Assignment of 10 canine genes to the canine linkage and comparative maps.
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Animals↗
Biomedical subjects
D F Patterson
Publications and source records attributed to D F Patterson.
Familial glomerulonephropathy in the Bullmastiff.
Glomerular disease was diagnosed by histopathologic examination in 11 related Bullmastiff dogs, and clinical and laboratory data were collected retrospectively. Four female and seven male dogs between the ages of 2.5 and 11 years were affected. Clinical signs, including lethargy and anorexia, were nonspecific and occurred shortly before death or euthanasia. In five affected dogs serial blood samples were obtained, and dramatically elevated blood urea nitrogen and creatinine levels were demonstrated up to 2.75 years before death. Protein-creatinine ratios were elevated in six of six dogs and were above normal 3.5 years before death in one dog. The kidneys appeared grossly normal to slightly smaller than normal at necropsy. Histologic abnormalities of the kidneys were consistent with chronic glomerulonephropathy with sclerosis. Examination of the pedigrees of related affected dogs yielded evidence supporting an autosomal recessive mode of inheritance.
Animals↗
An integrated linkage-radiation hybrid map of the canine genome.
Purebred dogs are a unique resource for dissecting the molecular basis of simple and complex genetic diseases and traits. As a result of strong selection for physical and behavioral characteristics among the 300 established breeds, modern dogs are characterized by high levels of interbreed variation, complemented by significant intrabreed homogeneity. A high-resolution map of the canine genome is necessary to exploit the mapping power of this unusual resource. We describe here the integration of an expanded canine radiation hybrid map, comprised of 600 markers, with the latest linkage map of 341 markers, to generate a map of 724 markers-the densest map of the canine genome described to date. Through the inclusion of 217 markers on both the linkage and RH maps, the 77 RH groups are reduced to 44 syntenic groups, thus providing comprehensive coverage of most of the canine genome.
Animals↗
Canine cystinuria: polymorphism in the canine SLC3A1 gene and identification of a nonsense mutation in cystinuric Newfoundland dogs.
Cystinuria is an inherited renal and intestinal disease characterized by defective amino acid reabsorption and cystine urolithiasis. Different forms of the disease, designated type I and non-type I in cystinuric humans, can be distinguished clinically and biochemically, and have been associated with mutations in the SLC3A1 (rBAT) and SLC7A9 genes, respectively. Type I cystinuria is the most common form and is inherited as an autosomal recessive trait in humans. Cystinuria has been recognized in more than 60 breeds of dogs and a severe form, resembling type I cystinuria, has been characterized in the Newfoundland breed. Here we report the cloning and sequencing of the canine SLC3A1 cDNA and gene, and the identification of a nonsense mutation in exon 2 of the gene in cystinuric Newfoundland dogs. A mutation-specific test was developed for the diagnosis and control of cystinuria in Newfoundland dogs. In cystinuric dogs of six other breeds, either heterozygosity at the SLC3A1 locus or lack of mutations in the coding region of the SLC3A1 gene were observed, indicating that cystinuria is genetically heterogeneous in dogs, as it is in humans. The canine homologue of human type I cystinuria provides the opportunity to use a large animal model to investigate molecular approaches for the treatment of cystinuria and other renal tubular diseases.
Amino Acid Sequence↗
Canine genetics comes of age.
The dog, as human's favored companion, is unique among animal species in providing new insights into human genetic disease. In this review, we will discuss both the breed and the population structure of dogs and why that makes canines amenable to genetic studies. We will review the current state of the map and discuss the particular disease states in which canines stand to make the greatest contribution to medical genetics.
Animals↗
A missense mutation in canine C1C-1 causes recessive myotonia congenita in the dog.
Myotonia congenita is an inherited disorder of sarcolemmal excitation leading to delayed relaxation of skeletal muscle following contractions. Mutations in a skeletal muscle voltage-dependent chloride channel, CIC-1, have been identified as the molecular genetic basis for the syndrome in humans, and in two well characterized animal models of the disease: the myotonic goat, and the arrested development of righting (adr) mouse. We now report the molecular genetic and electrophysiological characterization of a canine CIC-1 mutation that causes autosomal recessive myotonia congenita in miniature Schnauzers. The mutation results in replacement of a threonine residue in the D5 transmembrane segment with methionine. Functional characterization of the mutation introduced into a recombinant CIC-1 and heterologously expressed in a cultured mammalian cell line demonstrates a profound effect on the voltage-dependence of activation such that mutant channels have a greatly reduced open probability at voltages near the resting membrane potential of skeletal muscle. The degree of this dysfunction is greatly diminished when heterodimeric channels containing a wild-type and mutant subunit are expressed together as a covalent concatemer strongly supporting the observed recessive inheritance in affected dog pedigrees. Genetic and electrophysiological characterization of the myotonic dog provides a new and potentially valuable animal model of an inherited skeletal muscle disease that has advantages over existing models of myotonia congenita.
Amino Acid Sequence↗
Molecular basis of feline beta-glucuronidase deficiency: an animal model of mucopolysaccharidosis VII.
A family of domestic cats was found that exhibited clinical and biochemical abnormalities consistent with mucopolysaccharidosis VII, an autosomal recessive lysosomal storage disorder caused by beta-glucuronidase deficiency. beta-Glucuronidase activity was undetectable in affected cat fibroblasts and restored by retroviral gene transfer of rat beta-glucuronidase cDNA. beta-Glucuronidase mRNA was normal in affected cat testis by Northern blot analysis. Normal feline beta-glucuronidase cDNA was cloned and characterized, and amplified from affected cat fibroblasts by reverse transcription coupled polymerase chain reaction. There was a G-to-A transition in the affected cat cDNA that predicted an E351K substitution, destroyed a BssSI site, and eliminated GUSB enzymatic activity in expression studies. Multiple species comparison and the crystal structure of human beta-glucuronidase indicated that E351 is a highly conserved residue most likely essential in maintenance of the enzyme's conformation. BssSI digestion of polymerase chain reaction products amplified from genomic DNA indicated that affected cats were homozygous and cats with half-normal beta-glucuronidase activity were heterozygous for the missense mutation. Carriers identified in this manner produced affected kittens in prospective breedings, and a feline MPS VII breeding colony has been established.
Amino Acid Sequence↗
Retrovirus vector-mediated correction and cross-correction of lysosomal alpha-mannosidase deficiency in human and feline fibroblasts.
Lysosomal alpha-mannosidase (EC 3.2.1.24) is an exoglycosidase in the glycoprotein degradation pathway. A deficiency of this enzyme causes the lysosomal storage disease alpha-mannosidosis. Retrovirus vector transfer of a new human alpha-mannosidase cDNA resulted in high-level expression of alpha-mannosidase enzymatic activity in deficient human and feline fibroblasts. The expressed alpha-mannosidase had the same biochemical properties (thermal stability, pH profile, inhibitor/activator sensitivity) as the native enzyme expressed in normal cells. The transferred enzyme colocalized with a control lysosomal hydrolase in cell fractionation experiments. The vector-encoded enzyme also was released at high levels from the corrected cells, and was taken up by untreated mutant cells via the mannose 6-phosphate receptor-mediated endocytic pathway (cross-correction). It is envisioned that genetic correction of a subset of cells (e.g., hematopoietic stem cells) in patients will provide a source of corrective enzyme for other affected tissues in this multisystem disease. Development of a vector expressing high levels of alpha-mannosidase that cross-corrects mutant cells will enable somatic gene transfer experiments in the cat model of human alpha-mannosidosis.
Animals↗
Construction and characterization of an eightfold redundant dog genomic bacterial artificial chromosome library.
A large insert canine genomic bacterial artificial chromosome (BAC) library was built from a Doberman pinscher. Approximately 166,000 clones were gridded on nine high-density hybridization filters. Insert analysis of randomly selected clones indicated a mean insert size of 155 kb and predicted 8.1 coverage of the canine genome. Two percent of the clones were nonrecombinant. Chromosomal fluorescence in situ hybridization studies of 60 BAC clones indicated no chimerism. The library was hybridized with dog PCR products representing eight genes (ADA, TNFA, GCA, MYB, HOXA, GUSB, THY1, and TOP1). The resulting positive clones were characterized and shown to be compatible with an eightfold redundant library.
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Anchoring of canine linkage groups with chromosome-specific markers.
A high-resolution genetic map with polymorphic markers spaced frequently throughout the genome is a key resource for identifying genes that control specific traits or diseases. The lack of rigorous selection against genetic disorders has resulted in many breeds of dog suffering from a very high frequency of genetic diseases, which tend to be breed-specific and usually inherited as autosomal recessive or apparently complex genetic traits. Many of these closely resemble human genetic disorders in their clinical and pathologic features and are likely to be caused by mutations in homologous genes. To identify loci important in canine disease genes, as well as traits associated with morphological and behavioral variation, we are developing a genetic map of the canine genome. Here we report on an updated version of the canine linkage map, which includes 341 mapped markers distributed over the X and 37 autosomal linkage groups. The average distance between markers on the map is 9.0 cM, and the linkage groups provide estimated coverage of over 95% of the genome. Fourteen linkage groups contain either gene-associated or anonymous markers localized to cosmids that have been assigned to specific canine chromosomes by FISH. These 14 linkage groups contain 150 microsatellite markers and allow us to assign 40% of the linkage groups to specific canine chromosomes. This new version of the map is of sufficient density and characterization to initiate mapping of traits of interest.
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[Preliminary studies on gene therapy for lysosomal alpha-mannosidosis].
OBJECTIVE: Exploration of the feasibility of treating human lysosomal alpha-mannosidosis by gene therapy. METHODS: Retroviral vector-mediated transfer of human lysosomal alpha-mannosidase cDNA into the diseased cat skin fibroblasts. Detection of the enzymatic activity in the cells and their culture media at different pH conditions. Localization of the recombinant enzyme in the cells by chemical staining. Cross-correction of untransduced cat cells by incubation in medium containing the secreted enzyme in the absence and presence of mannose-6-phosphate or fetal calf serum. In vivo expression of the recombinant enzyme in organoids containing the vector-transduced cells. RESULTS: Among the two human cDNAs tested, only one encoded high levels of alpha-mannosidase activity in the cat cells, which shared the same pH profile and lysosomal localization with the normal enzyme. The recombinant enzyme was proportionally secreted into the medium of the cell culture and taken up by untransduced cells via mannose-6-phosphate receptor-mediated endocytosis. The uptake was partially inhibited in the presence of fetal calf serum, which was dose-dependent. In vivo, organoids containing the vector-transduced cells expressed detectable alpha-mannosidase activity for up to 6 weeks. CONCLUSION: The human cDNA was functional in the cat cells and the expression system could be used for development of gene therapy for lysosomal alpha-mannosidosis.
Animals↗
Cloning of the canine beta-glucuronidase cDNA, mutation identification in canine MPS VII, and retroviral vector-mediated correction of MPS VII cells.
Mucopolysaccharidosis type VII (MPS VII) is an inherited disease resulting from deficient activity of the lysosomal acid hydrolase beta-glucuronidase (GUSB) and has been reported in humans, mice, cats, and dogs. To characterize canine MPS VII, we have isolated and sequenced the canine GUSB cDNA from normal and affected animals. A single nucleotide substitution was detected in the GUSB cDNA derived from MPS VII dogs. This guanosine to adenine base change at nucleotide position 559 in the canine cDNA sequence causes an arginine to histidine substitution at amino acid position 166. Introduction of the G to A substitution at position 559 in a mammalian expression vector containing the normal canine GUSB cDNA nearly eliminated the GUSB enzymatic activity, demonstrating that this mutation is the cause of canine MPS VII. A retroviral vector expressing the full-length canine beta-glucuronidase cDNA corrected the deficiency in MPS VII cells.
Amino Acid Sequence↗
RXRA and HSPA5 map to the telomeric end of dog chromosome 9.
Previous results showed that loci from human chromosome 17q (HSA17q) map to the centromeric two-thirds of dog chromosome 9 (CFA9). In these studies fluorescence in situ hybridization (FISH) using a human total chromosome 17 painting probe, indicated that the telomeric one-third of CFA9 must have homology to one or more human chromosomes other than HSA17. Here we report that this distal part of CFA9 contains a segment syntenic to the telomeric end of HSA9q and mouse chromosome 2 (MMU2). The gene loci encoding retinoid X receptor, alpha (RXRA) and heat shock protein 5 (HSPA5 or GRP78), which are found on HSA9q34 and MMU2, occupy a region on CFA9 distal to NF1 and CRYBA1. FISH of a canine specific genomic cosmid clone for RXRA demonstrated the more telomeric localization of this locus to NF1 on CFA9. A linkage map developed for the distal region of CFA9 included: NF1-(2.7 CM)-CRYBA1-(6.5 CM)-RXRA-(22CM)-HSPA5. The next best order, RXRA-NF1-CRYBA1-HSPA5 with a difference in the log odds of 1.43 does not correspond to our findings with FISH. The most probable map order places HSPA5 distal to RXRA on CFA9 whereas in humans it lies centromeric of RXRA on HSA9q34.
Animals↗
Polycystic kidney and liver disease in two related West Highland White Terrier litters.
Polycystic kidney and liver disease was present in four of six female and three of five male offspring born in two matings between the same pair of West Highland White Terriers. Clinical signs were apparent and serum biochemistry analysis consistent with liver failure was evident by 5 weeks of age. Affected pups were euthanatized because of their disease. Renal cysts were confirmed to be of collecting duct origin by Dolichos bifluros agglutinin lectin histochemistry, and hepatic cysts were of biliary origin. The clinically unaffected parents were related through multiple common ancestors, and there were no reports of similar disease in related dogs. An autosomal recessive mode of inheritance is therefore suggested. This is the first report of polycystic kidney and liver disease in the West Highland White Terrier. The features of the disease in these pups are similar to those of autosomal recessive polycystic kidney disease (ARPKD) in humans. The West Highland White Terrier may therefore be a potential animal model for ARPKD.
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Physical and linkage mapping of human chromosome 17 loci to dog chromosomes 9 and 5.
Genome mapping in the dog is in its early stages. Here we illustrate an approach to combined physical and linkage mapping of type 1 anchor (gene) loci in the dog using information on syntenic homology from human and mouse, an interbreed cross/backcross, and a strategy for isolation of dog genomic clones containing both gene-specific sequences and simple sequence repeat polymorphisms. Eleven gene loci from human chromosome 17q (HSA17q) were mapped to the centromeric two-thirds of dog chromosome 9 (CFA9), an acrocentric chromosome of medium size: P4HB, GALK1, TK1, GH1, MYL4, BRCA1, RARA, THRA1, MPO, NF1, and CRYBA1. Eight of these were also positioned on a linkage map spanning 38.6 cM. Based on combined fluorescence in situ hybridization and linkage mapping, the gene order on CFA9 is similar to that of the homologous genes on HSA17q and mouse chromosome 11 (MMU11), but in the dog the gene order is inverted with respect to the centromere. Canine loci, GALK1, TK1, GH1, MYL4, THRA1, and RARA constitute a closely linked group near the centromeric end of CFA9, spanning a genetic distance of only 4.7 cM. Canine NF1 and CRYBA1 lie distally, near the lower border of the Giemsa band adjacent to the distal one-third of CFA9. NF1 and CRYBA1 are loosely linked to the more centromeric group (31.2 cM). No HSA17 genes were found on the telomeric one-third of CFA9. Painting of dog chromosomes with a human whole chromosome 17 probe showed hybridization with only the proximal two-thirds of CFA9, consistent with the conclusion that the distal one-third corresponds to a segment or segments of other human chromosomes. Two loci, GLUT4 and PMP22, located on HSA17p, were mapped by FISH to dog chromosome 5 in a region also identified by the whole human chromosome 17 paint, indicating disruption of HSA17 syntenic homology at the centromere.
Animals↗
Molecular basis of canine muscle type phosphofructokinase deficiency.
Muscle type phosphofructokinase (M-PFK) deficiency is a rare inherited glycogen storage disease in humans that causes exertional myopathy and hemolysis. The molecular basis of canine M-PFK deficiency, the only naturally occurring animal homologue, was investigated. Lack of M-PFK enzyme activity was caused by a nonsense mutation in the penultimate exon of the M-PFK gene, leading to rapid degradation of a truncated (40 amino acids) and therefore unstable M-PFK protein. A polymerase chain reaction-based test was devised to identify M-PFK-deficient and carrier animals. This represents one of only a few inborn errors of metabolism where the molecular defect has been identified in a large animal model which can now be used to develop and assess novel therapeutic strategies.
Animals↗
A cDNA encoding canine muscle-type phosphofructokinase.
The canine muscle-type-phosphofructokinase-encoding gene (M-PFK) was sequenced by using a combination of cDNA cloning and RT-PCR amplification. The canine M-PFK sequence shares 88 and 90% identity with rabbit and human M-PFK, respectively. The canine ORF was determined to be 6-bp longer than either human or rabbit M-PFK due to a 6-bp insertion at the end of exon 13.
Amino Acid Sequence↗
Blood type AB in the feline AB blood group system.
OBJECTIVE: To assess the genetics, frequency, and biochemistry of the AB blood type in cats. ANIMALS: Domestic shorthair and purebred cats in a breeding colony and privately owned catteries and blood samples from a large feline blood typing laboratory. PROCEDURES: Samples from cats with blood type AB were selected from the feline blood typing laboratory at the university. Breeding experiments and family studies were used for the genetic analysis of cats with blood type AB. Simple slide hemagglutination assays were used to type cats. Hemagglutination assays, flow cytometry, and ganglioside analysis by high-performance thin layer chromatography were applied to characterize the AB antigens. RESULTS: Type AB was rare (13/9,239 cats; 0.14% frequency) in cats of the United States and Canada. Type AB occurred only in breeds in which type B was also detected. Cats with type-AB blood express biochemical features of type-A and type-B antigens. Genetic analyses of families with blood type-AB cats are consistent with the hypothesis of 3 alleles: A, B, and AB. The AB allele is recessive to the A allele, but dominant over the B allele. There may be an additional genetic mechanism responsible for the inheritance of blood type AB in cats. CONCLUSION: Blood type AE is an extremely rare and separately inherited type in the feline AB blood group system. CLINICAL RELEVANCE: Kittens with type-AB blood born to queens with type-B blood are at similar risk for neonatal isoerythrolysis as kittens with type-A blood because anti-A alloantiserum from blood type-B queens recognizes AB red blood cells. Furthermore, cats with type-AB blood are best transfused with type-AB or type-A blood.
ABO Blood-Group System↗