Validation of a Chromosome 14 Risk Haplotype for Idiopathic Epilepsy in the Belgian Shepherd Dog Found to Be Associated with an Insertion in the RAPGEF5 Gene
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SUBMITTER: Belanger J
PROVIDER: S-EPMC9323784 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Epilepsy is the most common neurological disorder in dogs, with an incidence ranging from 0.5% to up to 20% in particular breeds. Canine epilepsy can be etiologically defined as idiopathic or symptomatic. Epileptic seizures may be classified as focal with or without secondary generalization, or as primary generalized. Nine genes have been identified for symptomatic (storage diseases) and one for idiopathic epilepsy in different breeds. However, the genetic background of common canine epilepsies remains unknown. We have studied the clinical and genetic background of epilepsy in Belgian Shepherds. We collected 159 cases and 148 controls and confirmed the presence of epilepsy through epilepsy questionnaires and clinical examinations. The MRI was normal while interictal EEG revealed abnormalities and variable foci in the clinically examined affected dogs. A genome-wide association study using Affymetrix 50K SNP arrays in 40 cases and 44 controls mapped the epilepsy locus on CFA37, which was replicated in an independent cohort (81 cases and 88 controls; combined p?=?9.70×10?¹?, OR?=?3.3). Fine mapping study defined a ?1 Mb region including 12 genes of which none are known epilepsy genes or encode ion channels. Exonic sequencing was performed for two candidate genes, KLF7 and ADAM23. No variation was found in KLF7 but a highly-associated non-synonymous variant, G1203A (R387H) was present in the ADAM23 gene (p?=?3.7×10??, OR?=?3.9 for homozygosity). Homozygosity for a two-SNP haplotype within the ADAM23 gene conferred the highest risk for epilepsy (p?=?6.28×10?¹¹, OR?=?7.4). ADAM23 interacts with known epilepsy proteins LGI1 and LGI2. However, our data suggests that the ADAM23 variant is a polymorphism and we have initiated a targeted re-sequencing study across the locus to identify the causative mutation. It would establish the affected breed as a novel therapeutic model, help to develop a DNA test for breeding purposes and introduce a novel candidate gene for human idiopathic epilepsies.
| S-EPMC3311644 | biostudies-literature
Project description:Background Idiopathic epilepsy (IE) is a common neurological disorder in the domestic dog, and is defined as repeated seizure activity having no identifiable underlying cause. Some breeds, such as the Belgian shepherd dog, have a greater prevalence of the disorder. Previous studies in this and other breeds have identified ADAM23 as a gene that confers risk of IE, although additional loci are known to exist. The present study sought to identify additional loci that influence IE in the Belgian shepherd dog. Results Genome-wide association studies (GWAS) revealed a significant association between IE and CFA 14 (p < 1.03 E− 08) and a suggestive association on CFA 37 (p < 2.91 E− 06) in a region in linkage disequilibrium with ADAM23. Logistic regression identified a 2-loci model that demonstrated interaction between the two chromosomal regions that when combined predicted IE risk with high sensitivity. Conclusions Two interacting loci, one each on CFAs 14 and 37, predictive of IE in the Belgian shepherd were identified. The loci are adjacent to potential candidate genes associated with neurological function. Further exploration of the region is warranted to identify causal variants underlying the association. Additionally, although the two loci were very good at predicting IE, they failed to capture all the risk, indicating additional loci or incomplete penetrance are also likely contributing to IE expression in the Belgian shepherd dog.
| S-EPMC7491283 | biostudies-literature
Project description:BackgroundIdiopathic epilepsy in the Belgian shepherd dog is known to have a substantial genetic component. The objective of this study was to identify genomic regions associated with the expression of generalized seizures in the Belgian Tervuren and Sheepdog.ResultsDNA from 366 dogs, of which 74 were classified as epileptic, representing two extended families were subjected to a genome-wide linkage scan using 410 microsatellite markers yielding informative coverage averaging 5.95 +/- 0.21 Mb. Though previous studies based on pedigree analyses proposed a major gene of influence, the present study demonstrated the trait to be highly polygenic. Studies of complex disorders in humans indicate that a liberal composite evaluation of genetic linkage is needed to identify underlying quantitative trait loci (QTLs). Four chromosomes yielded tentative linkage based upon LOD scores in excess of 1.0. Possible QTLs within these regions were supported also by analyses of multipoint linkage, allele frequency, TDT, and transmission of haplotype blocks.ConclusionsTaken together the data tentatively indicate six QTLs, three on CFA 2, and one on each of CFA 6, 12, and 37, that support fine mapping for mutations associated with epilepsy in the Belgian shepherd. The study also underscores the complexity of genomic linkage studies for polygenic disorders.
| S-EPMC2877138 | biostudies-literature
Project description:BackgroundIdiopathic epilepsy (IE) is a naturally occurring and significant seizure disorder affecting all dog breeds. Because dog breeds are genetically isolated populations, it is possible that IE is attributable to common founders and is genetically homogenous within breeds. In humans, a number of mutations, the majority of which are genes encoding ion channels, neurotransmitters, or their regulatory subunits, have been discovered to cause rare, specific types of IE. It was hypothesized that there are simple genetic bases for IE in some purebred dog breeds, specifically in Vizslas, English Springer Spaniels (ESS), Greater Swiss Mountain Dogs (GSMD), and Beagles, and that the gene(s) responsible may, in some cases, be the same as those already discovered in humans.ResultsCandidate genes known to be involved in human epilepsy, along with selected additional genes in the same gene families that are involved in murine epilepsy or are expressed in neural tissue, were examined in populations of affected and unaffected dogs. Microsatellite markers in close proximity to each candidate gene were genotyped and subjected to two-point linkage in Vizslas, and association analysis in ESS, GSMD and Beagles.ConclusionsMost of these candidate genes were not significantly associated with IE in these four dog breeds, while a few genes remained inconclusive. Other genes not included in this study may still be causing monogenic IE in these breeds or, like many cases of human IE, the disease in dogs may be likewise polygenic.
| S-EPMC3111397 | biostudies-literature
Project description:Spongy degeneration with cerebellar ataxia (SDCA) is a genetically heterogeneous neurodegenerative disorder with autosomal recessive inheritance in Malinois dogs, one of the four varieties of the Belgian Shepherd breed. Using a combined linkage and homozygosity mapping approach we identified an ∼10.6 Mb critical interval on chromosome 5 in a Malinois family with four puppies affected by cerebellar dysfunction. Visual inspection of the 10.6 Mb interval in whole-genome sequencing data from one affected puppy revealed a 227 bp SINE insertion into the ATP1B2 gene encoding the β2 subunit of the Na+/K+-ATPase holoenzyme (ATP1B2:c.130_131insLT796559.1:g.50_276). The SINE insertion caused aberrant RNA splicing. Immunohistochemistry suggested a reduction of ATP1B2 protein expression in the central nervous system of affected puppies. Atp1b2 knockout mice had previously been reported to show clinical and neurohistopathological findings similar to the affected Malinois puppies. Therefore, we consider ATP1B2:c.130_131ins227 the most likely candidate causative variant for a second subtype of SDCA in Malinois dogs, which we propose to term spongy degeneration with cerebellar ataxia subtype 2 (SDCA2). Our study further elucidates the genetic and phenotypic complexity underlying cerebellar dysfunction in Malinois dogs and provides the basis for a genetic test to eradicate one specific neurodegenerative disease from the breeding population in Malinois and the other varieties of the Belgian Shepherd breed. ATP1B2 thus represents another candidate gene for human inherited cerebellar ataxias, and SDCA2-affected Malinois puppies may serve as a naturally occurring animal model for this disorder.
| S-EPMC5555477 | biostudies-literature
Project description:One of the most popular dog breeds deployed by both the police and military has been the German Shepherd yet little is known about the morphology or body segment parameters of this breed. Such measures are essential for developing biomechanical models which, in turn, may guide clinicians in developing surgical interventions, injury treatment and prevention procedures. This paper provides a complete set of body segment parameters and inertial properties for the German Shepherd. Morphometric measures and 3-dimensional inertial properties, including mass, centre of mass, moment of inertia and volume, were measured from 17 segments from 6 German Shepherd police service dog cadavers. Using whole body mass and geometric modelling, 11 regression equations were developed for predicting segment masses, and 33 equations were developed for predicting moments of inertia. Using these data, inverse dynamic analyses may be applied in future investigations of canine mechanics, guiding surgical procedures, rehabilitation and training especially for the German Shepherd breed but potentially for other breeds too.
| S-EPMC6195294 | biostudies-literature
Project description:Epilepsy is a common and chronic neurological disease with a high degree of genetic heterogeneity. The etiology and pathogenesis of the disease have not been fully understood. Many studies suggested that there was a reciprocal relationship between mitochondrial dysfunction and epilepsy, but few studies focused on the mitochondrial genome (mtDNA) of the epilepsy patient which was extremely important for the mitochondrial function. In our study, we obtained complete mtDNA sequences of 27 idiopathic epilepsy patients and healthy people, and compared the sequence data with 30,000 GenBank sequences including 277 Han Chinese mtDNA sequences. We analyzed each variant that might be related to disease and examined the statistically significant variant in more than 300 patients and healthy people. Ultimately, we identified 27 variants which were reported to be associated with diseases, 4 rare variants (321T > G, 15973 T > C, 3897C > A, 12580 C > T), and a nonsynonymous variant (3571 C > T) which was predicted to be damaging. Although no variant was found to be significantly associated with epilepsy, our study provided a new insight into epilepsy study on an aspect of the mitochondrial genome.
| S-EPMC7707843 | biostudies-literature
Project description:Several genetically distinct forms of cerebellar ataxia exist in Belgian shepherd dogs. We investigated a litter in which two puppies developed cerebellar ataxia. The clinical signs stabilized at around six weeks of age, but remained visible into adulthood. Combined linkage and homozygosity mapping delineated a 5.5 Mb critical interval. The comparison of whole-genome sequence data of one affected dog to 929 control genomes revealed a private homozygous ~4.8 kb deletion in the critical interval, Chr8:14,468,376_14,473,136del4761. The deletion comprises exon 35 of the RALGAPA1 gene, XM_038544497.1:c.6080-2893_6944+1003del. It is predicted to introduce a premature stop codon into the transcript, truncating ~23% of the wild-type open reading frame of the encoded Ral GTPase-activating protein catalytic subunit α 1, XP_038400425.1:(p.Val2027Glnfs*7). Genotypes at the deletion showed the expected co-segregation with the phenotype in the family. Genotyping additional ataxic Belgian shepherd dogs revealed three additional homozygous mutant dogs from a single litter, which had been euthanized at five weeks of age due to their severe clinical phenotype. Histopathology revealed cytoplasmic accumulation of granular material within cerebellar Purkinje cells. Genotyping a cohort of almost 900 Belgian shepherd dogs showed the expected genotype-phenotype association and a carrier frequency of 5% in the population. Human patients with loss-of-function variants in RALGAPA1 develop psychomotor disability and early-onset epilepsy. The available clinical and histopathological data, together with current knowledge about RALGAPA1 variants and their functional impact in other species, suggest the RALGAPA1 deletion is the likely causative defect for the observed phenotype in the affected dogs.
| S-EPMC10454311 | biostudies-literature
Project description:Dog puppy loss by the age of six to eight weeks after normal development is relatively uncommon. Necropsy findings in two spontaneously deceased Belgian Shepherd puppies indicated an abnormal accumulation of material in several organs. A third deceased puppy exhibited mild signs of an inflammation in the central nervous system and an enteritis. The puppies were closely related, raising the suspicion of a genetic cause. Pedigree analysis suggested a monogenic autosomal recessive inheritance. Combined linkage and homozygosity mapping assigned the most likely position of a potential genetic defect to 13 genome segments totaling 82 Mb. The genome of an affected puppy was sequenced and compared to 645 control genomes. Three private protein changing variants were found in the linked and homozygous regions. Targeted genotyping in 96 Belgian Shepherd dogs excluded two of these variants. The remaining variant, YARS2:1054G>A or p.Glu352Lys, was perfectly associated with the phenotype in a cohort of 474 Belgian Shepherd dogs.YARS2 encodes the mitochondrial tyrosyl-tRNA synthetase 2 and the predicted amino acid change replaces a negatively charged and evolutionary conserved glutamate at the surface of the tRNA binding domain of YARS2 with a positively charged lysine. Human patients with loss-of-function variants in YARS2 suffer from myopathy, lactic acidosis, and sideroblastic anemia 2, a disease with clinical similarities to the phenotype of the studied dogs. The carrier frequency was 27.2% in the tested Belgian Shepherd dogs. Our data suggest YARS2:1054G>A as the candidate causative variant for the observed juvenile mortality.
| S-EPMC7140874 | biostudies-literature
Project description:Introduction. Infection with the Rasamsonia argillacea species complex represents an emerging problem in human and veterinary medicine with systemic mycoses presenting with significant clinical complications and being a cause of death. Case presentation. In this report, a case of systemic Rasamsonia piperina infection discovered in a 3-year-old male neutered, German shepherd cross dog is described together with the clinical presentation, the course of the disease and diagnosis. This report describes the first case of veterinary mycosis due to R. piperina in Europe and the first case in humans or animals in the UK. Conclusion. Although seemingly rare, R. argillacea species complex infection should be a differential diagnosis for dogs, especially German shepherds with the described presenting signs, and radiographic and ultrasonographic findings.
| S-EPMC5692241 | biostudies-literature