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Biomedical subjects

D F Patterson

Publications and source records attributed to D F Patterson.

At least 37 records · Page 2Linked to original sources
PubMed1995

Inheritance of cystinuria and renal defect in Newfoundlands.

OBJECTIVE: To describe clinical features, characterize metabolic renal abnormalities, and evaluate mode of inheritance of cystinuria in Newfoundlands. DESIGN: Prospective study. ANIMALS: Two families of Newfoundlands including 11 dogs with dysuria, stranguria, or obstruction attributable to cystine calculi. PROCEDURE: Urinalysis and nitroprusside spot tests were performed to evaluate cystinuria in the affected dogs. All calculi were analyzed by crystallography. Amino acid concentrations in urine and plasma of affected dogs were compared with those in clinically normal related dogs. Renal fractional excretion and reabsorption of amino acids were determined in 5 affected Newfoundlands. RESULTS: Nine dogs had pure cystine calculi in the bladder, and 4 of these had renal cystine calculi. Affected dogs persistently excreted excessive amounts of cystine (> 500 nmol/mg of creatinine; reference = 54 +/- 38 nmol/mg of creatinine) and had typical cystine crystals in acidic urine. Urinary excretion of ornithine, lysine, and arginine was also high. Dogs with cystinuria had complete lack of reabsorption and active secretion of cystine, and reabsorption of lysine, ornithine, and arginine was moderately impaired. Although clinical signs of urinary obstruction were observed only in males, cystinuric male and female offspring were produced from noncystinuric parents, consistent with an autosomal recessive mode of inheritance. Obligate heterozygotes did not have clinical signs, and had normal urinary cystine content and renal amino acid reabsorption. CLINICAL IMPLICATIONS: Because detection of carriers by routine urinalysis is currently not possible, Newfoundlands with cystinuria and their parents and offspring should be excluded from breeding.

Animals↗
PubMed1995

A single nucleotide insertion in the canine interleukin-2 receptor gamma chain results in X-linked severe combined immunodeficiency disease.

The immunologic and genetic analysis of a 14-week-old-male cardigan Welsh corgi puppy that presented with failure to thrive, diarrhea, and intermittent vomiting are described. The lack of palpable lymph nodes, the premature death of a male sibling, and similar clinical signs in a male cousin suggested that a primary immunodeficiency disease might be responsible for his poor clinical condition. Quantitation of serum immunoglobulins revealed low concentrations of IgG and undetectable IgA, yet normal concentrations of IgM. A complete blood cell count showed a slight anemia and lymphopenia. Although the peripheral blood contained a normal percentage of T cells, with an increased CD4:CD8 ratio, they were unable to proliferate in response to phytohemagglutinin (PHA) and/or interleukin 2 (IL-2). Furthermore, following PHA activation, the peripheral blood lymphocytes (PBL) demonstrated a nearly complete lack of IL-2 binding. All of these laboratory findings were identical with our previous findings from dogs with X-linked severe combined immunodeficiency (XSCID) that is due to a mutation in their IL-2 receptor gamma (IL-2R gamma) chain. Examination of the corgi's IL-2R gamma cDNA revealed an insertion of a cytosine following nucleotide 582, resulting in a premature stop codon prior to the transmembrane domain. The insertion also created an EcoO109 restriction enzyme site that enabled us to detect the mutation in the patient's genomic DNA. This new mutation in the IL-2R gamma chain discovered in a cardigan Welsh corgi puppy results in XSCID with similar immunologic abnormalities as observed in dogs with the same disease resulting from a different IL-2R gamma chain mutation.

Amino Acid Sequence↗
PubMed1994

IL-2R gamma gene microdeletion demonstrates that canine X-linked severe combined immunodeficiency is a homologue of the human disease.

X-linked severe combined immunodeficiency (SCID) is characterized by profound defects in cellular and humoral immunity and, in humans, is associated with mutations in the gene for the gamma chain of the IL-2 receptor (IL-2R gamma). We have examined this gene in a colony of dogs established from a single X-linked SCID carrier female. Affected dogs have a 4-bp deletion in the first exon of the IL-2R gamma gene, which precludes the production of a functional protein, demonstrating that the canine disease is a true homologue of human X-linked SCID.

Amino Acid Sequence↗
PubMed1994

Canine mitochondrial myopathy associated with reduced mitochondrial mRNA and altered cytochrome c oxidase activities in fibroblasts and skeletal muscle.

Skeletal muscle and fibroblast biopsies obtained from a normal dog and an old English sheep dog with exertional myopathy and lactic acidosis were examined for mitochondrial enzyme activities and mitochondrially coded mRNAs. The fibroblast cultures of the affected dog showed reduced cytochrome c oxidase (COX) I+II mRNA content (25% of control) and COX enzyme activities (23% of control). The skeletal muscle of the affected dog was similarly affected and showed not only decreased COX I+II mRNA content, but also decreased ATPase6 mRNA level. Apart from COX enzyme activity (62% of control), the oligomycin sensitive ATPase and NADH-Ferricyanide reductase activities were also reduced in the skeletal muscle of the affected dog (12-20% of control). These results suggest that a mitochondrial dysfunction may be the causative factor of the exertional metabolic myopathy with lactic acidosis in this affected old English sheep dog. These animals may serve as an excellent model for mitochondrial myopathies.

Adenosine Triphosphatases↗
PubMed1993

A single major-gene defect underlying cardiac conotruncal malformations interferes with myocardial growth during embryonic development: studies in the CTD line of keeshond dogs.

The common forms of isolated congenital heart disease are usually not inherited in a Mendelian pattern, and most are considered multifactorial threshold traits. A large subset consisting of a group of malformations of the ventricular outflow region, termed "conotruncal defects" (CTDs), include subarterial ventricular septal defects, tetralogy of Fallot, and persistent truncus arteriosus. Similar aggregations of CTDs have been reported in human families and in the keeshond breed of dog. The results of our early breeding experiments utilizing noninbred keeshonds were not consistent with any hypothesis of a fully penetrant monogenic inheritance. Here we report a recent series of genetic and embryologic studies conducted after more than 10 generations of selective inbred matings between affected-CTD-line dogs. The results are now consistent with a defect at a single autosomal locus, the Mendelian pattern of transmission having been obscured prior to selective inbreeding by genetic background. On the basis of morphometric embryologic studies, the mutant CTD allele causes conotruncal malformations in homozygous animals by interfering with myocardial growth in the conotruncus during the critical window when the conotruncal cushions fuse to form the conotruncal septum.

Animals↗
PubMed1992

Inherited phosphofructokinase deficiency in an American cocker spaniel.

A 3-year-old female American Cocker Spaniel with a chronic hemolytic disorder and hemolytic crises was found to have M-type phosphofructokinase deficiency. This inherited erythroenzymopathy and myopathy is commonly diagnosed in English Springer Spaniels, but the family study of this Cocker Spaniel, although supporting an autosomal recessive mode of inheritance, did not reveal any English Springer Spaniel ancestors. Molecular genetic studies did, however, identify the same mutation in this dog as we previously reported in the English Springer Spaniel breed, suggesting that this mutation originated prior to the separation of these 2 breeds.

Anemia, Hemolytic↗
PubMed1992

Glycogen storage disease type IV: inherited deficiency of branching enzyme activity in cats.

Glycogen storage disease type IV due to branching enzyme deficiency was found in an inbred family of Norwegian forest cats, an uncommon breed of domestic cats. Skeletal muscle, heart, and CNS degeneration were clinically apparent and histologically evident in affected cats older than 5 mo of age, but cirrhosis and hepatic failure, hallmarks of the human disorder, were absent. Beginning at or before birth, affected cats accumulated an abnormal glycogen in many tissues that was determined by histochemical, enzymatic, and spectral analysis to be a poorly branched alpha-1,4-D-glucan. Branching enzyme activity was less than 0.1 of normal in liver and muscle of affected cats and partially deficient (0.17-0.75 of normal) in muscle and leukocytes of the parents of affected cats. These data and pedigree analysis indicate that branching enzyme deficiency is a simple autosomal recessive trait in this family. This is the first reported animal model of human glycogen storage disease type IV. A breeding colony derived from a relative of the affected cats has been established.

1,4-alpha-Glucan Branching Enzyme↗
PubMed1991

Defective brush-border expression of intrinsic factor-cobalamin receptor in canine inherited intestinal cobalamin malabsorption.

Ligand binding activity of intrinsic factor-cobalamin receptor (IFCR) was determined in homogenates and isolated brush-border membranes (BBM) of ileum and kidney from dogs exhibiting simple autosomal recessive inheritance of selective cobalamin malabsorption (Fyfe, J. C., Giger, U., Hall, C. A., Jezyk, P. F., Klumpp, S. A., Levine, J. S., and Patterson, D. F. (1991) Pediatr. Res. 29, 24-31). IFCR activity of affected dog ileal homogenates was 3-4-fold higher than normal whereas IFCR activity in affected dog kidney homogenates was one-tenth of normal. The recovery of IFCR activity in the BBM of ileum and renal cortex of affected dogs was 30- and 20-fold less than normal, respectively. The dissociation constant (Kd) for intrinsic factor-cobalamin was similar in BBM of both tissues and was the same in affected and normal dogs. In the affected dog ileal BBM, activities of alkaline phosphatase and sucrase-isomaltase and vesicular transport of glucose and Na(+)-taurocholate were normal. Immunoblots showed no IFCR cross-reactive material in the ileal or renal BBM of affected dogs. IFCR purified by affinity chromatography from kidney of both normal and affected dogs had an Mr = 230,000. However, amino acid analysis revealed that the affected dog IFCR had more lysine than the normal, and protease cleavage of the purified IFCRs revealed different peptide maps. Asparagine-linked oligosaccharides of both proteins were sensitive to peptide N-glycosidase F cleavage, but only the affected dog IFCR was endoglycosidase H sensitive. These results suggest that cobalamin malabsorption in this canine family is caused by inefficient BBM expression of IFCR due to a mutation of IFCR and its retention in an early biosynthetic compartment.

Alkaline Phosphatase↗
PubMed1991

Inherited selective intestinal cobalamin malabsorption and cobalamin deficiency in dogs.

Inherited selective intestinal malabsorption of cobalamin (Cbl) was observed in a family of giant schnauzer dogs. Family studies and breeding experiments demonstrated simple autosomal recessive inheritance of this disease. Affected puppies exhibited chronic inappetence and failure to thrive beginning between 6 and 12 wk of age. Neutropenia with hypersegmentation, anemia with anisocytosis and poikilocytosis, and megaloblastic changes of the bone marrow were present. Serum Cbl concentrations were low, and methylmalonic aciduria and homocysteinemia were present. Parenteral, but not oral, cyanocobalamin administration rapidly eliminated all signs of Cbl deficiency except for low serum Cbl concentrations. Cbl malabsorption in affected dogs was documented by oral administration of [57Co]cyanocobalamin with or without simultaneous oral administration of intrinsic factor or normal dog gastric juice. Quantitation and function studies of intrinsic factor and transcobalamin-II from affected dogs revealed no abnormality. Other gastrointestinal functions and ileal morphology were normal, indicating a selective defect of Cbl absorption at the level of the ileal enterocyte. Immunoelectron microscopy of ileal biopsies showed that the receptor for intrinsic factor-Cbl complex was absent from the apical brush border microvillus pits of affected dogs. This canine disorder resembles inherited selective intestinal Cbl malabsorption (Imerslund-Gräsbeck syndrome) in humans, and is a spontaneously occurring animal model of early onset Cbl deficiency.

Animals↗
PubMed1990

Changes in distribution of elastin and elastin receptor during intimal cushion formation in the ductus arteriosus.

Changes in distribution of elastin and elastin receptor were studied during maturation of the ductus arteriosus. In this vessel intimal thickening is a normal process. It starts with separation of endothelial cells from the internal elastic lamina by the formation of a wide subendothelial region, followed by an increase in number of radially orientated cells in the inner media and subendothelial region. For the first time the nature of these originally inner media cells could be definitely determined as being derived from smooth muscle cells. Areas rich in these modified smooth muscle cells contained less elastin as compared with regions rich in circularly orientated smooth muscle cells. The internal elastic lamina had disappeared underneath intimal cushions of the canine ductus arteriosus, whereas in the fetal human ductus arteriosus, splitting of the internal elastic lamina was observed. Elastin was not present underneath separated endothelial cells, which suggests that these cells do not synthesize elastin, at least not after separation. Both smooth muscle cells and endothelial cells demonstrated the presence of the elastin receptor. Changes in its distribution were not observed. The temporal and spatial association between the altering distribution of elastin and the absence of normal cushion formation in the persistent ductus arteriosus suggests a role of the elastin receptor in the process of intimal thickening.

Animals↗
PubMed1990

Beta-glucuronidase mediated pathway essential for retinal pigment epithelial degradation of glycosaminoglycans. Disease expression and in vitro disease correction using retroviral mediated cDNA transfer.

A beta-glucuronidase mediated pathway for the degradation of glycosaminoglycans is present in the retinal pigment epithelium. The pathway has been defined using ocular tissues and cultured cells from mutant animals having a recessively inherited deficiency of the lysosomal enzyme. In situ, storage products accumulate in secondary lysosomes of the retinal pigment epithelium, the cytoplasm fills with inclusions and the cells hypertrophy; severity of the disease increases with aging. Deficient activity of beta-glucuronidase is present in primary and second passage cultures. Radiolabel studies with 35SO4 show a significant retention of cell layer label by mutant retinal pigment epithelial cells during a 72-hr pulse or 24-hr chase period. The labels is in newly synthesized chondroitin sulfate and heparan sulfate, which are natural substrates for the deficient enzyme. There is no difference from normal in the total radioactivity and electrophoretic profile of the glycosaminoglycans that are synthesized and released into the media. A retroviral vector was used to transfer normal rat beta-glucuronidase cDNA into the mutant cells. The vector treatment results in restoration of enzyme activity and correction of the degradative defect; 35SO4 labeling shows that chondroitin sulfate and heparan sulfate levels return to normal. The vector treatment studies indicate that a single gene defect determines the abnormal beta-glucuronidase mediated pathway in the mutant retinal pigment epithelium.

Animals↗
PubMed1990

Restoration of normal lysosomal function in mucopolysaccharidosis type VII cells by retroviral vector-mediated gene transfer.

Retroviral vectors were constructed containing a rat beta-glucuronidase cDNA driven by heterologous promoters. Vector-mediated gene transfer into human and canine beta-glucuronidase-deficient mucopolysaccharidosis type VII fibroblasts completely corrected the deficiency in beta-glucuronidase enzymatic activity. In primary cultures of canine mucopolysaccharidosis type VII retinal pigment epithelial cells, which contain large amounts of undegraded glycosaminoglycan substrates, vector correction restored normal processing of specific glycosaminoglycans in the lysosomal compartment. In canine mucopolysaccharidosis type VII bone marrow cells, beta-glucuronidase was expressed at high levels in transduced cells. Thus, the vector-encoded beta-glucuronidase was expressed at therapeutic levels in the appropriate organelle and corrected the metabolic defect in cells exhibiting the characteristic pathology of this lysosomal storage disorder.

Animals↗
PubMed1989

Testicular feminization in a cat.

Testicular feminization, caused by an inherited defect of the androgen receptor, was diagnosed in a domestic cat. Individuals affected with this syndrome are genetic males that have testes but fail to undergo masculinization because the internal and external genitalia cannot respond to androgens. The affected cat had the external appearance of a sexually normal female, but during surgery for ovariohysterectomy, only 2 abdominal gonads were found. Müllerian (uterus) or wolffian (epididymides) derivatives were not present. Only testicular tissue was found in histologic sections of the gonad. A normal male chromosome constitution (38,XY) was found in karyotypes prepared from lymphocyte cultures. High affinity binding of dihydrotestosterone was undetectable in fibroblasts cultured from genital skin of the affected cat, indicating that the cytosolic androgen receptor was nonfunctional. Pedigree analysis indicates that this is an X-linked disorder in cats, as it is in other mammals. Accurate diagnosis and genetic counseling are advocated to reduce the prevalence of the disorder.

Androgen-Insensitivity Syndrome↗
PubMed1989

Pulmonary atresia with intact ventricular septum and agenesis of the ductus arteriosus in a pup.

A 7-week-old Wire Fox Terrier was admitted with pulmonary atresia with intact ventricular septum. The right ventricle and tricuspid valve were hypoplastic, and venous return to the right atrium reached the left side through an atrial septal defect. Oxygenation was via hyperplastic bronchial arteries. There was no evidence of the ductus arteriosus. Physical examination, plain and contrast radiography, and electrocardiography were performed. Clinical findings for this combination of defects were similar to those of more common defects (tetralogy of Fallot, patent ductus arteriosus.

Angiocardiography↗
PubMed1989

Organic aciduria and butyryl CoA dehydrogenase deficiency in BALB/cByJ mice.

A metabolic screening program of inbred strains of mice has detected a marked organic aciduria in the BALB/cByJ strain. Gas chromatographic and mass spectrometric analysis identified large quantities of n-butyrylglycine plus lesser quantities of ethylmalonic acid. Crosses with the nonexcreting C57BL/6J strain indicate that this condition is inherited as an autosomal recessive trait. Independently from this screening a variant with no detectable enzyme activity of butyryl CoA dehydrogenase (BCD) in liver and kidney of the BALB/cByJ strain but not other BALB/c sublines was discovered. Data from a three-point cross indicated that the null variant maps to the structural locus for the enzyme, Bcd-1, on chromosome 5. The findings indicate that a mutation at or near Bcd-1 in the BALB/cByJ strain resulted in a biochemical abnormality manifest as the BCD deficiency. It is concluded that accumulation of butyryl CoA due to a block in the oxidation of short-chain fatty acids results in an overproduction of organic metabolites leading to the observed organic aciduria. The fact that other BALB/c substrains do not exhibit this abnormality further suggests that this disorder reflects subline divergence within the BALB/c family.

Animals↗