The Experts below are selected from a list of 189 Experts worldwide ranked by ideXlab platform
Jörg T. Epplen - One of the best experts on this subject based on the ideXlab platform.
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Generalized progressive retinal atrophy of Sloughi Dogs is due to an 8-bp insertion in exon 21 of the PDE6B gene
Cytogenetics and cell genetics, 2000Co-Authors: Gabriele Dekomien, Maren Runte, René Gödde, Jörg T. EpplenAbstract:We investigated the gene encoding the β subunit of cGMP phosphodiesterase (PDE6B) as a candidate for generalized progressive retinal atrophy (gPRA), an autosomal recessively transmitted eye disease in Dogs. The PDE6B gene was isolated from a genomic library. Single-strand conformation polymorphism analysis revealed eight intronic variations in different subsets of the 14 Dog breeds investigated. In addition, we identified an 8-bp insertion after codon 816 in certain Sloughi Dogs. Analysis of PRA-affected and obligatory carrier Sloughis showed that this mutation cosegregates with disease status in a large pedigree. All other exchanges identified were not located in functionally relevant parts of the gene (e.g., in the splice signal consensus sites). In most Dog breeds (Labrador retriever, Tibetan mastiff, dachshund, Tibetan terrier, miniature poodle, Australian Cattle Dog, cocker spaniel, collie, Saarloos wolfhound, Chesapeake Bay retriever, and Yorkshire terrier), PDE6B was excluded as a candidate gene for gPRA because heterozygous allele constellations were detected in diseased animals. Therefore, the PDE6B sequence variations did not segregate together with the mutation(s) causing gPRA. Direct and indirect DNA tests concerning gPRA can be offered now for a variety of different Dog breeds.
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evaluation of rds peripherin and rom1 as candidate genes in generalised progressive retinal atrophy and exclusion of digenic inheritance
Animal Genetics, 2000Co-Authors: Maren Runte, Gabriele Dekomien, Jörg T. EpplenAbstract:Summary Generalised progressive retinal atrophy (gPRA) is a heterogeneous group of hereditary diseases causing degeneration of the retina in Dogs and cats. As a combination of mutations in theRDS/Peripherin and the ROM1 genes leads to the phenotype of retinitis pigmentosa in man we first performed mutation analysis to screen these genes for disease causing mutations followed by the investigation of a digenic inheritance in Dogs. We cloned the RDS/Peripherin gene and investigated the RDS/Peripherin and ROM1 genes for disease causing mutations in 13 gPRA-affected Dog breeds including healthy animals, obligate gPRA carriers and gPRA-affected Dogs. We screened for mutations using single strand conformation polymorphism (SSCP) analysis. Sequence analysis revealed several sequence variations. In the coding region of the RDS/Peripherin gene three nucleotide exchanges were identified (A277C; C316T; G1255A), one of which leads to an amino acid substitution (Ala339Thr). Various silent sequence variations were found in the coding region of the ROM1 gene (A536G, G1006A, T1018C, T1111C, C1150T, C1195T), as well as an amino acid substitution (G252T; Ala54Ser). By excluding the respective gene as a cause for gPRA several sequence variations in the intronic regions were investigated. None of these sequence variations cosegregated with autosomal recessively (ar) transmitted gPRA in 11 breeds. The candidate geneRDS/Peripherin obviously does not harbour the critical mutation causing the autosomal recessive form of gPRA because diseased individuals show heterozygous genotypes for sequence variations in the Miniature Poodle, Dachshund, Australian Cattle Dog, Cocker Spaniel, Chesapeake Bay Retriever, Entlebucher Sennenhund, Sloughi, Yorkshire Terrier, Tibet Mastiff, Tibet Terrier and Labrador Retriever breeds. In the following breeds the ROM1 gene was also excluded indirectly for gPRA: Miniature Poodle, Dachshund, Australian Cattle Dog, Sloughi, Collie, Tibet Terrier, Labrador Retriever and Saarloos/Wolfhound. Digenic inheritance for gPRA is practically excluded for both these genes in four breeds: Miniature Poodle, Dachshund, Labrador Retriever and Saarloos/Wolfhound.
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Evaluation of RDS/Peripherin and ROM1 as candidate genes in generalised progressive retinal atrophy and exclusion of digenic inheritance
Animal genetics, 2000Co-Authors: Maren Runte, Gabriele Dekomien, Jörg T. EpplenAbstract:Summary Generalised progressive retinal atrophy (gPRA) is a heterogeneous group of hereditary diseases causing degeneration of the retina in Dogs and cats. As a combination of mutations in theRDS/Peripherin and the ROM1 genes leads to the phenotype of retinitis pigmentosa in man we first performed mutation analysis to screen these genes for disease causing mutations followed by the investigation of a digenic inheritance in Dogs. We cloned the RDS/Peripherin gene and investigated the RDS/Peripherin and ROM1 genes for disease causing mutations in 13 gPRA-affected Dog breeds including healthy animals, obligate gPRA carriers and gPRA-affected Dogs. We screened for mutations using single strand conformation polymorphism (SSCP) analysis. Sequence analysis revealed several sequence variations. In the coding region of the RDS/Peripherin gene three nucleotide exchanges were identified (A277C; C316T; G1255A), one of which leads to an amino acid substitution (Ala339Thr). Various silent sequence variations were found in the coding region of the ROM1 gene (A536G, G1006A, T1018C, T1111C, C1150T, C1195T), as well as an amino acid substitution (G252T; Ala54Ser). By excluding the respective gene as a cause for gPRA several sequence variations in the intronic regions were investigated. None of these sequence variations cosegregated with autosomal recessively (ar) transmitted gPRA in 11 breeds. The candidate geneRDS/Peripherin obviously does not harbour the critical mutation causing the autosomal recessive form of gPRA because diseased individuals show heterozygous genotypes for sequence variations in the Miniature Poodle, Dachshund, Australian Cattle Dog, Cocker Spaniel, Chesapeake Bay Retriever, Entlebucher Sennenhund, Sloughi, Yorkshire Terrier, Tibet Mastiff, Tibet Terrier and Labrador Retriever breeds. In the following breeds the ROM1 gene was also excluded indirectly for gPRA: Miniature Poodle, Dachshund, Australian Cattle Dog, Sloughi, Collie, Tibet Terrier, Labrador Retriever and Saarloos/Wolfhound. Digenic inheritance for gPRA is practically excluded for both these genes in four breeds: Miniature Poodle, Dachshund, Labrador Retriever and Saarloos/Wolfhound.
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Exclusion of the PDE6A gene for generalised progressive retinal atrophy in 11 breeds of Dog.
Animal genetics, 2000Co-Authors: Gabriele Dekomien, Jörg T. EpplenAbstract:The cyclic guanosine monophosphate specific phosphodiesterase (cGMP-specific PDE) is a key enzyme in the phototransduction cascade of the vertebrate retina. This enzyme consists of two catalytic alpha and beta subunits, two identical inhibitory gamma subunits as well as a delta subunit. Mutations in PDE6A and the PDE6B genes lead to autosomal recessive (ar) forms of retinitis pigmentosa (RP) in human and to the homologous disease in Dogs, designated generalised progressive retinal atrophy (gPRA). We investigated the PDE6A gene in 13 gPRA-affected Dog breeds including healthy animals, obligate gPRA carriers and gPRA-affected Dogs. In the coding region of PDE6A only a rare sequence variation (G103A; Asp35Asn) was found in exon 1 of two healthy Tibet Terriers and one affected Cocker Spaniel. Using single-stranded conformation polymorphism (SSCP) analyses we detected several sequence variations in eight of the PDE6A introns in different investigated breeds. Most informative for excluding the PDE6A gene as a cause for gPRA was a polymorphic microsatellite ((GT)10CG(GT)2CG(GT)12) in intron 14 and four sequence variations in intron 18 for almost all breeds investigated. The sequence variations of PDE6A did not segregate together with gPRA in 11 breeds. Since diseased animals were heterozygous for the polymorphisms, the PDE6A gene is unlikely to harbour the critical mutation causing gPRA in the following breeds: Chesapeake Bay Retriever. Entlebucher Sennenhund, Labrador Retriever. Tibet Mastiff, Dachshund (long- and wire-haired), Tibetan Terrier, Miniature Poodle. Australian Cattle Dog, Cocker Spaniel, Saarloos/Wolfshound, Sloughi.
Gabriele Dekomien - One of the best experts on this subject based on the ideXlab platform.
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Generalized progressive retinal atrophy of Sloughi Dogs is due to an 8-bp insertion in exon 21 of the PDE6B gene
Cytogenetics and cell genetics, 2000Co-Authors: Gabriele Dekomien, Maren Runte, René Gödde, Jörg T. EpplenAbstract:We investigated the gene encoding the β subunit of cGMP phosphodiesterase (PDE6B) as a candidate for generalized progressive retinal atrophy (gPRA), an autosomal recessively transmitted eye disease in Dogs. The PDE6B gene was isolated from a genomic library. Single-strand conformation polymorphism analysis revealed eight intronic variations in different subsets of the 14 Dog breeds investigated. In addition, we identified an 8-bp insertion after codon 816 in certain Sloughi Dogs. Analysis of PRA-affected and obligatory carrier Sloughis showed that this mutation cosegregates with disease status in a large pedigree. All other exchanges identified were not located in functionally relevant parts of the gene (e.g., in the splice signal consensus sites). In most Dog breeds (Labrador retriever, Tibetan mastiff, dachshund, Tibetan terrier, miniature poodle, Australian Cattle Dog, cocker spaniel, collie, Saarloos wolfhound, Chesapeake Bay retriever, and Yorkshire terrier), PDE6B was excluded as a candidate gene for gPRA because heterozygous allele constellations were detected in diseased animals. Therefore, the PDE6B sequence variations did not segregate together with the mutation(s) causing gPRA. Direct and indirect DNA tests concerning gPRA can be offered now for a variety of different Dog breeds.
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evaluation of rds peripherin and rom1 as candidate genes in generalised progressive retinal atrophy and exclusion of digenic inheritance
Animal Genetics, 2000Co-Authors: Maren Runte, Gabriele Dekomien, Jörg T. EpplenAbstract:Summary Generalised progressive retinal atrophy (gPRA) is a heterogeneous group of hereditary diseases causing degeneration of the retina in Dogs and cats. As a combination of mutations in theRDS/Peripherin and the ROM1 genes leads to the phenotype of retinitis pigmentosa in man we first performed mutation analysis to screen these genes for disease causing mutations followed by the investigation of a digenic inheritance in Dogs. We cloned the RDS/Peripherin gene and investigated the RDS/Peripherin and ROM1 genes for disease causing mutations in 13 gPRA-affected Dog breeds including healthy animals, obligate gPRA carriers and gPRA-affected Dogs. We screened for mutations using single strand conformation polymorphism (SSCP) analysis. Sequence analysis revealed several sequence variations. In the coding region of the RDS/Peripherin gene three nucleotide exchanges were identified (A277C; C316T; G1255A), one of which leads to an amino acid substitution (Ala339Thr). Various silent sequence variations were found in the coding region of the ROM1 gene (A536G, G1006A, T1018C, T1111C, C1150T, C1195T), as well as an amino acid substitution (G252T; Ala54Ser). By excluding the respective gene as a cause for gPRA several sequence variations in the intronic regions were investigated. None of these sequence variations cosegregated with autosomal recessively (ar) transmitted gPRA in 11 breeds. The candidate geneRDS/Peripherin obviously does not harbour the critical mutation causing the autosomal recessive form of gPRA because diseased individuals show heterozygous genotypes for sequence variations in the Miniature Poodle, Dachshund, Australian Cattle Dog, Cocker Spaniel, Chesapeake Bay Retriever, Entlebucher Sennenhund, Sloughi, Yorkshire Terrier, Tibet Mastiff, Tibet Terrier and Labrador Retriever breeds. In the following breeds the ROM1 gene was also excluded indirectly for gPRA: Miniature Poodle, Dachshund, Australian Cattle Dog, Sloughi, Collie, Tibet Terrier, Labrador Retriever and Saarloos/Wolfhound. Digenic inheritance for gPRA is practically excluded for both these genes in four breeds: Miniature Poodle, Dachshund, Labrador Retriever and Saarloos/Wolfhound.
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Evaluation of RDS/Peripherin and ROM1 as candidate genes in generalised progressive retinal atrophy and exclusion of digenic inheritance
Animal genetics, 2000Co-Authors: Maren Runte, Gabriele Dekomien, Jörg T. EpplenAbstract:Summary Generalised progressive retinal atrophy (gPRA) is a heterogeneous group of hereditary diseases causing degeneration of the retina in Dogs and cats. As a combination of mutations in theRDS/Peripherin and the ROM1 genes leads to the phenotype of retinitis pigmentosa in man we first performed mutation analysis to screen these genes for disease causing mutations followed by the investigation of a digenic inheritance in Dogs. We cloned the RDS/Peripherin gene and investigated the RDS/Peripherin and ROM1 genes for disease causing mutations in 13 gPRA-affected Dog breeds including healthy animals, obligate gPRA carriers and gPRA-affected Dogs. We screened for mutations using single strand conformation polymorphism (SSCP) analysis. Sequence analysis revealed several sequence variations. In the coding region of the RDS/Peripherin gene three nucleotide exchanges were identified (A277C; C316T; G1255A), one of which leads to an amino acid substitution (Ala339Thr). Various silent sequence variations were found in the coding region of the ROM1 gene (A536G, G1006A, T1018C, T1111C, C1150T, C1195T), as well as an amino acid substitution (G252T; Ala54Ser). By excluding the respective gene as a cause for gPRA several sequence variations in the intronic regions were investigated. None of these sequence variations cosegregated with autosomal recessively (ar) transmitted gPRA in 11 breeds. The candidate geneRDS/Peripherin obviously does not harbour the critical mutation causing the autosomal recessive form of gPRA because diseased individuals show heterozygous genotypes for sequence variations in the Miniature Poodle, Dachshund, Australian Cattle Dog, Cocker Spaniel, Chesapeake Bay Retriever, Entlebucher Sennenhund, Sloughi, Yorkshire Terrier, Tibet Mastiff, Tibet Terrier and Labrador Retriever breeds. In the following breeds the ROM1 gene was also excluded indirectly for gPRA: Miniature Poodle, Dachshund, Australian Cattle Dog, Sloughi, Collie, Tibet Terrier, Labrador Retriever and Saarloos/Wolfhound. Digenic inheritance for gPRA is practically excluded for both these genes in four breeds: Miniature Poodle, Dachshund, Labrador Retriever and Saarloos/Wolfhound.
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Exclusion of the PDE6A gene for generalised progressive retinal atrophy in 11 breeds of Dog.
Animal genetics, 2000Co-Authors: Gabriele Dekomien, Jörg T. EpplenAbstract:The cyclic guanosine monophosphate specific phosphodiesterase (cGMP-specific PDE) is a key enzyme in the phototransduction cascade of the vertebrate retina. This enzyme consists of two catalytic alpha and beta subunits, two identical inhibitory gamma subunits as well as a delta subunit. Mutations in PDE6A and the PDE6B genes lead to autosomal recessive (ar) forms of retinitis pigmentosa (RP) in human and to the homologous disease in Dogs, designated generalised progressive retinal atrophy (gPRA). We investigated the PDE6A gene in 13 gPRA-affected Dog breeds including healthy animals, obligate gPRA carriers and gPRA-affected Dogs. In the coding region of PDE6A only a rare sequence variation (G103A; Asp35Asn) was found in exon 1 of two healthy Tibet Terriers and one affected Cocker Spaniel. Using single-stranded conformation polymorphism (SSCP) analyses we detected several sequence variations in eight of the PDE6A introns in different investigated breeds. Most informative for excluding the PDE6A gene as a cause for gPRA was a polymorphic microsatellite ((GT)10CG(GT)2CG(GT)12) in intron 14 and four sequence variations in intron 18 for almost all breeds investigated. The sequence variations of PDE6A did not segregate together with gPRA in 11 breeds. Since diseased animals were heterozygous for the polymorphisms, the PDE6A gene is unlikely to harbour the critical mutation causing gPRA in the following breeds: Chesapeake Bay Retriever. Entlebucher Sennenhund, Labrador Retriever. Tibet Mastiff, Dachshund (long- and wire-haired), Tibetan Terrier, Miniature Poodle. Australian Cattle Dog, Cocker Spaniel, Saarloos/Wolfshound, Sloughi.
Maren Runte - One of the best experts on this subject based on the ideXlab platform.
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Generalized progressive retinal atrophy of Sloughi Dogs is due to an 8-bp insertion in exon 21 of the PDE6B gene
Cytogenetics and cell genetics, 2000Co-Authors: Gabriele Dekomien, Maren Runte, René Gödde, Jörg T. EpplenAbstract:We investigated the gene encoding the β subunit of cGMP phosphodiesterase (PDE6B) as a candidate for generalized progressive retinal atrophy (gPRA), an autosomal recessively transmitted eye disease in Dogs. The PDE6B gene was isolated from a genomic library. Single-strand conformation polymorphism analysis revealed eight intronic variations in different subsets of the 14 Dog breeds investigated. In addition, we identified an 8-bp insertion after codon 816 in certain Sloughi Dogs. Analysis of PRA-affected and obligatory carrier Sloughis showed that this mutation cosegregates with disease status in a large pedigree. All other exchanges identified were not located in functionally relevant parts of the gene (e.g., in the splice signal consensus sites). In most Dog breeds (Labrador retriever, Tibetan mastiff, dachshund, Tibetan terrier, miniature poodle, Australian Cattle Dog, cocker spaniel, collie, Saarloos wolfhound, Chesapeake Bay retriever, and Yorkshire terrier), PDE6B was excluded as a candidate gene for gPRA because heterozygous allele constellations were detected in diseased animals. Therefore, the PDE6B sequence variations did not segregate together with the mutation(s) causing gPRA. Direct and indirect DNA tests concerning gPRA can be offered now for a variety of different Dog breeds.
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evaluation of rds peripherin and rom1 as candidate genes in generalised progressive retinal atrophy and exclusion of digenic inheritance
Animal Genetics, 2000Co-Authors: Maren Runte, Gabriele Dekomien, Jörg T. EpplenAbstract:Summary Generalised progressive retinal atrophy (gPRA) is a heterogeneous group of hereditary diseases causing degeneration of the retina in Dogs and cats. As a combination of mutations in theRDS/Peripherin and the ROM1 genes leads to the phenotype of retinitis pigmentosa in man we first performed mutation analysis to screen these genes for disease causing mutations followed by the investigation of a digenic inheritance in Dogs. We cloned the RDS/Peripherin gene and investigated the RDS/Peripherin and ROM1 genes for disease causing mutations in 13 gPRA-affected Dog breeds including healthy animals, obligate gPRA carriers and gPRA-affected Dogs. We screened for mutations using single strand conformation polymorphism (SSCP) analysis. Sequence analysis revealed several sequence variations. In the coding region of the RDS/Peripherin gene three nucleotide exchanges were identified (A277C; C316T; G1255A), one of which leads to an amino acid substitution (Ala339Thr). Various silent sequence variations were found in the coding region of the ROM1 gene (A536G, G1006A, T1018C, T1111C, C1150T, C1195T), as well as an amino acid substitution (G252T; Ala54Ser). By excluding the respective gene as a cause for gPRA several sequence variations in the intronic regions were investigated. None of these sequence variations cosegregated with autosomal recessively (ar) transmitted gPRA in 11 breeds. The candidate geneRDS/Peripherin obviously does not harbour the critical mutation causing the autosomal recessive form of gPRA because diseased individuals show heterozygous genotypes for sequence variations in the Miniature Poodle, Dachshund, Australian Cattle Dog, Cocker Spaniel, Chesapeake Bay Retriever, Entlebucher Sennenhund, Sloughi, Yorkshire Terrier, Tibet Mastiff, Tibet Terrier and Labrador Retriever breeds. In the following breeds the ROM1 gene was also excluded indirectly for gPRA: Miniature Poodle, Dachshund, Australian Cattle Dog, Sloughi, Collie, Tibet Terrier, Labrador Retriever and Saarloos/Wolfhound. Digenic inheritance for gPRA is practically excluded for both these genes in four breeds: Miniature Poodle, Dachshund, Labrador Retriever and Saarloos/Wolfhound.
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Evaluation of RDS/Peripherin and ROM1 as candidate genes in generalised progressive retinal atrophy and exclusion of digenic inheritance
Animal genetics, 2000Co-Authors: Maren Runte, Gabriele Dekomien, Jörg T. EpplenAbstract:Summary Generalised progressive retinal atrophy (gPRA) is a heterogeneous group of hereditary diseases causing degeneration of the retina in Dogs and cats. As a combination of mutations in theRDS/Peripherin and the ROM1 genes leads to the phenotype of retinitis pigmentosa in man we first performed mutation analysis to screen these genes for disease causing mutations followed by the investigation of a digenic inheritance in Dogs. We cloned the RDS/Peripherin gene and investigated the RDS/Peripherin and ROM1 genes for disease causing mutations in 13 gPRA-affected Dog breeds including healthy animals, obligate gPRA carriers and gPRA-affected Dogs. We screened for mutations using single strand conformation polymorphism (SSCP) analysis. Sequence analysis revealed several sequence variations. In the coding region of the RDS/Peripherin gene three nucleotide exchanges were identified (A277C; C316T; G1255A), one of which leads to an amino acid substitution (Ala339Thr). Various silent sequence variations were found in the coding region of the ROM1 gene (A536G, G1006A, T1018C, T1111C, C1150T, C1195T), as well as an amino acid substitution (G252T; Ala54Ser). By excluding the respective gene as a cause for gPRA several sequence variations in the intronic regions were investigated. None of these sequence variations cosegregated with autosomal recessively (ar) transmitted gPRA in 11 breeds. The candidate geneRDS/Peripherin obviously does not harbour the critical mutation causing the autosomal recessive form of gPRA because diseased individuals show heterozygous genotypes for sequence variations in the Miniature Poodle, Dachshund, Australian Cattle Dog, Cocker Spaniel, Chesapeake Bay Retriever, Entlebucher Sennenhund, Sloughi, Yorkshire Terrier, Tibet Mastiff, Tibet Terrier and Labrador Retriever breeds. In the following breeds the ROM1 gene was also excluded indirectly for gPRA: Miniature Poodle, Dachshund, Australian Cattle Dog, Sloughi, Collie, Tibet Terrier, Labrador Retriever and Saarloos/Wolfhound. Digenic inheritance for gPRA is practically excluded for both these genes in four breeds: Miniature Poodle, Dachshund, Labrador Retriever and Saarloos/Wolfhound.
Martin L. Katz - One of the best experts on this subject based on the ideXlab platform.
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Neuronal ceroid lipofuscinosis in a German Shorthaired Pointer associated with a previously reported CLN8 nonsense variant
Molecular genetics and metabolism reports, 2019Co-Authors: Juyuan Guo, Gary S. Johnson, Tendai Mhlanga-mutangadura, Robert D. Schnabel, James L. Cook, Olivia K. Harris, Cheryl A. Jensen, Martin L. KatzAbstract:Abstract Two littermate German Shorthaired Pointers, a male and a female, were adopted as puppies from an animal shelter. Both puppies developed normally until approximately 11 months of age when the male began to exhibit neurological signs including ataxia, vision loss, and behavioral changes indicative of cognitive decline. These signs increased in severity over time. The female remained neurologically normal and healthy. The affected Dog was euthanized at approximately 21 months of age. Autofluorescent cytoplasmic storage bodies were detected in neurons in unstained tissue sections from the cerebellum, the cerebrum, and the retina. Electron micrographs of these storage bodies showed that they were membrane bound and that most contained tightly packed aggregates of membranous whorls along with a variety of other ultrastructural features. This ultrastructure, along with the autofluorescence and the clinical signs supported a diagnosis of neuronal ceroid lipofuscinosis (NCL). Unlike earlier investigated forms of canine NCL with causal alleles in ATP13A2, TPP1, MFSD8 and CLN5 that had autofluorescent cytoplasmic storage bodies in cardiac muscle, no autofluorescence was detected in cardiac muscle from the affected German Shorthaired Pointer. A 39-fold average coverage whole genome sequence indicated that the affected German Shorthaired Pointer was homozygous for the A allele of a G > A transversion at position 30,895,648 chromosome 37. This 37:30895648G > A mutation created a CLN8 termination codon that had been previously reported to cause NCL in a mixed breed Dog with Australian Shepherd and Australian Cattle Dog ancestry. This nonsense allele was heterozygous in the clinically normal female sibling, while archived DNA samples from 512 other German Shorthaired Pointers were all homozygous for the reference allele. The affected German Shorthaired Pointer and the previously diagnosed mixed breed Dog with the same nonsense mutation shaired an identical homozygous haplotype that extended for 4.41 Mb at the telomeric end of chromosome 37, indicating the both Dogs inherited the nonsense mutation from a common ancestor.
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A mixed breed Dog with neuronal ceroid lipofuscinosis is homozygous for a CLN5 nonsense mutation previously identified in Border Collies and Australian Cattle Dogs.
Molecular genetics and metabolism, 2019Co-Authors: Natalie A. Villani, Gary S. Johnson, Dennis P. O'brien, Tendai Mhlanga-mutangadura, Garrett Bullock, Jennifer R. Michaels, Osamu Yamato, Martin L. KatzAbstract:Abstract The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders characterized by progressive declines in neurological functions following normal development. The NCLs are distinguished from similar disorders by the accumulation of autofluorescent lysosomal storage bodies in neurons and many other cell types, and are classified as lysosomal storage diseases. At least 13 genes contain pathogenic sequence variants that underlie different forms of NCL. Naturally occurring canine NCLs can serve as models to develop better understanding of the disease pathologies and for preclinical evaluation of therapeutic interventions for these disorders. To date 14 sequence variants in 8 canine orthologs of human NCL genes have been found to cause progressive neurological disorders similar to human NCLs in 12 different Dog breeds. A mixed breed Dog with parents of uncertain breed background developed progressive neurological signs consistent with NCL starting at approximately 11 to 12 months of age, and when evaluated with magnetic resonance imaging at 21 months of age exhibited diffuse brain atrophy. Due to the severity of neurological decline the Dog was euthanized at 23 months of age. Cerebellar and cerebral cortical neurons contained massive accumulations of autofluorescent storage bodies the contents of which had the appearance of tightly packed membranes. A whole genome sequence, generated with DNA from the affected Dog contained a homozygous C-to-T transition at position 30,574,637 on chromosome 22 which is reflected in the mature CLN5 transcript (CLN5: c.619C > T) and converts a glutamine codon to a termination codon (p.Gln207Ter). The identical nonsense mutation has been previously associated with NCL in Border Collies, Australian Cattle Dogs, and a German Shepherd-Australian Cattle Dog mix. The current whole genome sequence and a previously generated whole genome sequence for an Australian Cattle Dog with NCL share a rare homozygous haplotype that extends for 87 kb surrounding 22: 30, 574, 637 and includes 21 polymorphic sites. When genotyped at 7 of these polymorphic sites, DNA samples from the German Shepherd-Australian Cattle Dog mix and from 5 Border Collies with NCL that were homozygous for the CLN5: c.619 T allele also shared this homozygous haplotype, suggesting that the NCL in all of these Dogs stems from the same founding mutation event that may have predated the establishment of the modern Dog breeds. If so, the CLN5 nonsence allele is probably segregating in other, as yet unidentified, breeds. Thus, Dogs exhibiting similar NCL-like signs should be screened for this CLN5 nonsense allele regardless of breed.
Tendai Mhlanga-mutangadura - One of the best experts on this subject based on the ideXlab platform.
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Neuronal ceroid lipofuscinosis in a German Shorthaired Pointer associated with a previously reported CLN8 nonsense variant
Molecular genetics and metabolism reports, 2019Co-Authors: Juyuan Guo, Gary S. Johnson, Tendai Mhlanga-mutangadura, Robert D. Schnabel, James L. Cook, Olivia K. Harris, Cheryl A. Jensen, Martin L. KatzAbstract:Abstract Two littermate German Shorthaired Pointers, a male and a female, were adopted as puppies from an animal shelter. Both puppies developed normally until approximately 11 months of age when the male began to exhibit neurological signs including ataxia, vision loss, and behavioral changes indicative of cognitive decline. These signs increased in severity over time. The female remained neurologically normal and healthy. The affected Dog was euthanized at approximately 21 months of age. Autofluorescent cytoplasmic storage bodies were detected in neurons in unstained tissue sections from the cerebellum, the cerebrum, and the retina. Electron micrographs of these storage bodies showed that they were membrane bound and that most contained tightly packed aggregates of membranous whorls along with a variety of other ultrastructural features. This ultrastructure, along with the autofluorescence and the clinical signs supported a diagnosis of neuronal ceroid lipofuscinosis (NCL). Unlike earlier investigated forms of canine NCL with causal alleles in ATP13A2, TPP1, MFSD8 and CLN5 that had autofluorescent cytoplasmic storage bodies in cardiac muscle, no autofluorescence was detected in cardiac muscle from the affected German Shorthaired Pointer. A 39-fold average coverage whole genome sequence indicated that the affected German Shorthaired Pointer was homozygous for the A allele of a G > A transversion at position 30,895,648 chromosome 37. This 37:30895648G > A mutation created a CLN8 termination codon that had been previously reported to cause NCL in a mixed breed Dog with Australian Shepherd and Australian Cattle Dog ancestry. This nonsense allele was heterozygous in the clinically normal female sibling, while archived DNA samples from 512 other German Shorthaired Pointers were all homozygous for the reference allele. The affected German Shorthaired Pointer and the previously diagnosed mixed breed Dog with the same nonsense mutation shaired an identical homozygous haplotype that extended for 4.41 Mb at the telomeric end of chromosome 37, indicating the both Dogs inherited the nonsense mutation from a common ancestor.
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A mixed breed Dog with neuronal ceroid lipofuscinosis is homozygous for a CLN5 nonsense mutation previously identified in Border Collies and Australian Cattle Dogs.
Molecular genetics and metabolism, 2019Co-Authors: Natalie A. Villani, Gary S. Johnson, Dennis P. O'brien, Tendai Mhlanga-mutangadura, Garrett Bullock, Jennifer R. Michaels, Osamu Yamato, Martin L. KatzAbstract:Abstract The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders characterized by progressive declines in neurological functions following normal development. The NCLs are distinguished from similar disorders by the accumulation of autofluorescent lysosomal storage bodies in neurons and many other cell types, and are classified as lysosomal storage diseases. At least 13 genes contain pathogenic sequence variants that underlie different forms of NCL. Naturally occurring canine NCLs can serve as models to develop better understanding of the disease pathologies and for preclinical evaluation of therapeutic interventions for these disorders. To date 14 sequence variants in 8 canine orthologs of human NCL genes have been found to cause progressive neurological disorders similar to human NCLs in 12 different Dog breeds. A mixed breed Dog with parents of uncertain breed background developed progressive neurological signs consistent with NCL starting at approximately 11 to 12 months of age, and when evaluated with magnetic resonance imaging at 21 months of age exhibited diffuse brain atrophy. Due to the severity of neurological decline the Dog was euthanized at 23 months of age. Cerebellar and cerebral cortical neurons contained massive accumulations of autofluorescent storage bodies the contents of which had the appearance of tightly packed membranes. A whole genome sequence, generated with DNA from the affected Dog contained a homozygous C-to-T transition at position 30,574,637 on chromosome 22 which is reflected in the mature CLN5 transcript (CLN5: c.619C > T) and converts a glutamine codon to a termination codon (p.Gln207Ter). The identical nonsense mutation has been previously associated with NCL in Border Collies, Australian Cattle Dogs, and a German Shepherd-Australian Cattle Dog mix. The current whole genome sequence and a previously generated whole genome sequence for an Australian Cattle Dog with NCL share a rare homozygous haplotype that extends for 87 kb surrounding 22: 30, 574, 637 and includes 21 polymorphic sites. When genotyped at 7 of these polymorphic sites, DNA samples from the German Shepherd-Australian Cattle Dog mix and from 5 Border Collies with NCL that were homozygous for the CLN5: c.619 T allele also shared this homozygous haplotype, suggesting that the NCL in all of these Dogs stems from the same founding mutation event that may have predated the establishment of the modern Dog breeds. If so, the CLN5 nonsence allele is probably segregating in other, as yet unidentified, breeds. Thus, Dogs exhibiting similar NCL-like signs should be screened for this CLN5 nonsense allele regardless of breed.
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Australian Cattle Dogs with Neuronal Ceroid Lipofuscinosis are Homozygous for a CLN5 Nonsense Mutation Previously Identified in Border Collies
Journal of veterinary internal medicine, 2016Co-Authors: A. Kolicheski, Gary S. Johnson, Dennis P. O'brien, Tendai Mhlanga-mutangadura, D. Gilliam, Juyuan Guo, T.d. Anderson‐sieg, Robert D. Schnabel, Jeremy F. Taylor, A. LebowitzAbstract:Background Neuronal ceroid lipofuscinosis (NCL), a fatal neurodegenerative disease, has been diagnosed in young adult Australian Cattle Dogs. Objective Characterize the Australian Cattle Dog form of NCL and determine its molecular genetic cause. Animals Tissues from 4 Australian Cattle Dogs with NCL-like signs and buccal swabs from both parents of a fifth affected breed member. Archived DNA samples from 712 individual Dogs were genotyped. Methods Tissues were examined by fluorescence, electron, and immunohistochemical microscopy. A whole-genome sequence was generated for 1 affected Dog. A TaqMan allelic discrimination assay was used for genotyping. Results The accumulation of autofluorescent cytoplasmic storage material with characteristic ultrastructure in tissues from the 4 affected Dogs supported a diagnosis of NCL. The whole-genome sequence contained a homozygous nonsense mutation: CLN5:c.619C>T. All 4 DNA samples from clinically affected Dogs tested homozygous for the variant allele. Both parents of the fifth affected Dog were heterozygotes. Archived DNA samples from 346 Australian Cattle Dogs, 188 Border Collies, and 177 Dogs of other breeds were homozygous for the reference allele. One archived Australian Cattle Dog sample was from a heterozygote. Conclusions and Clinical Importance The homozygous CLN5 nonsense is almost certainly causal because the same mutation previously had been reported to cause a similar form of NCL in Border Collies. Identification of the molecular genetic cause of Australian Cattle Dog NCL will allow the use of DNA tests to confirm the diagnosis of NCL in this breed.
