Progress 01/01/97 to 12/31/97
Outputs
During the present grant period (9/20/93-9/19/98)studies concentrated on the characterization of a number of genetic disorders that are models of human genetic disease. These studies included clinical and pathologic characterization as well as biochemical and molecular studies aimed at identifying and characterizing the underlying gene mutation. The following models were studied: Mucopolysaccharidosis IIIB in the Emu; Mucopolysaccharidosis VII in the dog; Cystinuria type I in the dog; Mucolipidosis II in the cat; Alpha mannosidosis in the cat; X-linked ectodermal dysplasia in the dog; Myotonia congenita in the dog; and Tricuspid valve dysplasia in the dog.
Impacts
(N/A)
Publications
- Giger U, Shivaprasad H, Wang P, Jezyk P, Patterson D, Bradley G: Mucopolysaccharidosis type IIB (Sanfilippo B syndrome) in emus. Am Soc Vet Pathol [abstract. Vet Pathol 34:473, 1997. Hubler M, Haskins ME, Arnold S et al: Mucolipidosis type II in a domestic shorthair car. J Small Anim Pract 37:355, 1996. Casal ML, Jezyk PF, Greek MH, Goldschmidt MH, Patterson DF: X-linked ectodermal dysplasia in the dog. J Heredity in press, 1997. Simonaro CM, Haskins ME, Visser JWM, Schuchman EH: Bone marrow transplantation in newborn MPS VI rats: biochemical, pathological and clinical findings. Transplantation, in press, 1997.
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Progress 01/01/94 to 12/30/94
Outputs
The objective during the current year has been to continue to serve as a National Referral Center for the identification, characterization, evaluation, and dissemination of animal models of human genetic disease. New and unique models that offer unusual opportunities for investigating poorly understood pathogenetic mechanisms or new approaches to the therapy of human genetic diseases are emphasized. The objectives of the Center are accomplished by providing medical genetic consultation and laboratory studies, including cytogenetics, screening of blood and urine for inborn errors of metabolism, evaluation of postmortem specimens and biopsies by histopathologic and biochemical analysis, and analysis of pedigrees. Family studies and breeding experiments are used to define modes of inheritance and reproduce disorders for further characterization. Following characterization and evaluation, promising models are made available to the general biomedical community and studied
collaboratively. Sperm and somatic cell cultures from selected models are cryopreserved and DNA isolated and stored for future molelcular genetic studies. In the competing renewal application for this grant, we proposed, and have implemented this year, the addition of a laboratory of Molecular Genetics, devoted to the cloning and description of the gene mutations in selected animal models of human genetic disease.
Impacts
(N/A)
Publications
- CHIEFFO C, STALIS IH, VANWINKLE T, ET AL. 1994. Cerebeller Purkinje's cell degeneration and coat color dilution in a family of Rhodesian Ridgeback dogs. J Vet Intern Med 8:112-116.
- FYFE JC, VANWINKLE TJ, HASKINS ME, PATTERSON DF. 1994. Glycogen storage disease type IV in domestic cats. Comp Pathol.
- VANWINKLE TJ, FYFE JC, DAYRELL-HART B, ET AL. 1994. Blindness due to polymicrogyria and asymmetrical dilation of the lateral ventricles in standard Poodles. Prog Vet Neurol 5:66-71.
- VIJAYASARATHY C, GIGER U, PROCIUK U, PATTERSON DF ET AL. 1994. Canine mitochondrial myopathy associated with reduced mitochondrial mRNA and altered cytochrome c oxidase activities in fibroblasts and skeletal muscle. Comp Biocheml.
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Progress 01/01/92 to 08/30/93
Outputs
The objective during the current year has been to continue to serve as a National Referral Center for the identification, characterization, evaluation, and dissemination of animal models of human genetic disease. New and unique models that offer unusual opportunities for investigating poorly understood pathogenetic mechanisms or new approaches to the therapy of human genetic diseases are emphasized. The objectives of the Center are accomplished by providing medical genetic consultation and laboratory studies, including cytogenetics, screening of blood and urine for inborn errors of metabolism, evaluation of postmortem specimens and biopsies by histopathologic and biochemical analysis, and analysis of pedigrees. Family studies and breeding experiments are used to define modes of inheritance and reproduce disorders for further characterization. Following characterization and evaluation, promising models are made available to the general biomedical community and studied
collaboratively. Sperm and somatic cell cultures from selected models are cryopreserved and DNA isolated and stored for future molelcular genetic studies. In the competing renewal application for this grant, we proposed, and have implemented this year, the addition of a laboratory of Molecular Genetics, devoted to the cloning and description of the gene mutations in selected animal models of human genetic disease.
Impacts
(N/A)
Publications
- VIJAYASARATHY C, GIGER U, PROCIUK U, PATTERSON DF ET AL. 1994. Canine mitochondrial myopathy associated with reduced mitochondrial mRNA and altered cytochrome c oxidase activities in fibroblasts and skeletal muscle. Comp Biocheml.
- CHIEFFO C, STALIS IH, VANWINKLE T, ET AL. 1994. Cerebeller Purkinje's cell degeneration and coat color dilution in a family of Rhodesian Ridgeback dogs. J Vet Intern Med 8:112-116.
- FYFE JC, VANWINKLE TJ, HASKINS ME, PATTERSON DF. 1994. Glycogen storage disease type IV in domestic cats. Comp Pathol.
- VANWINKLE TJ, FYFE JC, DAYRELL-HART B, ET AL. 1994. Blindness due to polymicrogyria and asymmetrical dilation of the lateral ventricles in standard Poodles. Prog Vet Neurol 5:66-71.
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Progress 01/01/92 to 12/30/92
Outputs
During the present grant period, the following advances were made: We identifiedand published description of a feline model of human glycogen storage disease type IV. This is the only animal model of this disorder. We established that the gene for X-linked severe combined immunodeficiency (XSCID) in the dog, which we previously described, is located in a homologous syntenic group and closely linked to the same loci as the XSCID in humans, providing further strong evidence that these are homologous genetic defects. A paper is in preparation. We have identified a metabolic myopathy associated with reduction of cytochrome oxidase subunits I and II. This appears to be the first mitochondrial myopathy identified in animals. A paper is in preparation. Muscle phosphofructokinase (MPFK) deficiency has been further characterized in the dog, the gene has been cloned, and the mutation responsible for this disorder shown to be a single base change (G->A) at position 2228 of the
coding sequence, resulting in a premature stop codon. A rapid PCR test for the mutant allele was developed and we have demonstrated that this same mutation occurs in both the English Springer Spaniel and the Cocker Spaniel.
Impacts
(N/A)
Publications
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Progress 01/01/90 to 12/30/90
Outputs
Demonstrated that an autosomal recessive defect in the intestinal absorption of Vitamin B12 (cobalamin) in Giant Schnauzer dogs is due to a defect in the intracellular processing of the intrinsic factor-cobalamin (IFCbl) brush border receptor. This is the first proven defect in the IFCbk receptor in any species. Discovered an inherited form of glycogen storage disease in the Norwegian Forest Cat. This defect is due to a defect in branching enzyme and appears to be homologous to Glycogenosis type Iv in humans. Proven the mode of inheritance of A and B blood types in the cat. Type A and B are allelic forms, type A being completely dominant over type B. Neonatal isoerythrolysis occurs in the B offspring of type A females due to naturally occurring isohemaglutinins in the colostrum. Discovered a model of familial benign pemphigus (Hailey-Hailey Disease) in the Springer Spaniel. As in man, this disorder is inherited as an autosomal dominant trait.
Impacts
(N/A)
Publications
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Progress 01/01/89 to 12/30/89
Outputs
The hereditary muscular dystrophy of Golden Retriever dogs was shown to be inherited as an X-linked recessive disorder and cytogenetic studies revealed no evidence of an X-chromosome deletion. A model of testicular feminization was discovered in the cat and shown to be due to a deficiency of cytosolic androgen receptor. A hereditary defect in the intestinal absorption of vitamin B 12 in the Giant Schnauzer was further characterized and shown to be due to a deficiency on the ileal brush border membrane of the Cobalamin-Intrinsic Factor Receptor (CBLIFR). A hereditary form of stomatocytosis was described in Miniature Schnauzers. The abnormal muscle energetics associated with muscle phosphofructokinase deficiency in English Springer Spaniels was characterized by magnetic resonance spectroscopy. Feline neonatal isoerythrolysis due to AB blood group incompatibility was studied and it was shown to be explained by naturally-occurring isohemaglutins to type A kitten
erythrocytes in the milk of type B mothers. Type A appears to be inherited as a complete dominant over B. A form of renal amyloidosis was characterized in Shar Pei dogs. This may be a counterpart of human familial Mediteranian Fever. Butryl CoA dehydrogenase deficiency was discovered and characterized in Balb/cByJ mice. A form of severe combined immunodeficiency in Basset hounds was shown to be inherited as an X-linked recessive trait and to closely resemble X-linked Severe Combined Immunodeficiency in humans.
Impacts
(N/A)
Publications
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