RESUMEN
Laryngeal paralysis (LP) is the inability to abduct the arytenoid cartilages during inspiration, resulting in a partial to complete airway obstruction and consequent respiratory distress. Different forms of LP with varying age of onset exist in dogs. Hereditary early onset forms were reported in several dog breeds. In most breeds, hereditary LP is associated with other neurologic pathologies. Using a genome-wide association study and haplotype analyses, we mapped a major genetic risk factor for an early onset LP in Miniature Bull Terriers to a ~1.3 Mb interval on chromosome 11. Whole genome sequencing of an affected Miniature Bull Terrier and comparison to 598 control genomes revealed a 36 bp insertion into exon 15 of the RAPGEF6 gene (c.1793_1794ins36). The imperfect genotype-phenotype correlation suggested a complex mode of inheritance with a major genetic risk factor involving a recessive risk allele. Homozygosity for the insertion was associated with a 10- to 17-fold increased risk for LP. The insertion allele was only found in Miniature Bull Terriers and Bull Terriers. It was absent from >1000 control dogs of other dog breeds. The insertion sequence contains a splice acceptor motif leading to aberrant splicing in transcripts originating from the mutant allele (r.1732_1780del). This leads to a frameshift and a premature stop codon, p.(Ile587ProfsTer5), removing 64% of the open reading frame. Our results suggest an important role of RAPGEF6 in laryngeal nerve function and provide new clues to its physiological significance.
Asunto(s)
Enfermedades de los Perros/genética , Predisposición Genética a la Enfermedad , Factores de Intercambio de Guanina Nucleótido/genética , Parálisis de los Pliegues Vocales/genética , Animales , Cartílago Aritenoides/patología , Cruzamiento , Codón sin Sentido/genética , Enfermedades de los Perros/fisiopatología , Perros , Exones , Mutación del Sistema de Lectura/genética , Estudio de Asociación del Genoma Completo , Haplotipos , Humanos , Nervios Laríngeos/patología , Empalme del ARN/genética , Parálisis de los Pliegues Vocales/fisiopatología , Parálisis de los Pliegues Vocales/veterinaria , Secuenciación Completa del GenomaRESUMEN
Enterobacteriaceae are a large family of Gram-negative, non-spore-forming bacteria. Although many species exist as part of the natural flora of animals including humans, some members are associated with both intestinal and extraintestinal diseases. In this review, we focus on members of this family that have important roles in human disease: Salmonella, Escherichia, Shigella, and Yersinia, providing a brief overview of the disease caused by these bacteria, highlighting the contribution of animal models to our understanding of their pathogenesis and of host genetic determinants involved in susceptibility or resistance to infection.
Asunto(s)
Resistencia a la Enfermedad , Susceptibilidad a Enfermedades , Infecciones por Enterobacteriaceae/microbiología , Enterobacteriaceae/fisiología , Interacciones Huésped-Patógeno , Alelos , Animales , Modelos Animales de Enfermedad , Resistencia a la Enfermedad/genética , Resistencia a la Enfermedad/inmunología , Infecciones por Enterobacteriaceae/genética , Infecciones por Enterobacteriaceae/inmunología , Infecciones por Enterobacteriaceae/metabolismo , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Humanos , Sitios de Carácter CuantitativoRESUMEN
Background: Susceptibility to infection is in part genetically driven, and C57BL/6 mice resist various pathogens through the proinflammatory response of their M1 macrophages (MPs). However, they are susceptible to plague. It has been reported elsewhere that Mus spretus SEG mice resist plague and develop an immune response characterized by a strong recruitment of MPs. Methods: The responses of C57BL/6 and SEG MPs exposed to Yersinia pestis in vitro were examined. Results: SEG MPs exhibit a stronger bactericidal activity with higher nitric oxide production, a more proinflammatory polarized cytokine response, and a higher resistance to Y. pestis-induced apoptosis. This response was not specific to Y. pestis and involved a reduced sensitivity to M2 polarization/signal transducer and activator of transcription 6 activation and inhibition of caspase 8. The enhanced M1 profile was inducible in C57BL/6 MPs in vitro, and when transferred to susceptible C57BL/6 mice, these MPs significantly increased survival of bubonic plague. Conclusions: MPs can develop an enhanced functional profile beyond the prototypic M1, characterized by an even more potent proinflammatory response coordinated with resistance to killing. This programming plays a key role in the plague-resistance phenotype and may be similarly significant in other highly lethal infections, suggesting that orienting the MP response may represent a new therapeutic approach.
Asunto(s)
Apoptosis , Macrófagos/inmunología , Peste/inmunología , Yersinia pestis , Animales , Células Cultivadas , Citocinas/sangre , Femenino , Macrófagos/microbiología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos , Óxido Nítrico/metabolismo , Transducción de SeñalRESUMEN
Cutaneous mast cell tumors are rarely reported in cattle. Although mutations in the c-KIT gene have been shown to play a central role in the oncogenesis of canine mast cell tumors, few data are available in cattle. This report describes the clinical, histologic, immunohistochemical, and genetic features of a multicentric cutaneous mast cell tumor in an adult cow. An 11-year-old Prim'Holstein cow was presented for a 5-month history of multiple skin nodules. Cytologic and histologic analyses of the nodules led to a diagnosis of mast cell tumors. Immunohistochemical analysis for KIT expression showed a moderate to strong signal in neoplastic mast cells with a cytoplasmic and membranous pattern. Sequencing of the c-KIT gene coding sequence revealed no mutation. Despite partial response after corticosteroid treatment, euthanasia was elected. No metastases to the lymph nodes, spleen, and liver were identified at post-mortem and histologic examinations.
Asunto(s)
Enfermedades de los Bovinos , Enfermedades de los Perros , Mastocitoma Cutáneo , Neoplasias Cutáneas , Femenino , Bovinos , Animales , Perros , Mastocitos/patología , Enfermedades de los Perros/diagnóstico , Neoplasias Cutáneas/veterinaria , Mastocitoma Cutáneo/patología , Mastocitoma Cutáneo/veterinaria , Mutación , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas Proto-Oncogénicas c-kit/metabolismo , Enfermedades de los Bovinos/patologíaRESUMEN
Hypohidrotic ectodermal dysplasia is a developmental defect characterized by sparse or absent hair, missing or malformed teeth and defects in eccrine glands. Loss-of-function variants in the X-chromosomal EDA gene have been reported to cause hypohidrotic ectodermal dysplasia in humans, mice, dogs and cattle. We investigated a male cat exhibiting diffuse truncal alopecia with a completely absent undercoat. The cat lacked several teeth, and the remaining teeth had an abnormal conical shape. Whole-genome sequencing revealed a hemizygous missense variant in the EDA gene, XM_011291781.3:c.1042G>A or XP_011290083.1:p.(Ala348Thr). The predicted amino acid exchange is located in the C-terminal TNF signaling domain of the encoded ectodysplasin. The corresponding missense variant in the human EDA gene, p.Ala349Thr, has been reported as a recurring pathogenic variant in several human patients with X-linked hypohidrotic ectodermal dysplasia. The identified feline variant therefore represents the likely cause of the hypohidrotic ectodermal dysplasia in the investigated cat, and the genetic investigation confirmed the suspected clinical diagnosis. This is the first report of an EDA-related hypohidrotic ectodermal dysplasia in cats.
Asunto(s)
Displasia Ectodermal Anhidrótica Tipo 1 , Ectodisplasinas , Mutación Missense , Animales , Masculino , Ectodisplasinas/genética , Gatos , Displasia Ectodermal Anhidrótica Tipo 1/genética , Displasia Ectodermal Anhidrótica Tipo 1/veterinaria , Displasia Ectodermal Anhidrótica Tipo 1/patología , Enfermedades de los Gatos/genética , Enfermedades de los Gatos/patología , Secuenciación Completa del GenomaRESUMEN
Ehlers-Danlos syndrome (EDS) is a group of heterogeneous, rare diseases affecting the connective tissues. The main clinical signs of EDS are skin hyperextensibility, joint hypermobility, and skin fragility. Currently, the classification of EDS in humans distinguishes 13 clinical subtypes associated with variants in 20 different genes, reflecting the heterogeneity of this set of diseases. At present, variants in three of these genes have also been identified in dogs affected by EDS. The purpose of this study was to characterize the clinical and histopathological phenotype of an EDS-affected Chihuahua and to identify the causative genetic variant for the disease. The clinical examination suggested a diagnosis of classical EDS. Skin histopathology revealed an abnormally thin dermis, which is compatible with classical EDS. Whole-genome sequencing identified a heterozygous de novo 27 bp deletion in the COL5A2 gene, COL5A2:c.3388_3414del. The in-frame deletion is predicted to remove 9 amino acids in the triple-helical region of COL5A2. The molecular analysis and identification of a likely pathogenic variant in COL5A2 confirmed the subtype as a form of classical EDS. This is the first report of a COL5A2-related EDS in a dog.
Asunto(s)
Síndrome de Ehlers-Danlos , Anomalías Cutáneas , Animales , Colágeno/genética , Perros , Síndrome de Ehlers-Danlos/patología , Eliminación de Secuencia , Anomalías Cutáneas/genéticaRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which originated in Wuhan, China, in 2019, is responsible for the COVID-19 pandemic. It is now accepted that the wild fauna, probably bats, constitute the initial reservoir of the virus, but little is known about the role pets can play in the spread of the disease in human communities, knowing the ability of SARS-CoV-2 to infect some domestic animals. In this cross-sectional study, we tested the antibody response in a cluster of 21 domestic pets (9 cats and 12 dogs) living in close contact with their owners (belonging to a veterinary community of 20 students) in which two students tested positive for COVID-19 and several others (n = 11/18) consecutively showed clinical signs (fever, cough, anosmia, etc.) compatible with COVID-19 infection. Although a few pets presented many clinical signs indicative for a coronavirus infection, no antibodies against SARS-CoV-2 were detectable in their blood one month after the index case was reported, using an immunoprecipitation assay. These original data can serve a better evaluation of the host range of SARS-CoV-2 in natural environment exposure conditions.
RESUMEN
Ichthyoses represent a heterogeneous group of hereditary cornification disorders characterized by generalized scaling of the skin. An autosomal recessive congenital ichthyosis (ARCI) has been described in American Bulldogs and is caused by a variant in the NIPAL4 gene encoding for the ICHTHYIN protein. So far, this variant has not been described in other breeds. A 1.5-year-old female pedigreed American Bully was referred for generalized scaling and bad coat quality since adoption at 8 weeks of age. Clinical examination, cytological and histopathological examination, and DNA testing were performed. Clinical examination revealed a generalized scaling; cytological evaluation using impression with acetate tapes showed a secondary Malassezia dermatitis. Histopathological examination revealed a moderate to marked, diffuse, compact orthokeratotic hyperkeratosis with the formation of large scales. Few Malassezia were observed in the stratum corneum associated with minimal mixed perivascular inflammation and moderate epidermal hyperplasia. DNA testing of the dog revealed that he carries two defective alleles of the NIPAL4 gene previously described in the American Bulldog. We performed a commercially available breed detection test which, although not specifically testing for "American Bully" signatures, revealed a high probability of American Bulldog DNA signature within the past three generations. Topical treatment using a combination of keratolytic and keratomodulator shampoo, emollient and moisturizers spray and antimicrobial wipes achieved a marked clinical improvement after only 1 month. Continuous topical treatment was necessary to maintain clinical improvement. To the authors' knowledge, this is the first description of the deleterious NIPAL4 variant in an American Bully as well as the first description of clinical management and follow-up of ARCI in this breed.
Asunto(s)
Secuencia de Bases , Enfermedades de los Perros/genética , Eritrodermia Ictiosiforme Congénita/veterinaria , Receptores de Superficie Celular/genética , Eliminación de Secuencia , Animales , Enfermedades de los Perros/patología , Perros , Epidermis/patología , Femenino , Genes Recesivos , Eritrodermia Ictiosiforme Congénita/genética , Eritrodermia Ictiosiforme Congénita/patología , Linaje , Receptores de Superficie Celular/metabolismoRESUMEN
Bipolar disorder is one of the most common and devastating psychiatric disorders whose mechanisms remain largely unknown. Despite a strong genetic contribution demonstrated by twin and adoption studies, a polygenic background influences this multifactorial and heterogeneous psychiatric disorder. To identify susceptibility genes on a severe and more familial sub-form of the disease, we conducted a genome-wide association study focused on 211 patients of French origin with an early age at onset and 1,719 controls, and then replicated our data on a German sample of 159 patients with early-onset bipolar disorder and 998 controls. Replication study and subsequent meta-analysis revealed two genes encoding proteins involved in phosphoinositide signalling pathway (PLEKHA5 and PLCXD3). We performed additional replication studies in two datasets from the WTCCC (764 patients and 2,938 controls) and the GAIN-TGen cohorts (1,524 patients and 1,436 controls) and found nominal P-values both in the PLCXD3 and PLEKHA5 loci with the WTCCC sample. In addition, we identified in the French cohort one affected individual with a deletion at the PLCXD3 locus and another one carrying a missense variation in PLCXD3 (p.R93H), both supporting a role of the phosphatidylinositol pathway in early-onset bipolar disorder vulnerability. Although the current nominally significant findings should be interpreted with caution and need replication in independent cohorts, this study supports the strategy to combine genetic approaches to determine the molecular mechanisms underlying bipolar disorder.