1,721,176 research outputs found
Case report: Sacral agenesis in two boxer dogs: clinical presentation, diagnostic investigations, and outcome
Full text linkTwo boxer dogs from the same litter were presented at 3 months of age for urinary and fecal incontinence. Both dogs had an abnormal tail consisting of a small stump, an atonic anal sphincter, and absent perineal reflex and sensation. Neurological evaluation was indicative of a lesion of the cauda equina or sacral spinal cord. Radiology and CT scan of the spine displayed similar findings in the two dogs that were indicative of sacral agenesis. Indeed, they had 6 lumbar vertebrae followed by a lumbosacral transitional vertebra, lacking a complete spinous process, and a hypoplastic vertebra carrying 2 hypoplastic sacral transverse processes as the only remnant of the sacral bone. Caudal vertebrae were absent in one of the dogs. On MRI, one dog had a dural sac occupying the entire spinal canal and ending in a subfascial fat structure. In the other dog, the dural sac finished in an extracanalar, subfascial, well-defined cystic structure, communicating with the subarachnoid space, and consistent with a meningocele. Sacral agenesis—that is the partial or complete absence of the sacral bones—is a neural tube defect occasionally reported in humans with spina bifida occulta. Sacral agenesis has been described in human and veterinary medicine in association with conditions such as caudal regression syndrome, perosomus elumbis, and Currarino syndrome. These neural tube defects are caused by genetic and/or environmental factors. Despite thorough genetic investigation, no candidate variants in genes with known functional impact on bone development or sacral development could be found in the affected dogs. To the best of the authors’ knowledge, this is the first report describing similar sacral agenesis in two related boxer dogs
Looking the cow in the eye: deletion in the NID1 gene is associated with recessive inherited cataract in Romagnola cattle
Full text linkCataract is a known condition leading to opacification of the eye lens causing partial or total blindness. Mutations are known to cause autosomal dominant or recessive inherited forms of cataracts in humans, mice, rats, guinea pigs and dogs. The use of large-sized animal models instead of those using mice for the study of this condition has been discussed due to the small size of rodent lenses. Four juvenile-onset cases of bilateral incomplete immature nuclear cataract were recently observed in Romagnola cattle. Pedigree analysis suggested a monogenic autosomal recessive inheritance. In addition to the cataract, one of the cases displayed abnormal head movements. Genome-wide association and homozygosity mapping and subsequent whole genome sequencing of a single case identified two perfectly associated sequence variants in a critical interval of 7.2 Mb on cattle chromosome 28: a missense point mutation located in an uncharacterized locus and an 855 bp deletion across the exon 19/intron 19 border of the bovine nidogen 1 (NID1) gene (c.3579_3604+829del). RT-PCR showed that NID1 is expressed in bovine lenses while the transcript of the second locus was absent. The NID1 deletion leads to the skipping of exon 19 during transcription and is therefore predicted to cause a frameshift and premature stop codon (p.1164fs27X). The truncated protein lacks a C-terminal domain essential for binding with matrix assembly complexes. Nidogen 1 deficient mice show neurological abnormalities and highly irregular crystal lens alterations. This study adds NID1 to the list of candidate genes for inherited cataract in humans and is the first report of a naturally occurring mutation leading to non-syndromic catarct in cattle provides a potential large animal model for human cataract
A frameshift mutation in MOCOS is associated with familial renal syndrome (xanthinuria) in Tyrolean Grey cattle
Full text linkBackground
Renal syndromes are occasionally reported in domestic animals. Two identical twin Tyrolean Grey calves exhibited weight loss, skeletal abnormalities and delayed development associated with kidney abnormalities and formation of uroliths. These signs resembled inherited renal tubular dysplasia found in Japanese Black cattle which is associated with mutations in the claudin 16 gene. Despite demonstrating striking phenotypic similarities, no obvious presence of pathogenic variants of this candidate gene were found. Therefore further analysis was required to decipher the genetic etiology of the condition.
Results
The family history of the cases suggested the possibility of an autosomal recessive inheritance. Homozygosity mapping combined with sequencing of the whole genome of one case detected two associated non-synonymous private coding variants: A homozygous missense variant in the uncharacterized KIAA2026 gene (g.39038055C > G; c.926C > G), located in a 15 Mb sized region of homozygosity on BTA 8; and a homozygous 1 bp deletion in the molybdenum cofactor sulfurase (MOCOS) gene (g.21222030delC; c.1881delG and c.1782delG), located in an 11 Mb region of homozygosity on BTA 24. Pathogenic variants in MOCOS have previously been associated with inherited metabolic syndromes and xanthinuria in different species including Japanese Black cattle. Genotyping of two additional clinically suspicious cases confirmed the association with the MOCOS variant, as both animals had a homozygous mutant genotype and did not show the variant KIAA2026 allele. The identified genomic deletion is predicted to be highly disruptive, creating a frameshift and premature termination of translation, resulting in severely truncated MOCOS proteins that lack two functionally essential domains. The variant MOCOS allele was absent from cattle of other breeds and approximately 4% carriers were detected among more than 1200 genotyped Tyrolean Grey cattle. Biochemical urolith analysis of one case revealed the presence of approximately 95% xanthine.
Conclusions
The identified MOCOS loss of function variant is highly likely to cause the renal syndrome in the affected animals. The results suggest that the phenotypic features of the renal syndrome were related to an early onset form of xanthinuria, which is highly likely to lead to the progressive defects. The identification of the candidate causative mutation thus enables selection against this pathogenic variant in Tyrolean Grey cattle
NHLRC1 dodecamer repeat expansion demonstrated by whole genome sequencing in a Chihuahua with Lafora disease.
Full text linkLafora disease is an autosomal recessive disor-der that causes myoclonic epilepsy.The disease is char-acterized by the presence of polyglucosan inclusion bodies (Lafora bodies), predominantly in the central nervous sys-tem. More than 90% of human Lafora disease cases arecaused by genetic variants in eitherEPM2A, encodinglaforin glucan phosphatase, orNHLRC1,encoding the NHLrepeat containing E3 ubiquitin protein ligase 1, also termedEPM2B or malin. Lafora disease in animals has similarclinical signs as the human disease, including spontaneousand reflex myoclonus, jerks and generalized tonic clonic sei-zures. Lafora disease has been reported in the dog, cat, cow and fennec fox.In dogs, Lafora disease is one of themost commonly recognized structural-metabolic epilepsiesand is inherited as an autosomal recessive condition. It ismost frequent in Miniature Wirehaired Dachshunds, BassetHounds and Beagles and has also been reported in theMiniature and Standard Poodle, Pointer and Corgi. Asingle disease-causing variant has been found in dogs. It consists of a massive expansion of a GC-rich dodecamerrepeat sequence in the canineNHLRC1gene, leading to lossof function of the gene. The wild type allele of this repeatconsists of two copies of a 12-bp motif in most mammalianspecies. In normal dogs and other canids two or threecopies are present. The pathogenic alleles leading to Laforadisease in dogs were reported to contain 14-26 copies ofthis repeat.2Genetic testing and carrier detection are notroutinely available, as the extremely GC-rich dodecamerrepeat expansion impedes PCR-based diagnostic approaches.Currently, a Southern-blot-based test is offered by theHospital for Sick Children in Toronto and represents an offi-cial DNA screening test recommended by the UK KennelClub.Fil: Barrientos, Laura Soledad. University of Bern; Suiza. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico CONICET- La Plata. Instituto de Genética Veterinaria "Ing. Fernando Noel Dulout". Universidad Nacional de La Plata. Facultad de Ciencias Veterinarias. Instituto de Genética Veterinaria; ArgentinaFil: Maiolini, Arianna. University of Bern; SuizaFil: Häni, Annakatrin. University of Bern; SuizaFil: Jagannathan, Vidhya. University of Bern; SuizaFil: Leeb, Tosso. University of Bern; Suiz
Single-cell profiling of bronchoalveolar cells reveals a Th17 signature in neutrophilic severe equine asthma
Full text linkSevere 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
Heterozygous DSP in-frame deletion in a poodle with syndromic ichthyosis involving additional hair and tooth abnormalities.
Full text linkIchthyoses 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
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