The Experts below are selected from a list of 303 Experts worldwide ranked by ideXlab platform
Kathryn M. Meurs - One of the best experts on this subject based on the ideXlab platform.
-
a missense variant in the titin gene in Doberman Pinscher dogs with familial dilated cardiomyopathy and sudden cardiac death
Human Genetics, 2019Co-Authors: Kathryn M. Meurs, Bruce W. Keene, Natasha J. Olby, Steven G. Friedenberg, Justin Kolb, Chandra Saripalli, Paola Tonino, Kathleen Woodruff, Darcy B Adin, Oriana YostAbstract:The dog provides a large animal model of familial dilated cardiomyopathy for the study of important aspects of this common familial cardiovascular disease. We have previously demonstrated a form of canine dilated cardiomyopathy in the Doberman Pinscher breed that is inherited as an autosomal dominant trait and is associated with a splice site variant in the pyruvate dehydrogenase kinase 4 (PDK4) gene, however, genetic heterogeneity exists in this species as well and not all affected dogs have the PDK4 variant. Whole genome sequencing of a family of Doberman pinchers with dilated cardiomyopathy and sudden cardiac death without the PDK4 variant was performed. A pathologic missense variant in the titin gene located in an immunoglobulin-like domain in the I-band spanning region of the molecule was identified and was highly associated with the disease (p < 0.0001). We demonstrate here the identification of a variant in the titin gene highly associated with the disease in this spontaneous canine model of dilated cardiomyopathy. This large animal model of familial dilated cardiomyopathy shares many similarities with the human disease including mode of inheritance, clinical presentation, genetic heterogeneity and a pathologic variant in the titin gene. The dog is an excellent model to improve our understanding of the genotypic phenotypic relationships, penetrance, expression and the pathophysiology of variants in the titin gene.
-
Deafness and vestibular dysfunction in a Doberman Pinscher puppy associated with a mutation in the PTPRQ gene.
Journal of veterinary internal medicine, 2018Co-Authors: Julien Guevar, Kathryn M. Meurs, Natasha J. Olby, Oriana Yost, Steven G. FriedenbergAbstract:Background A congenital syndrome of hearing loss and vestibular dysfunction affects Doberman Pinschers. Its inheritance pattern is suspected to be autosomal recessive and it potentially represents a spontaneous animal model of an autosomal recessive syndromic hearing loss. Hypothesis/objectives The objectives of this study were to use whole genome sequencing (WGS) to identify deleterious genetic variants in candidate genes associated with the syndrome and to study the prevalence of candidate variants among a population of unaffected Doberman Pinschers. Animals One affected Doberman Pinscher and 202 unaffected Doberman Pinschers. Methods WGS of the affected dog with filtering of variants against a database of 154 unaffected dogs of diverse breeds was performed. Confirmation of candidate variants was achieved by Sanger sequencing followed by genotyping of the control population of unaffected Doberman Pinschers. Results WGS and variant filtering identified an alteration in a gene associated with both deafness and vestibular disease in humans: protein tyrosine phosphatase, receptor type Q (PTPRQ). There was a homozygous A insertion at CFA15: 22 989 894, causing a frameshift mutation in exon 39 of the gene. This insertion is predicted to cause a protein truncation with a premature stop codon occurring after position 2054 of the protein sequence that causes 279 C-terminal amino acids to be eliminated. Prevalence of the variant was 1.5% in a cohort of 202 unaffected Doberman Pinschers; all unaffected Doberman Pinschers were heterozygous or heterozygous for the reference allele. Conclusion and clinical importance We report the identification of a genetic alteration on the PTPRQ gene that is associated with congenital hearing and vestibular disorder in a young Doberman Pinscher dog.
-
A splice site mutation in a gene encoding for PDK4, a mitochondrial protein, is associated with the development of dilated cardiomyopathy in the Doberman Pinscher
Human Genetics, 2012Co-Authors: Kathryn M. Meurs, Sunshine Lahmers, Bruce W. Keene, Stephen N. White, Mark A. Oyama, Evan Mauceli, Kerstin Lindblad-tohAbstract:Familial dilated cardiomyopathy is a primary myocardial disease that can result in the development of congestive heart failure and sudden cardiac death. Spontaneous animal models of familial dilated cardiomyopathy exist and the Doberman Pinscher dog is one of the most commonly reported canine breeds. The objective of this study was to evaluate familial dilated cardiomyopathy in the Doberman Pinscher dog using a genome-wide association study for a genetic alteration(s) associated with the development of this disease in this canine model. Genome-wide association analysis identified an area of statistical significance on canine chromosome 14 ( p _raw = 9.999e−05 corrected for genome-wide significance), fine-mapping of additional SNPs flanking this region localized a signal to 23,774,190–23,781,919 ( p = 0.001) and DNA sequencing identified a 16-base pair deletion in the 5′ donor splice site of intron 10 of the pyruvate dehydrogenase kinase 4 gene in affected dogs ( p
-
A splice site mutation in a gene encoding for PDK4, a mitochondrial protein, is associated with the development of dilated cardiomyopathy in the Doberman Pinscher.
Human genetics, 2012Co-Authors: Kathryn M. Meurs, Sunshine Lahmers, Bruce W. Keene, Stephen N. White, Mark A. Oyama, Evan Mauceli, Kerstin Lindblad-tohAbstract:Familial dilated cardiomyopathy is a primary myocardial disease that can result in the development of congestive heart failure and sudden cardiac death. Spontaneous animal models of familial dilated cardiomyopathy exist and the Doberman Pinscher dog is one of the most commonly reported canine breeds. The objective of this study was to evaluate familial dilated cardiomyopathy in the Doberman Pinscher dog using a genome-wide association study for a genetic alteration(s) associated with the development of this disease in this canine model. Genome-wide association analysis identified an area of statistical significance on canine chromosome 14 (p(raw) = 9.999e-05 corrected for genome-wide significance), fine-mapping of additional SNPs flanking this region localized a signal to 23,774,190-23,781,919 (p = 0.001) and DNA sequencing identified a 16-base pair deletion in the 5' donor splice site of intron 10 of the pyruvate dehydrogenase kinase 4 gene in affected dogs (p < 0.0001). Electron microscopy of myocardium from affected dogs demonstrated disorganization of the Z line, mild to moderate T tubule and sarcoplasmic reticulum dilation, marked pleomorphic mitochondrial alterations with megamitochondria, scattered mitochondria with whorling and vacuolization and mild aggregates of lipofuscin granules. In conclusion, we report the identification of a splice site deletion in the PDK4 gene that is associated with the development of familial dilated cardiomyopathy in the Doberman Pinscher dog.
-
A prospective genetic evaluation of familial dilated cardiomyopathy in the Doberman Pinscher.
Journal of veterinary internal medicine, 2007Co-Authors: Kathryn M. Meurs, Philip R. Fox, Michelle M. Norgard, Alan W. Spier, Allison Lamb, Shianne L. Koplitz, Ryan D. BaumwartAbstract:Background: The Doberman Pinscher is one of the most common breeds of dogs to develop dilated cardiomyopathy (DCM), a primary heart muscle disorder characterized by myocardial dysfunction, cardiac arrhythmias, and congestive heart failure. In the Doberman Pinscher, the disease is typically adult onset, and a familial etiology has been suggested. Hypothesis: DCM in the Doberman Pinscher, is a familial disease linked to a specific genetic marker. Animals: The study comprised an extended family of Doberman Pinschers with a history of DCM. Methods: Participating dogs were prospectively evaluated over an 8-year period. Phenotype of participating dogs was determined by annual echocardiography and ambulatory electrocardiography, and the pedigree was evaluated to determine a specific mode of inheritance. Three hundred seventy-two microsatellite markers were selected and genotyped to cover the 38 autosomal chromosomes. Phenotyping, genotyping, and pedigree information was entered into a database, and parametric, 2-point analysis was performed. Markers were considered to be linked to the development of DCM if the logarithm of odds LOD score was ±3.0. Results: An autosomal dominant mode of inheritance was defined by the appearance of the disease in multiple generations, equal gender representation (P = .973) and male-to-male transmission. A maximum LOD score of 1.31 was obtained for 1 marker on chromosome 20, a score not high enough to be associated with DCM. Conclusion: DCM in the Doberman Pinscher is a familial disease inherited as an autosomal dominant trait. The causative gene(s) responsible for this condition remain unresolved. Association studies by means of array technology may provide new insights into gene identification.
Bruce W. Keene - One of the best experts on this subject based on the ideXlab platform.
-
a missense variant in the titin gene in Doberman Pinscher dogs with familial dilated cardiomyopathy and sudden cardiac death
Human Genetics, 2019Co-Authors: Kathryn M. Meurs, Bruce W. Keene, Natasha J. Olby, Steven G. Friedenberg, Justin Kolb, Chandra Saripalli, Paola Tonino, Kathleen Woodruff, Darcy B Adin, Oriana YostAbstract:The dog provides a large animal model of familial dilated cardiomyopathy for the study of important aspects of this common familial cardiovascular disease. We have previously demonstrated a form of canine dilated cardiomyopathy in the Doberman Pinscher breed that is inherited as an autosomal dominant trait and is associated with a splice site variant in the pyruvate dehydrogenase kinase 4 (PDK4) gene, however, genetic heterogeneity exists in this species as well and not all affected dogs have the PDK4 variant. Whole genome sequencing of a family of Doberman pinchers with dilated cardiomyopathy and sudden cardiac death without the PDK4 variant was performed. A pathologic missense variant in the titin gene located in an immunoglobulin-like domain in the I-band spanning region of the molecule was identified and was highly associated with the disease (p < 0.0001). We demonstrate here the identification of a variant in the titin gene highly associated with the disease in this spontaneous canine model of dilated cardiomyopathy. This large animal model of familial dilated cardiomyopathy shares many similarities with the human disease including mode of inheritance, clinical presentation, genetic heterogeneity and a pathologic variant in the titin gene. The dog is an excellent model to improve our understanding of the genotypic phenotypic relationships, penetrance, expression and the pathophysiology of variants in the titin gene.
-
A splice site mutation in a gene encoding for PDK4, a mitochondrial protein, is associated with the development of dilated cardiomyopathy in the Doberman Pinscher
Human Genetics, 2012Co-Authors: Kathryn M. Meurs, Sunshine Lahmers, Bruce W. Keene, Stephen N. White, Mark A. Oyama, Evan Mauceli, Kerstin Lindblad-tohAbstract:Familial dilated cardiomyopathy is a primary myocardial disease that can result in the development of congestive heart failure and sudden cardiac death. Spontaneous animal models of familial dilated cardiomyopathy exist and the Doberman Pinscher dog is one of the most commonly reported canine breeds. The objective of this study was to evaluate familial dilated cardiomyopathy in the Doberman Pinscher dog using a genome-wide association study for a genetic alteration(s) associated with the development of this disease in this canine model. Genome-wide association analysis identified an area of statistical significance on canine chromosome 14 ( p _raw = 9.999e−05 corrected for genome-wide significance), fine-mapping of additional SNPs flanking this region localized a signal to 23,774,190–23,781,919 ( p = 0.001) and DNA sequencing identified a 16-base pair deletion in the 5′ donor splice site of intron 10 of the pyruvate dehydrogenase kinase 4 gene in affected dogs ( p
-
A splice site mutation in a gene encoding for PDK4, a mitochondrial protein, is associated with the development of dilated cardiomyopathy in the Doberman Pinscher.
Human genetics, 2012Co-Authors: Kathryn M. Meurs, Sunshine Lahmers, Bruce W. Keene, Stephen N. White, Mark A. Oyama, Evan Mauceli, Kerstin Lindblad-tohAbstract:Familial dilated cardiomyopathy is a primary myocardial disease that can result in the development of congestive heart failure and sudden cardiac death. Spontaneous animal models of familial dilated cardiomyopathy exist and the Doberman Pinscher dog is one of the most commonly reported canine breeds. The objective of this study was to evaluate familial dilated cardiomyopathy in the Doberman Pinscher dog using a genome-wide association study for a genetic alteration(s) associated with the development of this disease in this canine model. Genome-wide association analysis identified an area of statistical significance on canine chromosome 14 (p(raw) = 9.999e-05 corrected for genome-wide significance), fine-mapping of additional SNPs flanking this region localized a signal to 23,774,190-23,781,919 (p = 0.001) and DNA sequencing identified a 16-base pair deletion in the 5' donor splice site of intron 10 of the pyruvate dehydrogenase kinase 4 gene in affected dogs (p < 0.0001). Electron microscopy of myocardium from affected dogs demonstrated disorganization of the Z line, mild to moderate T tubule and sarcoplasmic reticulum dilation, marked pleomorphic mitochondrial alterations with megamitochondria, scattered mitochondria with whorling and vacuolization and mild aggregates of lipofuscin granules. In conclusion, we report the identification of a splice site deletion in the PDK4 gene that is associated with the development of familial dilated cardiomyopathy in the Doberman Pinscher dog.
Steven G. Friedenberg - One of the best experts on this subject based on the ideXlab platform.
-
a missense variant in the titin gene in Doberman Pinscher dogs with familial dilated cardiomyopathy and sudden cardiac death
Human Genetics, 2019Co-Authors: Kathryn M. Meurs, Bruce W. Keene, Natasha J. Olby, Steven G. Friedenberg, Justin Kolb, Chandra Saripalli, Paola Tonino, Kathleen Woodruff, Darcy B Adin, Oriana YostAbstract:The dog provides a large animal model of familial dilated cardiomyopathy for the study of important aspects of this common familial cardiovascular disease. We have previously demonstrated a form of canine dilated cardiomyopathy in the Doberman Pinscher breed that is inherited as an autosomal dominant trait and is associated with a splice site variant in the pyruvate dehydrogenase kinase 4 (PDK4) gene, however, genetic heterogeneity exists in this species as well and not all affected dogs have the PDK4 variant. Whole genome sequencing of a family of Doberman pinchers with dilated cardiomyopathy and sudden cardiac death without the PDK4 variant was performed. A pathologic missense variant in the titin gene located in an immunoglobulin-like domain in the I-band spanning region of the molecule was identified and was highly associated with the disease (p < 0.0001). We demonstrate here the identification of a variant in the titin gene highly associated with the disease in this spontaneous canine model of dilated cardiomyopathy. This large animal model of familial dilated cardiomyopathy shares many similarities with the human disease including mode of inheritance, clinical presentation, genetic heterogeneity and a pathologic variant in the titin gene. The dog is an excellent model to improve our understanding of the genotypic phenotypic relationships, penetrance, expression and the pathophysiology of variants in the titin gene.
-
Deafness and vestibular dysfunction in a Doberman Pinscher puppy associated with a mutation in the PTPRQ gene.
Journal of veterinary internal medicine, 2018Co-Authors: Julien Guevar, Kathryn M. Meurs, Natasha J. Olby, Oriana Yost, Steven G. FriedenbergAbstract:Background A congenital syndrome of hearing loss and vestibular dysfunction affects Doberman Pinschers. Its inheritance pattern is suspected to be autosomal recessive and it potentially represents a spontaneous animal model of an autosomal recessive syndromic hearing loss. Hypothesis/objectives The objectives of this study were to use whole genome sequencing (WGS) to identify deleterious genetic variants in candidate genes associated with the syndrome and to study the prevalence of candidate variants among a population of unaffected Doberman Pinschers. Animals One affected Doberman Pinscher and 202 unaffected Doberman Pinschers. Methods WGS of the affected dog with filtering of variants against a database of 154 unaffected dogs of diverse breeds was performed. Confirmation of candidate variants was achieved by Sanger sequencing followed by genotyping of the control population of unaffected Doberman Pinschers. Results WGS and variant filtering identified an alteration in a gene associated with both deafness and vestibular disease in humans: protein tyrosine phosphatase, receptor type Q (PTPRQ). There was a homozygous A insertion at CFA15: 22 989 894, causing a frameshift mutation in exon 39 of the gene. This insertion is predicted to cause a protein truncation with a premature stop codon occurring after position 2054 of the protein sequence that causes 279 C-terminal amino acids to be eliminated. Prevalence of the variant was 1.5% in a cohort of 202 unaffected Doberman Pinschers; all unaffected Doberman Pinschers were heterozygous or heterozygous for the reference allele. Conclusion and clinical importance We report the identification of a genetic alteration on the PTPRQ gene that is associated with congenital hearing and vestibular disorder in a young Doberman Pinscher dog.
Giovambattista Guillermo - One of the best experts on this subject based on the ideXlab platform.
-
von Willebrand disease type 1 in Doberman Pinscher dogs: genotyping and prevalence of the mutation in the Buenos Aires region, Argentina
2019Co-Authors: Crespi, Julián Alejandro, Barrientos, Laura Soledad, Giovambattista GuillermoAbstract:von Willebrand disease (vWD) is the most common inherited coagulopathy in dogs, particularly in Doberman Pinschers. We developed a pyrosequencing-based assay to estimate the frequency of the c.7437G>A mutation associated with vWD type 1 in the Doberman Pinscher population of Buenos Aires, Argentina. We found a 0.41 frequency for the mutated allele, which varied significantly within families (family 1 = 0.43, family 2 = 0.58, unrelated animals = 0.35). The use of a popular founder male carrier of mutant allele A increased vWD incidence within a family and in the general population. The mode of inheritance was confirmed as autosomal dominant with incomplete penetrance. No differences were found between sexes and coat colors. Pyrosequencing was a good complement to clinical and coagulation tests for vWD type 1 diagnosis and a useful alternative for detecting the c.7437G>A mutation.Facultad de Ciencias Veterinaria
-
von Willebrand disease type 1 in Doberman Pinscher dogs: genotyping and prevalence of the mutation in the Buenos Aires region, Argentina
'SAGE Publications', 2018Co-Authors: Crespi, Julián Alejandro, Barrientos, Laura Soledad, Giovambattista GuillermoAbstract:von Willebrand disease (vWD) is the most common inherited coagulopathy in dogs, particularly in Doberman Pinschers. We developed a pyrosequencing-based assay to estimate the frequency of the c.7437G>A mutation associated with vWD type 1 in the Doberman Pinscher population of Buenos Aires, Argentina. We found a 0.41 frequency for the mutated allele, which varied significantly within families (family 1 = 0.43, family 2 = 0.58, unrelated animals = 0.35). The use of a popular founder male carrier of mutant allele A increased vWD incidence within a family and in the general population. The mode of inheritance was confirmed as autosomal dominant with incomplete penetrance. No differences were found between sexes and coat colors. Pyrosequencing was a good complement to clinical and coagulation tests for vWD type 1 diagnosis and a useful alternative for detecting the c.7437G>A mutation.Fil: Crespi, Julian Alejandro. 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: Barrientos, Laura Soledad. 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: Giovambattista, Guillermo. 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; Argentin
-
Nuevas perspectivas en el diagnóstico genético de la cardiomiopatía dilatada en Doberman Pinscher
2017Co-Authors: Arizmendi Analía, Batista, Pablo Rodrigo, Arias, Daniel Osvaldo, Vercellini, María Del Rosario, Crespi, Julián Alejandro, Barrientos, Laura Soledad, Giovambattista GuillermoAbstract:La Cardiomiopatía Dilatada (CMD) es una de las enfermedades cardiovasculares más frecuentes en caninos. Se presenta principalmente en perros de razas grandes y gigantes, siendo el Doberman Pinscher (DP) una de las más afectadas. Esta enfermedad tiene alta prevalencia en este grupo racial, oscilando la misma entre 45% y 63%. La CMD se caracteriza por desarrollar una dilatación de las cámaras cardíacas con pérdida progresiva de la capacidad de contracción del miocardio. Esto genera una disminución del volumen minuto, pudiendo derivar en una falla cardíaca congestiva y/o muerte súbita debido a la aparición de arritmias. Durante la progresión de la misma se identifica una fase oculta, en la cual el animal no presenta signos clínicos, pero aparecen cambios morfológicos y/o eléctricos, diagnosticables mediante ecocardiografía y electrocardiografía. Se ha demostrado que la CMD es una enfermedad de base hereditaria, por lo cual en los últimos años las investigaciones se orientaron a definir las bases genéticas de la misma. El objetivo de este trabajo fue realizar una revisión bibliográfica acerca de los avances en estudios relacionados con el diagnóstico genético de la CMD en DP.Facultad de Ciencias VeterinariasInstituto de Genética Veterinari
Ryan D. Baumwart - One of the best experts on this subject based on the ideXlab platform.
-
A prospective genetic evaluation of familial dilated cardiomyopathy in the Doberman Pinscher.
Journal of veterinary internal medicine, 2007Co-Authors: Kathryn M. Meurs, Philip R. Fox, Michelle M. Norgard, Alan W. Spier, Allison Lamb, Shianne L. Koplitz, Ryan D. BaumwartAbstract:Background: The Doberman Pinscher is one of the most common breeds of dogs to develop dilated cardiomyopathy (DCM), a primary heart muscle disorder characterized by myocardial dysfunction, cardiac arrhythmias, and congestive heart failure. In the Doberman Pinscher, the disease is typically adult onset, and a familial etiology has been suggested. Hypothesis: DCM in the Doberman Pinscher, is a familial disease linked to a specific genetic marker. Animals: The study comprised an extended family of Doberman Pinschers with a history of DCM. Methods: Participating dogs were prospectively evaluated over an 8-year period. Phenotype of participating dogs was determined by annual echocardiography and ambulatory electrocardiography, and the pedigree was evaluated to determine a specific mode of inheritance. Three hundred seventy-two microsatellite markers were selected and genotyped to cover the 38 autosomal chromosomes. Phenotyping, genotyping, and pedigree information was entered into a database, and parametric, 2-point analysis was performed. Markers were considered to be linked to the development of DCM if the logarithm of odds LOD score was ±3.0. Results: An autosomal dominant mode of inheritance was defined by the appearance of the disease in multiple generations, equal gender representation (P = .973) and male-to-male transmission. A maximum LOD score of 1.31 was obtained for 1 marker on chromosome 20, a score not high enough to be associated with DCM. Conclusion: DCM in the Doberman Pinscher is a familial disease inherited as an autosomal dominant trait. The causative gene(s) responsible for this condition remain unresolved. Association studies by means of array technology may provide new insights into gene identification.
-
A Prospective Genetic E valuation o f F amilial D ilated Cardiomyopathy i n t he Doberman Pinscher
2007Co-Authors: Kathryn M. Meurs, Philip R. Fox, Michelle M. Norgard, Alan W. Spier, Allison Lamb, Shianne L. Koplitz, Ryan D. BaumwartAbstract:Background: The Doberman Pinscher is one of the most common breeds of dogs to develop dilated cardiomyopathy (DCM), a primary heart muscle disorder characterized by myocardial dysfunction, cardiac arrhythmias, and congestive heart failure. In the Doberman Pinscher, the disease is typically adult onset, and a familial etiology has been suggested. Hypothesis: DCM in the Doberman Pinscher, is a familial disease linked to a specific genetic marker. Animals: The study comprised an extended family of Doberman Pinschers with a history of DCM. Methods: Participating dogs were prospectively evaluated over an 8-year period. Phenotype of participating dogs was determined by annual echocardiography and ambulatory electrocardiography, and the pedigree was evaluated to determine a specific mode of inheritance. Three hundred seventy-two microsatellite markers were selected and genotyped to cover the 38 autosomal chromosomes. Phenotyping, genotyping, and pedigree information was entered into a database, and parametric, 2point analysis was performed. Markers were considered to be linked to the development of DCM if the logarithm of odds LOD score was $3.0. Results: An autosomal dominant mode of inheritance was defined by the appearance of the disease in multiple generations, equal gender representation (P 5 .973) and male-to-male transmission. A maximum LOD score of 1.31 was obtained for 1 marker on chromosome 20, a score not high enough to be associated with DCM. Conclusion: DCM in the Doberman Pinscher is a familial disease inherited as an autosomal dominant trait. The causative gene(s) responsible for this condition remain unresolved. Association studies by means of array technology may provide new insights into gene identification.