were similar to those in mice with lanceolate hair phenotype caused by loss-of-function variants in Dsg4 encoding desmoglein 4. We sequenced the genomes from both affected cats and compared the data of each affected cat to 61 control genomes. A search for private homozygous variants in the DSG4 candidate gene revealed independent frameshift variants in each case, c.76del or p.Ile26fsLeu*4 in case no. 1 and c.1777del or p.His593Thrfs*23 in case no. 2. DSG4 is a transmembrane glycoprotein located primarily in the extracellular part of desmosomes, a complex of adhesion molecules responsible for connecting the keratin intermediate filaments of neighbouring epithelial cells. Desmosomes are essential for normal hair shaft formation. Both identified DSG4 variants in the affected cats lead to premature stop codons and truncate major parts of the open-reading frame. We assume that this leads to a complete loss of DSG4 function, resulting in an incorrect formation of the desmosomes and causing the development of defective hair shafts. Together with the knowledge on the effects of DSG4 variants in other species, our data suggest that the identified DSG4 variants cause the hair shaft dystrophy. To the best of our knowledge, this study represents the first report of pathogenic DSG4 variants in domestic animals

Quantitative PCR for the diagnosis of cutaneous leishmaniasis from formalin-fixed and paraffin-embedded skin sections.

The present report describes a real-time PCR-based procedure to reliably determine the quantity of Leishmania amastigotes in relation to the amount of host tissue in histological skin sections from canine and equine cases of cutaneous leishmaniasis. The novel diagnostic Leishmania-PCR has a detection limit of <0.02 amastigotes per μg tissue, which corresponds well to the detection limit of immunohistochemistry and is far beyond that of conventional histology. Our results emphasise the importance of PCR to complement routine histology of cutaneous leishmaniasis cases, particularly in laboratories in which no immunohistochemical assay is available