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Split paw pad disease is a scarcely defined phenotype characterized by skin lesions on the paw pads of dogs. We studied a family of German Shepherd dogs, in which four dogs developed intermittent paw pad lesions and lameness. The paw pads of two of the affected dogs were biopsied and demonstrated cleft formation in the stratum spinosum and stratum corneum, the outermost layers of the epidermis. Whole genome sequencing data from an affected dog revealed a private heterozygous 18 bp in frame deletion in the KRT5 gene. The deletion NM_001346035.1:c.988_1005del or NP_001332964.1:p.(Asn330_Asp335del) is predicted to lead to a loss of six amino acids in the L12 linker domain of the encoded keratin 5. KRT5 variants in human patients lead to various subtypes of epidermolysis bullosa simplex (EBS). Localized EBS is the mildest of the KRT5‐related human diseases and may be caused by variants affecting the L12 linker domain of keratin 5. We therefore think that the detected KRT5 deletion in dogs represents a candidate causal variant for the observed skin lesions in dogs. However, while the clinical phenotype of KRT5‐mutant dogs of this study closely resembles human patients with localized EBS, there are differences in the histopathology. EBS is defined by cleft formation within the basal layer of the epidermis while the cleft formation in the dogs described herein occurred in the outermost layers, a hallmark of split paw pad disease. Our study provides a basis for further studies into the exact relation of split paw pad disease and EBS. [ABSTRACT FROM AUTHOR]

Neuronal ceroid lipofuscinoses (NCL) are among the most prevalent neurodegenerative disorders of early life in humans. Disease‐causing variants have been described for 13 different NCL genes. In this study, a refined pathological characterization of a female rabbit with progressive neurological signs reminiscent of NCL was performed. Cytoplasmic pigment present in neurons was weakly positive with Sudan black B and autofluorescent. Immunohistology revealed astrogliosis, microgliosis and axonal degeneration. During the subsequent genetic investigation, the genome of the affected rabbit was sequenced and examined for private variants in NCL candidate genes. The analysis revealed a homozygous ~10.7 kb genomic duplication on chromosome 15 comprising parts of the MFSD8 gene, NC_013683.1:g.103,727,963_103,738,667dup. The duplication harbors two internal protein coding exons and is predicted to introduce a premature stop codon into the transcript, truncating ~50% of the wild‐type MFSD8 open reading frame encoding the major facilitator superfamily domain containing protein 8, XP_002717309.2:p.(Glu235Leufs*23). Biallelic loss‐of‐function variants in MFSD8 have been described to cause NCL7 in human patients, dogs and a single cat. The available clinical and pathological data, together with current knowledge about MFSD8 variants and their functional impact in other species, point to the MFSD8 duplication as a likely causative defect for the observed phenotype in the affected rabbit. [ABSTRACT FROM AUTHOR]

Severe equine asthma (SEA) is a complex respiratory condition characterized by chronic airway inflammation. It shares many clinical and pathological features with human neutrophilic asthma, making it a valuable model for studying this condition. However, the immune mechanisms driving SEA have remained elusive. Although SEA has been primarily associated with a Th2 response, there have also been reports of Th1, Th17, or mixed‐mediated responses. To uncover the elusive immune mechanisms driving SEA, we performed single‐cell mRNA sequencing (scRNA‐seq) on cryopreserved bronchoalveolar cells from 11 Warmblood horses, 5 controls and 6 with SEA. We identified six major cell types, including B cells, T cells, monocytes–macrophages, dendritic cells, neutrophils, and mast cells. All cell types exhibited significant heterogeneity, with previously identified and novel cell subtypes. Notably, we observed monocyte–lymphocyte complexes and detected a robust Th17 signature in SEA, with CXCL13 upregulation in intermediate monocytes. Asthmatic horses exhibited expansion of the B‐cell population, Th17 polarization of the T‐cell populations, and dysregulation of genes associated with T‐cell function. Neutrophils demonstrated enhanced migratory capacity and heightened aptitude for neutrophil extracellular trap formation. These findings provide compelling evidence for a predominant Th17 immune response in neutrophilic SEA, driven by dysregulation of monocyte and T‐cell genes. The dysregulated genes identified through scRNA‐seq have potential as biomarkers and therapeutic targets for SEA and provide insights into human neutrophilic asthma. [ABSTRACT FROM AUTHOR]

This article discusses a case study of a female Maine Coon cat with classical Ehlers-Danlos syndrome (cEDS), a hereditary connective tissue disorder characterized by skin hyperextensibility, poor wound healing, and joint hypermobility. The cat exhibited symptoms such as nonhealing wounds, alopecia, and scarring. Through genomic sequencing, researchers identified a heterozygous deletion in the COL5A1 gene, which is known to be associated with cEDS in cats. This study highlights the potential of whole genome sequencing for precision medicine and diagnostics in veterinary medicine. [Extracted from the article]

This article discusses a case study of an Appenzeller Mountain Dog with a skin disorder called verrucous epidermal keratinocytic nevi. The disorder is caused by a heterozygous deletion of the NSDHL gene, which disrupts cholesterol biosynthesis in the skin. The dog presented with severe hyperkeratosis of the paw pads and haired skin, causing lameness and alopecia. Treatment with oral ketoconazole improved the lesions on the haired skin, but the paw pads remained hyperkeratotic. Genetic analysis revealed a large heterozygous de novo deletion of the NSDHL gene. The study highlights the importance of advanced genomic analysis in identifying structural variants that may be missed by traditional sequencing methods. [Extracted from the article]

Background: Polioencephalopathies secondary to inborn errors of metabolism have been described in dogs, but few genetically characterized. Objectives: Clinically and genetically characterize polioencephalopathy in a family of Eurasier dogs. Animals: Three Eurasier dogs (littermates) presented with early onset movement disorders (9 weeks in 2, 4‐6 months in 1). Progressive gait abnormalities were detected in 2 of the dogs, persistent divergent strabismus in 1, whereas consciousness and behavior remained intact in all dogs. One dog was euthanized at 25 months. Methods: Video footage was assessed in all dogs, and Dogs 1 and 2 had examinations and investigations performed. Whole genome sequencing of Dog 1 and further genetic analyses in the family were performed. A cohort of 115 Eurasier controls was genotyped for specific variants. Results: Episodes were characterized by generalized ataxia, as well as a hypermetric thoracic limb gait, dystonia, and irregular flexion and extension movements of the thoracic limbs. Magnetic resonance imaging of the brain in Dogs 1 and 2 identified symmetrical, bilateral T2 and fluid attenuated inversion recovery hyperintense, T1 hypo to isointense, nonenhancing lesions of the caudate nucleus, lateral and medial geniculate nuclei, thalamus, hippocampus, rostral colliculus and mild generalized brain atrophy. Genetic analyses identified a homozygous mitochondrial trans‐2‐enoyl‐CoA reductase (MECR) missense variant in all 3 dogs, and a homozygous autophagy‐related gene 4D (ATG4D) missense variant in Dogs 1 and 2. Conclusions and Clinical Importance: We describe a presumed hereditary and progressive polioencephalopathy in a family of Eurasier dogs. Further research is needed to establish the role of the MECR gene in dogs and the pathogenic effects of the detected variants. [ABSTRACT FROM AUTHOR]

This article, published in Animal Genetics, discusses a case study of a Pembroke Welsh Corgi with ichthyosis, a skin disorder characterized by scaly and hyperkeratotic skin. The study used whole-genome sequencing to identify a heterozygous frameshift variant in the ASPRV1 gene, which is responsible for the structural integrity of the outermost layer of the epidermis. The identified variant is likely a de novo mutation and may result in a complete loss of ASPRV1 function. The study highlights the potential of precision medicine in investigating genodermatoses in veterinary medicine. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

Darier disease is caused by heterozygous loss of function variants in the ATP2A2 gene encoding the endoplasmic/sarcoplasmic reticulum Ca2+ pump ATP2A2. Defective intracellular calcium signaling in the epidermis results in a loss of desmosomal adhesion and the development of characteristic skin lesions. In this study, we investigated a Shih Tzu that developed erythematous papules on the ventrum and, over time, the dorsal neck and a nodule in the right ear canal with secondary ear infection. Histopathologic examination demonstrated discrete foci of acantholysis affecting suprabasal layers of the epidermis. Whole genome sequencing of the affected dog identified a heterozygous missense variant, p.N809H, affecting an evolutionarily conserved amino acid residue of the ATP2A2 protein. The highly characteristic clinical and histopathologic findings together with a plausible variant in the only known functional candidate gene establish the diagnosis of canine Darier disease in the studied dog and highlight the potential of genetic analyses as complementary diagnostic approach in veterinary medicine. [ABSTRACT FROM AUTHOR]

Ichthyoses are a group of heritable cornification disorders. Clinical examination revealed severe, multifocal hyperkeratosis, mainly affecting paw pads, axillas and the skin around the anus, lips and eyes (Figure 1). (d-f) Severe paw pad hyperkeratosis and mild palmar and plantar erythema affecting all pads on all four paws. gl Whole genome sequencing at 28× coverage was performed on genomic DNA extracted from leukocytes. [Extracted from the article]

Primary ciliary dyskinesia (PCD) represents a group of diseases characterized by impaired movement of cilia and subsequent health problems in diverse organ systems, notably the respiratory tract. Almost 50 candidate genes for PCD are known in humans. In this study, we investigated an Australian Shepherd dog with a history of recurrent respiratory infections and nasal discharge. A transmission electron microscopy investigation led to the diagnosis of PCD with central pair defect, in which the normal 9:2 arrangement of respiratory cilia was altered and reduced to a 9:0 arrangement. Whole genome sequencing data from the affected dog was obtained and searched for variants in PCD candidate genes that were not present in 918 control genomes from different breeds. This revealed a homozygous single base pair exchange at a splice site of STK36, XM_038585732.1:c.2868‐1G>A. The mutant allele was absent from 281 additionally genotyped Australian Shepherd dogs. RT‐PCR confirmed aberrant splicing in the affected dog with the skipping of exon 20 and the insertion of a cryptic exon, which is predicted to lead to a premature stop codon and truncation of 36% of the STK36 wild‐type open reading frame, XP_038441660.1:(p.Met957Profs*11). STK36 variants were previously reported to cause PCD in humans and mice. The knowledge from other species together with the absence of the mutant allele in more than 1000 control dogs suggests STK36:c.2868‐1G>A as the most likely candidate variant for PCD in the investigated case. [ABSTRACT FROM AUTHOR]

Background: Some paroxysmal movement disorders remain without an identified genetic cause. Objectives: The aim was to identify the causal genetic variant for a paroxysmal dystonia–ataxia syndrome in Weimaraner dogs. Methods: Clinical and diagnostic investigations were performed. Whole genome sequencing of one affected dog was used to identify private homozygous variants against 921 control genomes. Results: Four Weimaraners were presented for episodes of abnormal gait. Results of examinations and diagnostic investigations were unremarkable. Whole genome sequencing revealed a private frameshift variant in the TNR (tenascin‐R) gene in an affected dog, XM_038542431.1:c.831dupC, which is predicted to truncate more than 75% of the open read frame. Genotypes in a cohort of 4 affected and 70 unaffected Weimaraners showed perfect association with the disease phenotype. Conclusions: We report the association of a TNR variant with a paroxysmal dystonia–ataxia syndrome in Weimaraners. It might be relevant to include sequencing of this gene in diagnosing humans with unexplained paroxysmal movement disorders. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Case Description: A 9‐month‐old intact male domestic shorthair cat was evaluated for increasing frequency of generalized tonic‐clonic seizures. Clinical Findings: The cat was reported to have had episodes of circling between the seizures. Upon examination, the cat had bilateral inconsistent menace response but otherwise normal physical and neurological examinations. Diagnostics: Magnetic resonance imaging (MRI) of the brain identified multifocal, small, rounded intra‐axial lesions within the subcortical white matter containing fluid with similar characteristics as cerebrospinal fluid. Evaluation of urine organic acids showed increased excretion of 2‐hydroxyglutaric acid. An XM_023255678.2:c.397C>T nonsense variant in the L2HGDH gene encoding L‐2‐hydroxyglutarate dehydrogenase was identified using whole genome sequencing. Treatment and Outcome: Levetiracetam treatment was initiated at 20 mg/kg PO q8h, but the cat died after a seizure 10 days later. Clinical Relevance: We report the second pathogenic gene variant in L‐2‐hydroxyglutaric aciduria in cats and describe for the first time multicystic cerebral lesions on MRI. [ABSTRACT FROM AUTHOR]

Congenital coat‐colour‐related deafness is common among certain canine breeds especially those exhibiting extreme white spotting or merle patterning. We identified a non‐syndromic deafness in Beauceron dogs characterised by a bilateral hearing loss in puppies that is not linked to coat colour. Pedigree analysis suggested an autosomal recessive transmission. By combining homozygosity mapping with whole genome sequencing and variant filtering in affected dogs we identified a CDH23:c.700C>T variant. The variant, located in the CHD23 (cadherin related 23) gene, was predicted to induce a CDH23:p.(Pro234Ser) change in the protein. Proline‐234 of CDH23 protein is highly conserved across different vertebrate species. In silico tools predicted the CDH23:p.(Pro234Ser) change to be deleterious. CDH23 encodes a calcium‐dependent transmembrane glycoprotein localised near the tips of hair‐cell stereocilia in the mammalian inner ear. Intact function of these cilia is mandatory for the transformation of the acoustical wave into a neurological signal, leading to sensorineural deafness when impaired. By genotyping a cohort of 90 control Beauceron dogs sampled in France, we found a 3.3% carrier frequency. The CDH23:c.[700C>T] allele is easily detectable with a genetic test to avoid at‐risk matings. [ABSTRACT FROM AUTHOR]

Background: Congenital insensitivity to pain (CIP) and hereditary sensory and autonomic neuropathies (HSANs) are a rare group of genetic disorders causing inability to feel pain. Three different associated variants have been identified in dogs: 1 in Border Collies, 1 in mixed breed dogs, and 1 in Spaniels and Pointers. Objectives: To clinically and genetically characterize CIP in a family of mixed breed dogs. Animals: Two mixed breed dogs from the same litter were independently presented: 1 for evaluation of painless fractures, and the other for chronic thermal skin injuries. Methods: Physical, neurological, and histopathological evaluations were performed. Whole genome sequencing of 1 affected dog was used to identify homozygous protein‐changing variants that were not present in 926 control genomes from diverse dog breeds. Results: Physical and neurological examinations showed the absence of superficial and deep pain perception in the entire body. Histopathological evaluations of the brain, spinal cord and sensory ganglia were normal. Whole genome sequencing identified a homozygous missense variant in SCN9A, XM_038584713.1:c.2761C>T or XP_038440641.1:(p.Arg921Cys). Both affected dogs were homozygous for the mutant allele, which was not detected in 926 dogs of different breeds. Conclusions and Clinical Importance: We confirmed the diagnosis of CIP in a family of mixed breed dogs and identified a likely pathogenic variant in the SCN9A gene. The clinical signs observed in these dogs mimic those reported in humans with pathogenic SCN9A variants causing CIP. This report is the first of a spontaneous pathogenic SCN9A variant in domestic animals. [ABSTRACT FROM AUTHOR]

Familial cerebellar ataxia with hydrocephalus in Bullmastiffs was described almost 40 years ago as a monogenic autosomal recessive trait. We investigated two young Bullmastiffs showing similar clinical signs. They developed progressive gait and behavioural abnormalities with an onset at around 6 months of age. Neurological assessment was consistent with a multifocal brain disease. Magnetic resonance imaging of the brain showed intra‐axial bilateral symmetrical focal lesions localised to the cerebellar nuclei. Based on the juvenile age, nature of neurological deficits and imaging findings, an inherited disorder of the brain was suspected. We sequenced the genome of one affected Bullmastiff. The data were compared with 782 control genomes of dogs from diverse breeds. This search revealed a private homozygous frameshift variant in the MFF gene in the affected dog, XM_038574000.1:c.471_475delinsCGCTCT, that is predicted to truncate 55% of the wild type MFF open reading frame, XP_038429928.1: p.(Glu158Alafs*14). Human patients with pathogenic MFF variants suffer from 'encephalopathy due to defective mitochondrial and peroxisomal fission 2'. Archived samples from two additional affected Bullmastiffs related to the originally described cases were obtained. Genotypes in a cohort of four affected and 70 unaffected Bullmastiffs showed perfect segregation with the disease phenotype. The available data together with information from previous disease reports allow classification of the investigated MFF frameshift variant as pathogenic and probably causative defect of the observed neurological phenotype. In analogy to the human phenotype, we propose to rename this disease 'mitochondrial fission encephalopathy (MFE)'. [ABSTRACT FROM AUTHOR]

Epidermolysis bullosa (EB) is a group of blistering disorders that includes several subtypes, classified according to their level of cleavage. Typical clinical signs are blisters and erosions resulting from minimal trauma. The disease has been described in many mammalian species and pathogenic variants in at least 18 different genes have been identified. In the present study, we investigated a Cardigan Welsh Corgi with congenital clinical signs consistent with epidermolysis bullosa. The puppy had blisters and erosions on the paw pads, and the oral mucosa. Histologic examination demonstrated the typical clefting between the dermis and epidermis and confirmed the clinical suspicion. We obtained whole genome sequencing data from the affected puppy and searched for variants in candidate genes known to cause EB. This revealed a heterozygous missense variant, KRT5:p.(E476K), affecting the highly conserved KLLEGE motif of keratin 5. The mutant allele in the affected puppy arose owing to a de novo mutation event as it was absent from both unaffected parents. Knowledge of the functional impact of KRT5 variants in other species together with the demonstration of the de novo mutation event establishes KRT5:p.(E476K) as causative variant for the observed EBS. [ABSTRACT FROM AUTHOR]

Hereditary ataxias are common among canine breeds with various molecular etiology. We identified a hereditary ataxia in young‐adult Australian Shepherd dogs characterized by uncoordinated movements and spasticity, worsening progressively and leading to inability to walk. Pedigree analysis suggested an autosomal recessive transmission. By whole genome sequencing and variant filtering of an affected dog we identified a PNPLA8:c.1169_1170dupTT variant. This variant, located in PNPLA8 (Patatin Like Phospholipase Domain Containing 8), was predicted to induce a PNPLA8:p.(His391PhefsTer394) frameshift, leading to a premature stop codon in the protein. The truncated protein was predicted to lack the functional patatin catalytic domain of PNPLA8, a calcium‐independent phospholipase. PNPLA8 is known to be essential for maintaining mitochondrial energy production through tailoring mitochondrial membrane lipid metabolism and composition. The Australian Shepherd ataxia shares molecular and clinical features with Weaver syndrome in cattle and the mitochondrial‐related neurodegeneration associated with PNPLA8 loss‐of‐function variants in humans. By genotyping a cohort of 85 control Australian Shepherd dogs sampled in France, we found a 4.7% carrier frequency. The PNPLA8:c.[1169_1170dupTT] allele is easily detectable with a genetic test to avoid at‐risk matings. [ABSTRACT FROM AUTHOR]

Deficient homozygosity of a variant maintained in a population suggests that the variant may be embryonic lethal. We examined whole genome sequence data from 675 canids to investigate for variants with missing homozygosity and high predicted impact. Our analysis identified 45 variants, in 32 genes. However, further scrutiny of the sequence reads revealed that all but one of these variants were artifacts of the variant calling process when using CanFam3.1, a widely utilized canine reference genome. We demonstrate that the use of multiple, newer reference genomes could reduce artifacts and lead to more accurate variant identification. [ABSTRACT FROM AUTHOR]

Background: Shaking puppy syndrome is commonly attributed to abnormal myelination of the central nervous system. Hypothesis/Objectives: To report the long‐term clinical course and the imaging characteristics of hypomyelinating leukodystrophy in German Shepherd dogs. Animals and Methods: Three related litters with 11 affected dogs. Results: The 11 affected dogs experienced coarse, side‐to‐side tremors of the head and trunk, which interfered with normal goal‐oriented movements and disappeared at rest. Signs were noticed shortly after birth. Nine dogs were euthanized, 3 dogs underwent pathological examination, and 2 littermates were raised by their breeder. Tremors improved gradually until 6 to 7 months of age. Adult dogs walked with severe residual pelvic limb ataxia. One dog developed epilepsy with tonic‐clonic seizures at 15 months of age. Conventional magnetic resonance imaging (MRI) disclosed homogenous hyperintense signal of the entire subcortical white matter in 3 affected 7‐week‐old dogs and a hypointense signal in a presumably unaffected littermate. Subcortical white matter appeared isointense to gray matter at 15 and 27 weeks of age on repeated MRI. Abnormal white matter signal with failure to display normal gray‐white matter contrast persisted into adulthood. Cerebellar arbor vitae was not visible at any time point. Clinical signs, MRI findings, and pathological examinations were indicative of a hypomyelinating leukodystrophy. All parents of the affected litters shared a common ancestor and relatedness of the puppies suggested an autosomal recessive mode of inheritance. Conclusion: We describe a novel hypomyelinating leukodystrophy in German Shepherd dogs with a suspected inherited origin. [ABSTRACT FROM AUTHOR]

Background: Collagen VI related myopathies are congenital diseases of variable phenotype. The severe phenotype is referred to as Ullrich congenital muscular dystrophy. In this study, we describe analoguos clinical signs and histopathological alterations in Landseer dogs. Materials: We collected clinical data from two affected dogs and investigated the neuromuscular changes in five dogs from two different litters with immunohistochemistry and immunofluorescence. All affected dogs were homozygous for the p.Glu97* nonsense variant in the COL6A1 gene encoding the alpha‐1 chain of collagen VI. Results: Muscle biopsies revealed alterations similar to those in human patients with Ullrich congenital muscular dystrophy including the virtual absence of collagen VI in skeletal muscles. Conclusions: The clinical and pathological characterization of the affected Landseer dogs enhances the value of this animal model for human Ullrich congenital muscular dystrophy. [ABSTRACT FROM AUTHOR]

Glycogen storage diseases (GSD) are a group of inherited disorders of carbohydrate metabolism that occur in humans and animals. We then visually inspected the short read alignments in the candidate genes for structural variants using the Integrative Genomics Viewer.7 This revealed a homozygous 76 bp insertion into exon 5 of the I G6PC1 i candidate gene, which probably causes a loss of function (chr9:g.20,134,857 20,134,858ins76; XM 038676372.1:c.634 635ins76). [Extracted from the article]

A 2‐year‐old male domestic shorthair cat was presented for a progressive history of abnormal posture, behavior, and mentation. Menace response was absent bilaterally, and generalized tremors were identified on neurological examination. A neuroanatomical diagnosis of diffuse brain dysfunction was made. A neurodegenerative disorder was suspected. Magnetic resonance imaging findings further supported the clinical suspicion. Whole‐genome sequencing of the affected cat with filtering of variants against a database of unaffected cats was performed. Candidate variants were confirmed by Sanger sequencing followed by genotyping of a control population. Two homozygous private (unique to individual or families and therefore absent from the breed‐matched controlled population) protein‐changing variants in the major facilitator superfamily domain 8 (MFSD8) gene, a known candidate gene for neuronal ceroid lipofuscinosis type 7 (CLN7), were identified. The affected cat was homozygous for the alternative allele at both variants. This is the first report of a pathogenic alteration of the MFSD8 gene in a cat strongly suspected to have CLN7. [ABSTRACT FROM AUTHOR]

Serum and whole blood microRNA (miRNA) fingerprints have been proposed as a new class of non‐invasive human cancer biomarkers. In this study, we compared equine sarcoid (ES) disease‐specific serum and whole blood miRNA fingerprints and correlated them to miRNA expression in sarcoid tissue. After high throughput sequencing, miRNA differential expression analysis between six ES‐affected and five control horses was carried out in serum and whole blood using a DESeq algorithm, accounting for the influence of hemolysis and the white blood cell count. Target gene, pathway prediction and enrichment analyses were conducted using TarBase, mirPath and GeneCodis. After exclusion of 4 hemolyzed out of a total of 11 serum samples, 9 miRNAs were found to be differentially expressed in serum of ES vs control horses. In whole blood, all 11 samples showed normal white blood cell counts and 19 miRNAs were found to be differentially expressed. A total of 2/9 serum and 7/19 whole blood differentially expressed miRNAs were also highly expressed at the tissue level and their predicted target genes were associated with cancer pathways. Serum and whole blood miRNA expression allowed discrimination between ES and control horses and merits further validation in a larger study cohort. The use of whole blood might be superior because it has higher miRNA content and is less influenced by pre‐analytical variables compared to serum. Concurrent dysregulation of single miRNAs in tissue and blood suggests a possible biological function of circulating miRNAs. [ABSTRACT FROM AUTHOR]

Background: Currently no methods are available to predict the clinical outcome of individual horses with equine sarcoid (ES) disease. Objective: To investigate if whole blood microRNA (miRNA) profiles can predict the long‐term development of ES tumors. Animals Five horses with regression and 5 with progression of ES lesions monitored over 5‐7 years and 5 control horses free of ES for at least 5 years. Methods: For this cohort study, RNA extracted from whole blood samples from the regression, progression, and control groups was used for high throughput sequencing. Known and novel miRNAs were identified using miRDeep2 and differential expression analysis was carried out by the DESeq2 algorithm. Target gene and pathway prediction as well as enrichment and network analyses were conducted using TarBase, mirPath, and metaCore from GeneGo. Results: Fourteen miRNAs were differentially expressed between regression and progression groups after accounting for the control condition: 4 miRNAs (28.6%) were upregulated and 10 miRNAs (71.4%) were downregulated with >2‐fold change. Seven of the 10 downregulated miRNAs are encoded in an miRNA cluster on equine chromosome 24, homologous to the well‐known 14q32 cluster in humans. Their target genes show enrichment for pathways involved in viral carcinogenesis. Conclusions and Clinical Importance: Whole blood miRNA expression profiles are associated with long‐term ES growth in horses and warrant further validation as prognostic biomarkers in a larger study cohort. Deregulation of miRNAs on equine chromosome 24 might represent a trigger for ES development. [ABSTRACT FROM AUTHOR]

Taisuke Ishikawa and Hiroshi Aoki, in our publication we present several complementary lines of evidence that support the pathogenicity of the homozygous missense variant in I SCN9A i , XM 038584713.1:c.2761C>T or XP 038440641.1:(p.Arg921Cys) identified in our dogs. Taisuke Ishikawa and Hiroshi Aoki for their comment that provides further evidence of the pathogenicity of the reported variant in dogs with congenital insensitivity to pain. [Extracted from the article]

Background Molecular genetics has made significant advances in the analysis of hereditary dermatoses during the last several years. Objectives To provide an update on currently available genetic tests for skin diseases of dogs, cats and horses, and to aid the veterinary clinician in the appropriate selection and applications of genetic tests. Methods The scientific literature on the topic was critically reviewed. The list of known causative variants for genodermatoses and hair morphology traits was compiled by searching the Online Mendelian Inheritance in Animals ( OMIA) database. Results Genetic testing has become an important diagnostic method in veterinary medicine. Genetic tests can help to establish the correct diagnosis in some diseases with relatively nonspecific signs. Genetic tests are also essential for sustainable breeding programmes and to help minimize the frequency of animals with hereditary diseases. Advances in genetic methodology and bioinformatics already allow genome-wide screening for potential disease causing mutations for research purposes. It is anticipated that this will become a routine process in clinical practice in the future. Conclusion and clinical importance As specific DNA tests and broad genome-wide analyses come into more common use, it is critical that clinicians understand the proper application and interpretation of these test results. [ABSTRACT FROM AUTHOR]

Copyright of Veterinary Dermatology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

We report on the molecular characterization of a microdeletion of approximately 2.5 Mb at 2p11.2 in a female baby with left congenital aural atresia, microtia, and ipsilateral internal carotid artery agenesis. The deletion was characterized by fluorescence in situ hybridization, array comparative genomic hybridization, and whole genome re-sequencing. Among the genes present in the deleted region, we focused our attention on the FOXI3 gene. Foxi3 is a member of the Foxi class of Forkhead transcription factors. In mouse, chicken and zebrafish Foxi3 homologues are expressed in the ectoderm and endoderm giving rise to elements of the jaw as well as external, middle and inner ear. Homozygous Foxi3-/- mice have recently been generated and show a complete absence of the inner, middle, and external ears as well as severe defects in the jaw and palate. Recently, a 7-bp duplication within exon 1 of FOXI3 that produces a frameshift and a premature stop codon was found in hairless dogs. Mild malformations of the outer auditory canal (closed ear canal) and ear lobe have also been noted in a fraction of FOXI3 heterozygote Peruvian hairless dogs. Based on the phenotypes of Foxi3 mutant animals, we propose that FOXI3 may be responsible for the phenotypic features of our patient. Further characterization of the genomic region and the analysis of similar patients may help to demonstrate this point. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background: Foxi3 is a member of the large forkhead box family of transcriptional regulators, which have a wide range of biological activities including manifold developmental processes. Heterozygous mutation in Foxi3 was identified in several hairless dog breeds characterized by sparse fur coat and missing teeth. A related phenotype called hypohidrotic ectodermal dysplasia (HED) is caused by mutations in the ectodysplasin (Eda) pathway genes. Results: Expression of Foxi3 was strictly confined to the epithelium in developing ectodermal appendages in mouse embryos, but no expression was detected in the epidermis. Foxi3 was expressed in teeth and hair follicles throughout embryogenesis, but in mammary glands only during the earliest stages of development. Foxi3 expression was decreased and increased in Eda loss- and gain-of-function embryos, respectively, and was highly induced by Eda protein in embryonic skin explants. Also activin A treatment up-regulated Foxi3 mRNA levels in vitro. Conclusions: Eda and activin A were identified as upstream regulators of Foxi3. Foxi3 is a likely transcriptional target of Eda in ectodermal appendage placodes suggesting that HED phenotype may in part be produced by compromised Foxi3 activity. In addition to hair and teeth, Foxi3 may have a role in nail, eye, and mammary, sweat, and salivary gland development. Developmental Dynamics 242:593-603, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Copyright of Veterinary Dermatology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Transmissible spongiform encephalopathies (TSEs) are a group of neurodegenerative diseases that can occur spontaneously or can be caused by infection or mutations within the prion protein gene PRNP. Nonsynonymous DNA polymorphisms within the PRNP gene have been shown to influence susceptibility/ resistance to infection in sheep and humans. Analysis of DNA polymorphisms within the core promoter region of the PRNP gene in four major German bovine breeds resulted in the identification of both SNPs and insertion/deletion (indel) polymorphisms. Comparative genotyping of both controls and animals that tested positive for bovine spongiform encephalopathy (BSE) revealed a significantly different distribution of two indel polymorphisms and two SNPs within Braunvieh animals, suggesting an association of these polymorphisms with BSE susceptibility. The functional relevance of these polymorphisms was analyzed using reporter gene constructs in neuronal cells. A specific haplotype near exon 1 was identified that exhibited a significantly lower expression level. Genotyping of nine polymorphisms within the promoter region and haplotype calculation revealed that the haplotype associated with the lowest expression level was underrepresented in the BSE group of all breeds compared to control animals, indicating a correlation of reduced PRNP expression and increased resistance to BSE. [ABSTRACT FROM AUTHOR]

Four Large Münsterländer cross-bred dogs affected with black hair follicular dysplasia (BHFD) and one unaffected control littermate were observed, and skin was sampled weekly over the first 19 weeks of life. Affected dogs were born with silvery grey hair, a consequence of melanin clumping in the hair shafts. Hair bulb melanocytes were densely pigmented, and contained abundant stage IV melanosomes but adjacent matrix keratinocytes lacked melanosomes. Melanin clumping was not prominent in epidermal melanocytes in the haired skin but occurred in the foot pads. Follicular changes progressed from bulbar clumping, clumping in the isthmus/infundibulum and finally to dysplastic hair shafts. Alopecia developed progressively in pigmented areas. Silver-grey hair, melanin clumping, accumulation of stage IV melanosomes within melanocytes and insufficient melanin transfer to adjacent keratinocytes are also classic features of human Griscelli syndrome. The underlying cause in Griscelli syndrome is a defect of melanocytic intracellular transport proteins leading to inadequate and disorganized melanosome transfer to keratinocytes with resultant melanin clumping. In view of the correlation in the phenotype, histology and ultrastructure between both disorders, a defect in intracellular melanosome transport is postulated as the pathogenic mechanism in BHFD. [ABSTRACT FROM AUTHOR]

Abstract Hypotrichosis, an almost complete lack of teeth and the complete absence of eccrine nasolabial glands, was observed among the progeny of a normal cow of the black and white German Holstein breed. Similar congenital anomalies are known in humans and mice as X-linked anhidrotic ectodermal dysplasia (ED1), leading to the impaired formation of hair, teeth and sweat glands. The pedigree of the four affected male calves in the investigated cattle family indicated that the described phenotype is inherited as a monogenic X-linked recessive trait. We used a diagnostic reverse transcription–polymerase chain reaction (RT–PCR) assay to study the heredity of a previously reported causative large genomic deletion in the bovine ED1 gene. This test allowed the unequivocal classification of disease carriers that were phenotypically normal. As the clinical, pathological and genetic findings in human ED1 show striking similarities to the described phenotype in cattle, this bovine disorder may serve as an animal model for human ED1. [ABSTRACT FROM AUTHOR]

We have identified a novel mammalian gene, termed nicolin 1 gene (NICN1 ), that is present in human, dog and mouse, whereas it is absent from the available genome sequences of nonmammalian organisms. The NICN1 gene consists of six exons and spans about 6 kb of genomic DNA. It encodes a 213 amino acid protein that does not belong to any known protein family. Experiments using green fluorescent protein (GFP)-tagged nicolin 1 fusion proteins indicate that nicolin 1 is a nuclear protein. Northern analysis and semiquantitative RT-PCR demonstrated that the 2.5 kb NICN1 mRNA is expressed in a tissue-specific manner. The highest NICN1 expression levels are found in brain, testis, liver, and kidney. On the other hand the NICN1 expression is weak in spleen, leukocytes, small intestine and colon. The NICN1 gene is also expressed during development. [ABSTRACT FROM AUTHOR]

Background Objectives Methods Results Conclusions Neuroaxonal dystrophy (NAD) is a group of inherited neurodegenerative disorders characterized primarily by the presence of spheroids (swollen axons) throughout the central nervous system. In humans, NAD is heterogeneous, both clinically and genetically. NAD has also been described to naturally occur in large animal models, such as dogs. A newly recognized disorder in Miniature American Shepherd dogs (MAS), consisting of a slowly progressive neurodegenerative syndrome, was diagnosed as NAD via histopathology.To describe the clinical and pathological phenotype together with the identification of the underlying genetic cause.Clinical and postmortem evaluations, together with a genome‐wide association study and autozygosity mapping approach, followed by whole‐genome sequencing.Affected dogs were typically young adults and displayed an abnormal gait characterized by pelvic limb weakness and ataxia. The underlying genetic cause was identified as a 1‐bp (base pair) deletion in RNF170 encoding ring finger protein 170, which perfectly segregates in an autosomal recessive pattern. This deletion is predicted to create a frameshift (XM_038559916.1:c.367delG) and early truncation of the RNF170 protein (XP_038415844.1:(p.Ala123Glnfs*11)). The age of this canine RNF170 variant was estimated at ~30 years, before the reproductive isolation of the MAS breed.RNF170 variants were previously identified in human patients with autosomal recessive spastic paraplegia‐85 (SPG85); this clinical phenotype shows similarities to the dogs described herein. We therefore propose that this novel MAS NAD could serve as an excellent large animal model for equivalent human diseases, particularly since affected dogs demonstrate a relatively long lifespan, which represents an opportunity for therapeutic trials. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Ichthyoses comprise a large heterogeneous group of skin disorders, characterized by generalized scaly and hyperkeratotic skin. We investigated a miniature poodle with early onset generalized scaling, dry and irregularly thickened skin, paw pad hyperkeratosis and abnormalities in hair and teeth. The clinical signs of ichthyosis were confirmed by histopathological examination, which revealed mild epidermal hyperplasia and lamellar orthokeratotic hyperkeratosis. A hereditary condition was suspected and a genetic investigation was initiated. We sequenced the whole genome of the affected dog and searched for potentially causative variants in functional candidate genes for the observed phenotype. The analysis revealed a heterozygous in‐frame deletion in DSP, NC_049256.1:g.8804542_8804544del resulting from a de novo mutation event as evidenced by genotyping leukocyte DNA from both parents. The 3 bp deletion is predicted to remove one aspartic acid without disrupting the open reading frame (XM_038584124.1:c.1821_1823del, XP_038440052.1:p.(Asp608del)). The DSP gene encodes desmoplakin, a desmosomal plaque protein, responsible for cell–cell adhesion to provide resistance to mechanical stress in epidermal and cardiac tissues. We hypothesize that the deletion of one amino acid in the N‐terminal globular head domain acts in a dominant negative manner and thus impairs the proper connection with other proteins. Several variants in DSP in humans and cattle have been described to result in different phenotypes associated with hair and skin abnormalities, sometimes in combination with variable cardiac and/or dental manifestations. In conclusion, we characterized a new syndromic ichthyosis phenotype in a dog and identified a de novo 3 bp deletion in the DSP gene as causal variant. [ABSTRACT FROM AUTHOR]

Background Hypothesis/Objectives Animals Materials and Methods Results Conclusions and Clinical Relevance Autosomal recessive ichthyosis leads to structural or biochemical changes that impair skin barrier function.To assess (1) the phenotype and genotype in a litter of Jack Russell Terriers with autosomal recessive congenital ichthyosis (ARCI), and (2) the defective skin barrier and determine if a topical ceramide can modulate the barrier.A healthy dam and litter of Jack Russell Terrier puppies (healthy male, affected male and female), one affected adult Jack Russell Terrier and one unrelated healthy Jack Russell Terrier.A severe cornification defect was identified via examination of affected puppies. As the phenotype worsened, the affected puppies received a topical application of ω‐0‐acylceramide for 10 days. Before humane euthanasia, the skin barrier was evaluated via transepidermal water loss (TEWL), corneometry and pH in affected dogs. Genomic testing was performed, and skin samples were analysed by light and electron microscopy.Affected puppies were homozygous for the 1980 bp LINE‐1 insertion in the TGM1 (transglutaminase 1) gene; the unaffected littermate and the dam were heterozygous carriers. ARCI puppies were underweight and had a severe hyperkeratotic phenotype that impaired mobility. TEWL was markedly higher in affected dogs. The cutaneous pH of affected puppies was higher than the normal littermate. Treatment of the skin with ω‐0‐acylceramide normalised the pH to match the littermate and decreased TEWL. Electron microscopy revealed marked attenuation of the cornified envelope.Dogs with TGM1‐deficient ARCI have an impaired skin barrier. Topical therapy can partially repair the barrier defect. [ABSTRACT FROM AUTHOR]

The author reflects on the study of epidermal keratinocytes in dog. The author sates that keratinocytes provided bases for establishing long-term keratinocyte cultures from mice and dogs. The author notes that the self-organizing principle of tissue provides starting point for regenerative medicine. The author mentions the progress of understanding keratinocyte biology and pathology.

Mammals are unable to synthesize cobalamin or vitamin B12 and rely on the uptake of dietary cobalamin. The cubam receptor expressed on the intestinal endothelium is required for the uptake of cobalamin from the gut. Cubam is composed of two protein subunits, amnionless and cubilin, which are encoded by the AMN and CUBN genes respectively. Loss-of-function mutations in either the AMN or the CUBN gene lead to hereditary selective cobalamin malabsorption or Imerslund- Gräsbeck syndrome ( IGS). We investigated Beagles with IGS and resequenced the whole genome of one affected Beagle at 15× coverage. The analysis of the AMN and CUBN candidate genes revealed a homozygous deletion of a single cytosine in exon 8 of the CUBN gene (c.786delC). This deletion leads to a frameshift and early premature stop codon (p. Asp262 Glufs*47) and is, thus, predicted to represent a complete loss-of-function allele. We tested three IGS-affected and 89 control Beagles and found perfect association between the IGS phenotype and the CUBN:c.786del C variant. Given the known role of cubilin in cobalamin transport, which has been firmly established in humans and dogs, our data strongly suggest that the CUBN:c.786del C variant is causing IGS in the investigated Beagles. [ABSTRACT FROM AUTHOR]

Variants in the EDNRB, KIT, MITF, PAX3 and TRPM1 genes are known to cause white spotting phenotypes in horses, which can range from the common white markings up to completely white horses. In this study, we investigated these candidate genes in 169 horses with white spotting phenotypes not explained by the previously described variants. We identified a novel missense variant, PAX3:p.Pro32Arg, in Appaloosa horses with a splashed white phenotype in addition to their leopard complex spotting patterns. We also found three novel variants in the KIT gene. The splice site variant c.1346+1G>A occurred in a Swiss Warmblood horse with a pronounced depigmentation phenotype. The missense variant p.Tyr441Cys was present in several part-bred Arabians with sabino-like depigmentation phenotypes. Finally, we provide evidence suggesting that the common and widely distributed KIT:p.Arg682His variant has a very subtle white-increasing effect, which is much less pronounced than the effect of the other described KIT variants. We termed the new KIT variants W18-W20 to provide a simple and unambiguous nomenclature for future genetic testing applications. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 7-month-old female Labrador retriever-cross dog showing cutaneous mosaicism. It discusses the Alopecic scaly plaques following the Blaschko's lines on the limbs, the head, the dorsal neck and the trunk. It notes that Oclacitinib administered to treat seasonal flares of atopic dermatitis, and alternation of antiseptic, emollient and keratolytic shampoos used for the long-term management.

The article presents the case study of the 10-year-old spayed female Chihuahua that was brought to the University of Bern's Small Animal Hospital due to suspected Lafora disease in Switzerland. The topics discussed include the results of his neurological, magnetic resonance (MRI), and cerebral spinal fluid (CSF) findings, definition of Lafora disease, and the other breeds of dogs that can inherit Lafora disease.

The article discusses the variants of the microphthalmia-associated transcription factor (MITF) gene observed in American Standardbred foal. The SW1, SW2 and macchiato variants of MITF cause coat colour depigmentation in foals which range from white spotted to white phenotypes. The authors concluded that the foals' white colour phenotype was caused by the MITF244Glu allele.

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The article presents a case study of a 9-year old Swiss Warmblood horse who was taken to the hospital because of anorexia. Topics discussed include administration of tiletamine-zolazepam and medetomidine for clinical examination, genome sequencing of horse, and designing of polymerase chain reaction (PCR) primers for the amplification of ADRA2A, ADRA2B and ADRA2C genes.

The article focuses on a study on frame-shift variant in the CHRNE gene in a juvenile dog with suspected myasthenia gravis-like disease. Topics discussed include functional disturbances of the skeletal muscle resulting in exercise intolerance by antibodies directed against the acetylcholine receptor; steroid treatment and antibiotic treatment of puppies; and no proof that CHRNE variant is pathogenic.

The article focuses on the aspects of single-base pair deletion of major facilitator superfamily domain-containing protein 8 (MFSD8) in Chihuahua with neuronal ceroid lipofuscinosis (NCL). Topics discussed include the genetic sequence of the NCL affected puppy, the analysis of the genetic variant of the sequence data, and the result which reveals the same variant of MFSD8 among Chinese Crested dogs and Chihuahuas.