Since its domestication, the dog has served in many roles, from protector, guide, hunter, and best friend, to model organism. Every role in which the dog serves is important; however, this work highlights the importance of the dog as a model organism for study of human hereditary diseases. Roughly half of the 450 hereditary diseases found in the dog have clinical presentations similar to those found in the human. Included in these are auditory-pigmentation conditions and skin diseases for which the dog is a working model. Described herein are studies of the merle coat pattern and dermatomyositis. Through research on these topics, important information can be obtained that can be used to help both the dog and the human. Merle is a pattern of coloring observed in the coat of the domestic dog and is characterized by patches of diluted pigment. Dogs heterozygous or homozygous for the merle locus exhibit a wide range of auditory and ophthalmologic abnormalities. Linkage disequilibrium was identified for a microsatellite marker with the merle phenotype in the Shetland Sheepdog. This region of the human genome contains SILV, a gene important in mammalian pigmentation. Therefore, this gene was evaluated as a candidate for merle patterning. A short interspersed element insertion at the boundary of intron 10/exon 11 was found, and this insertion segregates with the merle phenotype in multiple breeds. These data show that SILV is responsible for merle patterning and is associated with impaired function of the auditory and ophthalmologic systems. Dermatomyositis (DM) is an inflammatory disease of the skin and muscle that occurs most often in the rough collie and Shetland Sheepdog. Gene transcript profiles were generated for affected and normal skin using a canine-specific oligonucleotide array. Two-hundred and eight-five gene transcripts, many of which are involved in immune function, were found to be differentially regulated in these tissues. Also reported are western blot, immunohistochemistry, and immunofluorescence analyses. While our work suggests that canine DM is a disease that may be immune mediated, it did not detect the production of specific disease-associated autoantibodies.

Since its domestication, the dog has served in many roles, from protector, guide, hunter, and best friend, to model organism. Every role in which the dog serves is important; however, this work highlights the importance of the dog as a model organism for study of human hereditary diseases. Roughly half of the 450 hereditary diseases found in the dog have clinical presentations similar to those found in the human. Included in these are auditory-pigmentation conditions and skin diseases for which the dog is a working model. Described herein are studies of the merle coat pattern and dermatomyositis. Through research on these topics, important information can be obtained that can be used to help both the dog and the human. Merle is a pattern of coloring observed in the coat of the domestic dog and is characterized by patches of diluted pigment. Dogs heterozygous or homozygous for the merle locus exhibit a wide range of auditory and ophthalmologic abnormalities. Linkage disequilibrium was identified for a microsatellite marker with the merle phenotype in the Shetland Sheepdog. This region of the human genome contains SILV, a gene important in mammalian pigmentation. Therefore, this gene was evaluated as a candidate for merle patterning. A short interspersed element insertion at the boundary of intron 10/exon 11 was found, and this insertion segregates with the merle phenotype in multiple breeds. These data show that SILV is responsible for merle patterning and is associated with impaired function of the auditory and ophthalmologic systems. Dermatomyositis (DM) is an inflammatory disease of the skin and muscle that occurs most often in the rough collie and Shetland Sheepdog. Gene transcript profiles were generated for affected and normal skin using a canine-specific oligonucleotide array. Two-hundred and eight-five gene transcripts, many of which are involved in immune function, were found to be differentially regulated in these tissues. Also reported are western blot, immunohistochemistry, and immunofluorescence analyses. While our work suggests that canine DM is a disease that may be immune mediated, it did not detect the production of specific disease-associated autoantibodies.

Although typically thought of as a beloved companion or indispensable aide, the domestic dog (Canis lupus familiaris) has emerged as an excellent model for the study of human hereditary diseases. Many hereditary diseases of the dog have nearly identical clinical presentations as those of the human and are, most often, caused by mutations in the same genes. One such disease is hereditary nephropathy; an inherited glomerular disease in the domestic dog that is similar to Alport syndrome of the human. Both diseases are caused by mutations in the type IV collagens genes, and the disease has nearly identical pathology and clinical presentations in the dog and human. By studying this disease in the dog, our laboratory hopes to increase understanding of the disease so that information that can be applied to both the human and the dog. Reported here is 1) the development of a genomic based test to determine genotypes of mixed breed dogs in a colony presenting with X-linked hereditary nephropathy, 2) the determination of patterns of X-chromosome inactivation in normal dogs and dogs that are carriers of Xlinked hereditary nephropathy, 3) the design of a synthetic COL4A5 cDNA to be used for gene therapy treatment of dogs with X-linked hereditary nephropathy, 4) the investigation of type IV collagen gene expression changes in normal dogs and those affected with X-linked and autosomal recessive hereditary nephropathy, and 5) the discovery of the mutation causative for autosomal recessive hereditary nephropathy in the English Cocker Spaniel. Utilization of the colony of dogs affected with X-linked hereditary nephropathy (for which the causative mutation was previously identified) allowed for comparisons of type IV collagen gene expression to English Cocker Spaniels with autosomal recessive hereditary nephropathy. These data were critical to identification of the gene harboring the causative mutation for autosomal recessive hereditary nephropathy. Sequencing was performed to identify the mutation. With the ability to test for carriers of this disease, it is our hope that breeders will use it to to maintain the desired traits in the ECS while simultaneously eliminating the production of affected offspring.

Although typically thought of as a beloved companion or indispensable aide, the domestic dog (Canis lupus familiaris) has emerged as an excellent model for the study of human hereditary diseases. Many hereditary diseases of the dog have nearly identical clinical presentations as those of the human and are, most often, caused by mutations in the same genes. One such disease is hereditary nephropathy; an inherited glomerular disease in the domestic dog that is similar to Alport syndrome of the human. Both diseases are caused by mutations in the type IV collagens genes, and the disease has nearly identical pathology and clinical presentations in the dog and human. By studying this disease in the dog, our laboratory hopes to increase understanding of the disease so that information that can be applied to both the human and the dog. Reported here is 1) the development of a genomic based test to determine genotypes of mixed breed dogs in a colony presenting with X-linked hereditary nephropathy, 2) the determination of patterns of X-chromosome inactivation in normal dogs and dogs that are carriers of X-linked hereditary nephropathy, 3) the design of a synthetic COL4A5 cDNA to be used for gene therapy treatment of dogs with X-linked hereditary nephropathy, 4) the investigation of type IV collagen gene expression changes in normal dogs and those affected with X-linked and autosomal recessive hereditary nephropathy, and 5) the discovery of the mutation causative for autosomal recessive hereditary nephropathy in the English Cocker Spaniel. Utilization of the colony of dogs affected with X-linked hereditary nephropathy (for which the causative mutation was previously identified) allowed for comparisons of type IV collagen gene expression to English Cocker Spaniels with autosomal recessive hereditary nephropathy. These data were critical to identification of the gene harboring the causative mutation for autosomal recessive hereditary nephropathy. Sequencing was performed to identify the mutation. With the ability to test for carriers of this disease, it is our hope that breeders will use it to to maintain the desired traits in the ECS while simultaneously eliminating the production of affected offspring.

The domestic dog, Canis lupus familiaris, has emerged as a model system for the study of human hereditary diseases. Of the approximately 450 hereditary diseases described in the dog, half have clinical presentations that are quite similar to specific human diseases. Understanding the genetic bases of canine hereditary diseases will not only complement comparative genetics studies but also facilitate selective breeding practices to reduce incidences in the dog. Whole genome screens have great potential to identify the marker(s) that segregate with canine hereditary diseases for which no reasonable candidate genes exist. The Minimal Screening Set-1 (MSS-1) was the first set of microsatellite markers described for linkage analysis in the dog and was, until recently, the best tool for genome screens. The MSS-2 is the most recently described screening set and offers increased density and more polymorphic markers. The first objective of this work was to develop tools to streamline genomic analyses in the study of canine hereditary diseases. This was achieved through the development of 1) multiplexing strategies for the MSS-1, 2) a multiplex of microsatellite markers for use in canine forensics and parentage assays and 3) chromosome-specific multiplex panels for the MSS-2. Multiplexing is the simultaneous amplification and analysis of markers and significantly reduces the expense and time required to collect genotype information. Pancreatic acinar atrophy (PAA) is a disease characterized by the degeneration of acinar cells of the exocrine pancreas and is the most important cause of exocrine pancreatic insufficiency (EPI) in the German Shepherd Dog (GSD). Although the prognosis for dogs having EPI is typically good with treatment, many dogs are euthanized because the owners are unable to afford the expensive enzyme supplements. The second objective of this work was to determine the mode of transmission of EPI in the GSD and conduct a whole genome screen for linkage. Two extended families of GSDs having PAA were assembled and used to determine the pattern of transmission. The results of this indicate that PAA is an autosomal recessive disease. The multiplexed MSS-1 was used to conduct an initial whole genome screen, although no markers were suggestive of linkage.

The domestic dog, Canis lupus familiaris, has emerged as a model system for the study of human hereditary diseases. Of the approximately 450 hereditary diseases described in the dog, half have clinical presentations that are quite similar to specific human diseases. Understanding the genetic bases of canine hereditary diseases will not only complement comparative genetics studies but also facilitate selective breeding practices to reduce incidences in the dog. Whole genome screens have great potential to identify the marker(s) that segregate with canine hereditary diseases for which no reasonable candidate genes exist. The Minimal Screening Set-1 (MSS-1) was the first set of microsatellite markers described for linkage analysis in the dog and was, until recently, the best tool for genome screens. The MSS-2 is the most recently described screening set and offers increased density and more polymorphic markers. The first objective of this work was to develop tools to streamline genomic analyses in the study of canine hereditary diseases. This was achieved through the development of 1) multiplexing strategies for the MSS-1, 2) a multiplex of microsatellite markers for use in canine forensics and parentage assays and 3) chromosome-specific multiplex panels for the MSS-2. Multiplexing is the simultaneous amplification and analysis of markers and significantly reduces the expense and time required to collect genotype information. Pancreatic acinar atrophy (PAA) is a disease characterized by the degeneration of acinar cells of the exocrine pancreas and is the most important cause of exocrine pancreatic insufficiency (EPI) in the German Shepherd Dog (GSD). Although the prognosis for dogs having EPI is typically good with treatment, many dogs are euthanized because the owners are unable to afford the expensive enzyme supplements. The second objective of this work was to determine the mode of transmission of EPI in the GSD and conduct a whole genome screen for linkage. Two extended families of GSDs having PAA were assembled and used to determine the pattern of transmission. The results of this indicate that PAA is an autosomal recessive disease. The multiplexed MSS-1 was used to conduct an initial whole genome screen, although no markers were suggestive of linkage.