ABSTRACT
OBJECTIVES: To quantify the extent of inflammation in psoriatic dactylitis and to examine the relationship between clinical and magnetic resonance imaging (MRI) data in both tender and non-tender dactylitis. METHODS: Seventeen patients with psoriatic dactylitis underwent clinical assessment for 6 months after change of treatment, usually to methotrexate. Measures of dactylitis included the Leeds Dactylitis Index, the assessment tool used in the Infliximab in Psoriatic Arthritis Clinical Trial (IMPACT), a simple count of tender dactlylitic digits and a count of all dactylitic digits, both tender and non-tender. MRI scans of the affected hand or foot were performed before and after treatment using a 1.5T Siemen's scanner pre- and post-contrast. RESULTS: All patients improved clinically, as did their respective dactylitis scores and MRI images. The findings on MRI in both dactylitic and non-dactylitic digits were profound and widespread. The difference between tender and non-tender dactylitis was quantitative rather than qualitative. Synovitis and soft-tissue oedema were the most frequent abnormalities being present in 69% of tender dactylitic digits but bone oedema and flexor tenosynovitis were also frequently seen. Soft-tissue oedema was circumferential and enhancing and not limited to association with the flexor or extensor tendons. None of the clinical indices of dactylitis showed a close relationship to the extent of MRI abnormalities. CONCLUSIONS: MRI images demonstrate widespread abnormalities in digits of people with psoriatic arthritis. Tender dactylitic digits have more abnormalities than other digits but the relationship between clinical and MRI scores is not strong.
Subject(s)
Arthritis, Psoriatic/pathology , Edema/pathology , Finger Joint/pathology , Magnetic Resonance Imaging , Synovitis/pathology , Toe Joint/pathology , Adult , Antirheumatic Agents/therapeutic use , Arthritis, Psoriatic/complications , Arthritis, Psoriatic/drug therapy , Edema/complications , Edema/drug therapy , Female , Humans , Hyperalgesia/pathology , Hyperalgesia/physiopathology , Male , Methotrexate/therapeutic use , Pain/pathology , Pain/physiopathology , Severity of Illness Index , Synovitis/complications , Synovitis/drug therapy , Treatment OutcomeABSTRACT
OBJECTIVE: To develop a routine procedure for establishing the inherited congenital myoclonus (ICM) genotype of cattle and to obtain an estimate of the prevalence of heterozygotes for ICM and maple syrup urine disease (MSUD) in Australian Poll Herefords. DESIGN: A mismatch amplification procedure was developed to genotype for ICM. The ICM and MSUD genotypes of subjects from a 'neuraxial oedema' experimental breeding herd were investigated. Tail hair roots were used as a source of target DNA to determine the ICM and MSUD genotypes of 455 Poll Hereford bulls. RESULTS: An Acc I mismatch procedure was found to be suitable to genotype cattle for the ICM alleles using tail hair roots as the source of DNA. Based on the prevalence of heterozygotes among saleyard and sale bulls in the early 1990s, and contemporary slaughter bulls, the frequencies of the alleles responsible for ICM and MSUD were estimated to be between 0.01 and 0.02. CONCLUSION: This survey demonstrates that the mutations responsible for ICM and MSUD are present in the Australian Poll Hereford population. PCR tests could be used to advantage in differential diagnosis of neurological disease in newly born calves and in selection of Poll Hereford seed stock.
Subject(s)
Cattle Diseases/epidemiology , Cattle Diseases/genetics , Maple Syrup Urine Disease/veterinary , Myoclonus/veterinary , Animals , Australia/epidemiology , Cattle , DNA Primers , Genetic Carrier Screening , Genotype , Heterozygote , Incidence , Male , Maple Syrup Urine Disease/genetics , Myoclonus/genetics , Polymerase Chain Reaction/veterinary , PrevalenceABSTRACT
OBJECTIVE: To develop procedures for genotyping Brahman cattle for loss-of-function alleles within the acidic alpha-glucosidase gene and to assess the risk of generalised glycogenosis in Australian Brahman cattle. DESIGN: PCR assays for three loss-of-function alleles were designed to exploit internal restriction sites within acidic alpha-glucosidase amplicons that are independent of allelic variants at the mutant sites. RESULTS: Genotyping 8529 clinically normal Brahmans between August 1996 and August 2001 revealed 16.4% were heterozygous for the more common of the two mutations (1057deltaTA, often referred to as the 'E7' mutation) that cause generalised glycogenosis in this breed. The less common 1783T mutation (often referred to as the 'E13' mutation) was restricted to descendants of one imported bull, and was not detected in 600 randomly selected Brahmans. Prior to definition of these two disease-causing mutations, 640 (18%), and 14 (0.4%), of 3559 clinically normal Brahmans analysed between January 1994 and December 1996, were heterozygous, and homozygous, respectively, for a silent polymorphism (2223G-->A) that is associated with generalised glycogenosis. In addition to the 1057deltaTA and 1783T mutations, approximately 15% of Brahmans were found to be heterozygous for a single base substitution in exon 9 (1351T, commonly referred to as the 'E9' mutation) that significantly reduces acidic alpha-glucosidase activity, but has not been associated with clinical disease. These three loss-of-function alleles were found in Brahmans imported, or selected for import, from the USA. CONCLUSION: The PCR procedures reported here represent a significant improvement in reliability and accuracy over previous published methods. Utilisation of these PCR/restriction enzyme based assays will facilitate precise selection against the 1057deltaTA and 1783T alleles, and consequently reduce the incidence of generalised glycogenosis in registered and commercial Brahman herds.
Subject(s)
Cattle Diseases/genetics , Glycogen Storage Disease/veterinary , Polymerase Chain Reaction/veterinary , Animals , Breeding , Cattle , Cattle Diseases/enzymology , Cattle Diseases/prevention & control , DNA Primers , Genetic Testing/methods , Genetic Testing/veterinary , Genotype , Glycogen Storage Disease/genetics , Predictive Value of Tests , alpha-Glucosidases/deficiency , alpha-Glucosidases/geneticsABSTRACT
Inherited congenital myoclonus of Poll Hereford calves is an autosomal recessive disease characterized by hyperesthesia and myoclonic jerks of the skeletal musculature that occur both spontaneously and in response to sensory stimuli. Binding studies have previously shown that myoclonus is associated with specific loss of [(3)H]strychnine-binding sites from spinal cord and brain stem in affected calves. In order to identify the mutation responsible for myoclonus, we examined the candidate genes, glycine receptor alpha1 (Glra1) and beta (Glrb) subunits, in affected and normal cattle. A nonsense mutation was found at amino acid 24, located in exon 2 of the Glra1 gene in both cDNA and genomic sequences from affected but not control animals. Immunohistochemistry, with a monoclonal antibody to alpha and beta subunits of the glycine receptor, revealed a loss of cell surface immunoreactivity in myoclonic animals, suggesting a failure in the assembly of the receptor that could explain the characteristic phenotype of the disease.
Subject(s)
Codon, Nonsense , Myoclonus/genetics , Receptors, Glycine/genetics , Alleles , Amino Acid Sequence , Animals , Base Sequence , Binding Sites/genetics , Brain Chemistry , Cattle , Cloning, Molecular , DNA, Complementary , Genetic Testing , Glycine Agents/metabolism , Glycine Agents/pharmacology , Immunohistochemistry , Molecular Sequence Data , Phenotype , Polymorphism, Genetic , Receptors, Glycine/analysis , Receptors, Glycine/metabolism , Strychnine/metabolism , Strychnine/pharmacologyABSTRACT
OBJECTIVE: To develop a procedure for routine genotyping of Shorthorn cattle for the generalised glycogenosis allele in exon 18 of the acidic alpha-glucosidase gene. PROCEDURE: Allele-specific amplification and double mismatch amplification procedures for the discrimination of the exon 18 alleles were evaluated using leucocytes and hair roots as sources of target DNA. RESULTS: Allele-specific amplification was effective for genotyping Shorthorn cattle at the 2454 site when purified DNA was used as target for the polymerase chain reaction. However, when the target DNA was derived from hair roots, differences in the relative yield of wild-type and mutant amplicons were observed. The double mismatch amplification procedure was effective in genotyping all subjects, independent of the source of DNA. The unique cleavage sites for Drd I and PshA I within exon 18 are present and absent respectively in the wildtype amplicon, and are lost and acquired, respectively, in the mutant amplicon. In addition, the Drd I and PshA I mismatching cleavage sites incorporated into the primers serve as internal controls for Drd I and PshA I cleavage. CONCLUSION: The double Drd I/PshA I mismatch amplification procedure using hair root samples as the source of DNA is a robust method for genotyping Shorthorns for generalised glycogenosis.
Subject(s)
Cattle Diseases/genetics , Glycogen Storage Disease/veterinary , Polymerase Chain Reaction/veterinary , Alleles , Animals , Breeding , Cattle , Cattle Diseases/enzymology , DNA Primers , Electrophoresis, Agar Gel/veterinary , Female , Genotype , Glycogen Storage Disease/genetics , Glycogen Storage Disease Type II/genetics , Glycogen Storage Disease Type II/veterinary , Hair Follicle , Leukocytes , Male , Sensitivity and Specificity , alpha-Glucosidases/deficiency , alpha-Glucosidases/geneticsABSTRACT
We report here cDNA and genomic sequence of the bovine acidic alpha-glucosidase gene, from the initiation codon to the most 3' polyadenylation signal. The 2814-bp coding sequence predicts a 937-amino acid protein, which is highly conserved compared with the human alpha-glucosidase gene (86% and 83% identity respectively). The intron/exon boundaries are also conserved between the two species. Two mutations have been identified in Brahmans, and one in Shorthorns, that lead to generalized glycogenosis. All three mutations result in premature termination of translation. Evidence is also presented for a missense mutation segregating with the Brahman population, which is responsible for a 70-80% reduction in alpha-glucosidase activity.
Subject(s)
alpha-Glucosidases/genetics , Amino Acid Substitution , Animals , Cattle , Cattle Diseases/enzymology , Cattle Diseases/genetics , DNA/chemistry , DNA/genetics , DNA, Complementary/chemistry , DNA, Complementary/genetics , Exons , Female , Genes/genetics , Genes, Lethal/genetics , Genotype , Glycogen Storage Disease Type II/enzymology , Glycogen Storage Disease Type II/genetics , Glycogen Storage Disease Type II/veterinary , Introns , Male , Molecular Sequence Data , Mutation , Point Mutation , Sequence Analysis, DNA , Sequence Deletion , Species Specificity , alpha-Glucosidases/deficiencyABSTRACT
The organisation of the E1alpha subunit of bovine branched-chain alpha-keto acid dehydrogenase gene was established. c DNA was cloned from Poll Shorthorn x Poll Hereford calves affected with Maple Syrup Urine Disease to identify the mutation responsible for the disease in Poll Shorthorns. Clones containing the c DNA sequences inherited from the Poll Shorthorn sire of the affected calves were identified. Paternal clones were sequenced and a cytidine to thymidine transition was found at nucleotide 1380. The mutation is predicted to substitute leucine in place of a highly conserved proline at codon 372. A polymerase chain reaction procedure was developed for detection of the 1380C-->T mutation in genomic DNA. Three Poll Shorthorn parents of affected calves and three affected Poll Shorthorn x Poll Hereford calves were heterozygous and an affected Poll Shorthorn calf was homozygous for this mutation. An improved polymerase chain reaction procedure was also devised to genotype Poll Herefords for the 248C-->T mutation. The procedures will facilitate disease prevention programs and assist in differential diagnosis of conditions in new-born calves that present with a rapid onset of progressive neurological disease and are characterised histologically by 'status spongiosus'. Maple Syrup Urine Disease (MSUD) is an autosomal recessive defect reported in humans (Danner and Elsas 1989), and in Poll Hereford (PH) and Poll Shorthorn (PS) calves (Harper et al 1986, Healy et al 1992). The clinical, biochemical and pathological manifestations of the disease are identical in the two breeds of cattle, and are characterised by the rapid onset of progressive neurological disease, leading to death within a few days of birth. The disease is caused by a deficiency of activity of the mitochondrial enzyme branched-chain alpha-keto acid dehydrogenase (BCKADH). This deficiency leads to elevated concentrations, in blood and tissues, of branched chain alpha-keto acids and their precursors, the branched chain amino acids, valine, leucine and isoleucine. BCKADH consists of four subunits E1alpha, E1beta, E2 and E3 that are encoded by separate genes, and MSUD may result from deficiency of any of the subunits. In PH s, the disease in caused by premature termination of translation, of the E1alpha subunit, that is induced by a cytidine to thymidine transition exon 2 (248C-->T), that converts the glutamine codon -6 to a stop codon (Q-6ST; Zhang et al 1990). We have shown that MSUD -affected PSxPH calves are heterozygous at the PH locus, illustrating molecular heterogeneity exists for bovine MSUD (Healy and Dennis 1994a). The fact that these crossbred calves are affected, indicates the PS, like the PH mutation, resides in the E1alpha subunit.
Subject(s)
Alleles , Cattle Diseases/genetics , Maple Syrup Urine Disease/veterinary , Animals , Base Sequence , Cattle , Female , Genotype , Male , Maple Syrup Urine Disease/genetics , Molecular Sequence Data , Pedigree , Polymerase Chain ReactionABSTRACT
The development of gene-replacement therapy for inborn errors of metabolism has been hindered by the limited number of suitable large-animal models of these diseases and by inadequate methods of assessing the efficacy of treatment. Such methods should provide sensitive detection of expression in vivo and should be unaffected by concurrent pharmacologic and dietary regimens. We present the results of studies in a neonatal bovine model of citrullinemia, an inborn error of urea-cycle metabolism characterized by deficiency of argininosuccinate synthetase and consequent life-threatening hyperammonemia. Measurements of the flux of nitrogen from orally administered 15NH4 to [15N]urea were used to determine urea-cycle activity in vivo. In control animals, these isotopic measurements proved to be unaffected by pharmacologic treatments. Systemic administration of a first-generation E1-deleted adenoviral vector expressing human argininosuccinate synthetase resulted in transduction of hepatocytes and partial correction of the enzyme defect. The isotopic method showed significant restoration of urea synthesis. Moreover, the calves showed clinical improvement and normalization of plasma glutamine levels after treatment. The results show the clinical efficacy of treating a large-animal model of an inborn error of hepatocyte metabolism in conjunction with a method for sensitively measuring correction in vivo. These studies will be applicable to human trials of the treatment of this disorder and other related urea-cycle disorders.
Subject(s)
Amino Acid Metabolism, Inborn Errors/therapy , Argininosuccinate Synthase/deficiency , Argininosuccinate Synthase/genetics , Cell Transplantation , Citrulline/blood , Genetic Therapy/methods , Liver/cytology , Adenoviridae , Amino Acid Metabolism, Inborn Errors/genetics , Ammonia/metabolism , Ammonia/toxicity , Animals , Animals, Newborn , Argininosuccinate Synthase/biosynthesis , Cattle , Female , Genetic Vectors , Glutamine/blood , Heterozygote , Humans , MaleSubject(s)
Cattle Diseases/diagnosis , Genetic Carrier Screening/methods , Mannosidases/blood , Polymerase Chain Reaction/veterinary , alpha-Mannosidosis/veterinary , Animals , Australia , Blood Chemical Analysis/economics , Blood Chemical Analysis/veterinary , Cattle , Cattle Diseases/genetics , Cattle Diseases/prevention & control , DNA/analysis , Female , Hair/chemistry , Male , Polymerase Chain Reaction/economics , alpha-Mannosidosis/diagnosis , alpha-Mannosidosis/genetics , alpha-Mannosidosis/prevention & controlABSTRACT
Citrullinaemia is an autosomal recessive disorder caused by the deficiency of argininosuccinate synthase. The deficiency of this enzyme results in an interruption in the urea cycle and the inability to dispose of excess ammonia derived from the metabolism of protein. The only treatment for this disorder has been dietary restriction of protein and supplementation with medications allowing for alternative excretion of excess nitrogen. Gene therapy offers the possibility of a long-term cure for disorders like citrullinaemia by expressing the deficient gene in the target organ. We have explored the use of adenoviral vectors as a treatment modality for citrullinaemia in two animal models, a naturally occurring bovine model and a murine model created by molecular mutagenesis. Mice treated with adenoviral vectors expressing argininosuccinate synthase lived significantly longer than untreated animals (11 days vs 1 day; however, the animals did not exhibit normal weight gain during the experiment, indicating that the therapeutic effectiveness of the transducing virus was suboptimal. It is speculated that part of the failure to observe better clinical outcome might be due to the deficiency of arginine. In the bovine model, the use of adenoviral vectors did not result in any change in the clinical condition of the animals or in the level of plasma ammonia. However, the use of 15N isotopic ammonia allowed us to assess the flux of nitrogen through the urea cycle during the experiment. These studies revealed a significant increase in the flux through the urea cycle following administration of adenoviral vectors expressing argininosuccinate synthase. We conclude that the use of adenoviral vectors in the treatment of citrullinaemia is a viable approach to therapy but that it will be necessary to increase the level of transduction and to increase the level of enzyme produced from the recombinant viral vector. Future experiments will be designed to address these issues.
Subject(s)
Amino Acid Metabolism, Inborn Errors/therapy , Argininosuccinate Synthase/genetics , Citrulline/blood , Genetic Therapy , Adenoviruses, Human/genetics , Amino Acid Metabolism, Inborn Errors/drug therapy , Amino Acid Metabolism, Inborn Errors/pathology , Ammonia/blood , Animals , Arginine/pharmacology , Argininosuccinate Synthase/biosynthesis , Argininosuccinate Synthase/deficiency , Benzoates/pharmacology , Benzoic Acid , Cattle , Disease Models, Animal , Evaluation Studies as Topic , Gene Transfer Techniques , Genetic Vectors , Liver , Mice , Nitrogen/blood , Treatment Outcome , Urea/bloodSubject(s)
Cattle/genetics , Factor XI/genetics , Amino Acid Sequence , Animals , Base Sequence , DNA, Complementary/chemistry , Exons , Factor XI/chemistry , Gene Library , Introns , Molecular Sequence Data , Polymerase Chain Reaction , Polymorphism, Restriction Fragment Length , Sequence Alignment , Sequence Analysis, DNA/methodsABSTRACT
DNA tests, based on the polymerase chain reaction (PCR), were developed for the detection of two breed-specific mutations responsible for the autosomal recessive disorder bovine alpha-mannosidosis. The tests involve separate amplification of two exons of the lysosomal alpha-mannosidase gene followed by restriction enzyme digestion of the amplicons. We demonstrate that one of the mutations, the 662G-->A transition, is responsible for alpha-mannosidosis in Galloway cattle. The other mutation, the 961T-->C transition, is uniquely associated with alpha-mannosidosis in Angus, Murray Grey and Brangus cattle from Australia. The 961T-->C mutation was also detected in Red Angus cattle exported from Canada to Australia as embryos. All 39 animals classified as heterozygotes on the basis of biochemical assays were heterozygous for one of the two mutations. None of 102 animals classified as homozygous-normal on the basis of biochemical assays possessed the mutations. Our results indicate that the two breed-specific mutations may have arisen in Scotland and by the export of animals and germplasm disseminated to America, New Zealand and Australia.
Subject(s)
Cattle Diseases/genetics , Mannosidases/genetics , Point Mutation , alpha-Mannosidosis/veterinary , Animals , Australia , Base Sequence , Canada , Cattle , DNA Primers , Genetic Carrier Screening , Homozygote , Lysosomes/enzymology , Mannosidases/deficiency , Polymerase Chain Reaction/methods , Polymerase Chain Reaction/veterinary , Species Specificity , alpha-Mannosidase , alpha-Mannosidosis/geneticsABSTRACT
A variety of autosomal recessive defects, many lethal to the newborn calf, have been recognized in Australia. Definition of a defect at the biochemical or molecular level facilitates development of heterozygote detection tests essential for efficient disease control programs. The prevalence of alpha-mannosidosis in Angus and Murray Greys, generalized glycogenosis in Brahmans and Shorthorns, and citrullinemia in Holstein/Friesians has been reduced as a result of industry-sponsored disease-control programs. These defects were disseminated as a consequence of selection focused on desirable traits carried by individuals. In the long term, an increase in crossbreeding in commercial beef production will reduce the significance of recessive defects. Caution will be required to reduce the risk of dissemination of recessive defects resulting from increased selection pressure within the dairy industry presently dominated by Holstein/Friesians.
Subject(s)
Cattle Diseases/diagnosis , Cattle Diseases/genetics , Cattle/genetics , Genetic Diseases, Inborn/veterinary , Animal Welfare , Animals , Australia/epidemiology , Cattle Diseases/epidemiology , Dairying/methods , Genetic Diseases, Inborn/diagnosis , Genetic Diseases, Inborn/epidemiology , Heterozygote , Selection, GeneticSubject(s)
Cattle Diseases/diagnosis , DNA/analysis , Genes, Recessive/genetics , Genetic Carrier Screening/methods , Hair Follicle/chemistry , Animals , Cattle , Cattle Diseases/blood , Cattle Diseases/genetics , Citrulline/blood , Citrulline/genetics , DNA/genetics , Genetic Testing , Genotype , Leukocyte-Adhesion Deficiency Syndrome/diagnosis , Leukocyte-Adhesion Deficiency Syndrome/genetics , Leukocyte-Adhesion Deficiency Syndrome/veterinary , Maple Syrup Urine Disease/diagnosis , Maple Syrup Urine Disease/genetics , Maple Syrup Urine Disease/veterinary , Polymerase Chain Reaction/veterinary , Polymorphism, Genetic , Porphyrias/diagnosis , Porphyrias/genetics , Porphyrias/veterinaryABSTRACT
The clinical, pathological and biochemical manifestations of maple syrup urine disease (MSUD) are similar in Poll Hereford and Poll Shorthorn x Poll Hereford calves. No significant differences were observed in branched-chain amino acid concentrations in plasma, or of branched-chain keto acid dehydrogenase activity in fibroblasts, between Poll Herefords homozygous normal and heterozygous for the mutation responsible for MSUD. Haemopoietic chimerism resulted in incorrect diagnosis of the MSUD genotype in 30% of non-identical twins when blood DNA was analysed using allele-specific amplification. Hair roots are shown to be a suitable source of target DNA for genotyping Poll Hereford cattle for the MSUD mutation. Twelve of 203 (5.8%) aged Poll Hereford bulls, sampled at saleyards during the last 4 months of 1993, were found to be heterozygous for the mutation. In contrast, the mutant sequence was detected in only 1 of 150 (0.7%) 2- and 3-year-old Poll Hereford bulls offered for sale at 2 stud sales held during 1993, suggesting that the prevalence of the disease may decline over the next few years.
Subject(s)
Cattle Diseases/diagnosis , Cattle Diseases/genetics , Genetic Carrier Screening/methods , Heterozygote , Maple Syrup Urine Disease/veterinary , 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) , Alleles , Amino Acids, Branched-Chain/blood , Animals , Cattle , Cattle Diseases/epidemiology , Female , Fibroblasts/enzymology , Gene Amplification , Genotype , Homozygote , Ketone Oxidoreductases/analysis , Male , Maple Syrup Urine Disease/diagnosis , Maple Syrup Urine Disease/genetics , Multienzyme Complexes/analysis , Mutation , New South Wales/epidemiologyABSTRACT
Northern analyses revealed normal levels of acidic alpha-glucosidase mRNA in cultured fibroblasts from a Shorthorn calf affected with glycogenosis but a gross deficiency in an affected Brahman calf. Analyses of acidic alpha-glucosidase activity, relative to that of other lysosomal enzymes, in blood mononuclear cells revealed greater variation within and between Brahman herds than Shorthorn herds. A Msp1 restriction fragment length polymorphism associated with glycogenosis in Brahmans was not found in Shorthorns. These results are considered in relation to molecular heterogeneity for AAG deficiency in cattle and its implications for disease control programs.
Subject(s)
Breeding , Cattle Diseases/genetics , Crosses, Genetic , Glycogen Storage Disease/veterinary , Heterozygote , Animals , Blotting, Northern , Cattle , Cattle Diseases/enzymology , Cattle Diseases/pathology , Cells, Cultured , DNA, Complementary/analysis , DNA, Complementary/genetics , Female , Fibroblasts/chemistry , Fibroblasts/enzymology , Fibroblasts/pathology , Genetic Carrier Screening , Genetic Variation , Glycogen Storage Disease/genetics , Glycogen Storage Disease/metabolism , Male , Polymerase Chain Reaction , Polymorphism, Restriction Fragment Length , RNA, Messenger/analysis , RNA, Messenger/genetics , alpha-Glucosidases/analysis , alpha-Glucosidases/deficiency , alpha-Glucosidases/geneticsABSTRACT
In Poll Herefords, it is known that maple syrup urine disease results from a nonsense mutation in codon -6 of the gene for the E1 alpha subunit of branched-chain alpha-keto acid dehydrogenase. The disease also occurs in Poll Shorthorns, but its molecular basis in this breed has not yet been determined. Allele-specific hybridization and allele-specific amplification, both based on the Poll Hereford mutation, failed to detect the mutant allele in Poll Shorthorn heterozygotes, and detected the normal allele in affected Poll Hereford-cross-Poll Shorthorn calves. These results demonstrate between breed molecular heterogeneity for bovine maple syrup urine disease.
Subject(s)
Cattle Diseases/genetics , Ketone Oxidoreductases/genetics , Maple Syrup Urine Disease/veterinary , Multienzyme Complexes/genetics , Point Mutation , 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) , Alleles , Animals , Base Sequence , Cattle , Consensus Sequence , DNA/blood , DNA/genetics , DNA Primers , Genetic Carrier Screening , Introns , Macromolecular Substances , Maple Syrup Urine Disease/genetics , Molecular Sequence Data , Nucleic Acid Hybridization , Polymerase Chain ReactionABSTRACT
Several observations are documented which illustrate that haemopoietic chimaerism is a potential source of error when using assays of cellular components of blood to determine genotype for inherited defects in cattle. Acidic alpha-glucosidase activity in peripheral mononuclear cells of a twin Brahman bull that had sired calves affected with generalized glycogenosis was similar to that in cells from homozygous normal animals. Activity in fibroblasts from this bull was similar to that in heterozygotes. alpha-mannosidase activity in fibroblasts of a twin Murray Grey bull with low activity in peripheral granulocytes but high activity in plasma was similar to that in animals homozygous normal for alpha-mannosidosis. Normal argininosuccinate synthetase nucleotide sequence was detected in leucocytes from two calves affected with citrullinemia and mutant sequence detected in leucocytes from their homozygous normal co-twins.
Subject(s)
Cattle Diseases/genetics , Chimera , Genetic Carrier Screening , Glycogen Storage Disease Type II/veterinary , Animals , Bone Marrow , Cattle , Cells, Cultured , Citrulline/blood , DNA , Female , Fibroblasts/enzymology , Fibroblasts/metabolism , Genetic Carrier Screening/methods , Genotype , Glycogen Storage Disease Type II/genetics , Homozygote , Male , Mannosidases/metabolism , Twins/genetics , alpha-MannosidaseABSTRACT
The biochemical basis of over 300 inherited diseases has been defined in humans, and the majority involve abnormalities in enzymes. The rate of discovery of new defects is accelerating as biochemical and molecular technologies improve. The majority of inherited defects are expressed before puberty and approximately 25% are apparent at birth. Genomes of other mammals are similar and have been subjected to similar mutation pressures; therefore, it is probable that a range of inherited defects exists in livestock similar to that in humans. Because modern livestock populations have emerged from small population bases, the range of genetic aberrations, within breeds, will be less than in the general human population. Even if there is a 10-fold difference, however, there will be a bewildering array of defects possible in each breed. Because the level of inbreeding within livestock populations is greater than in the general human population, on the other hand, the prevalence of specific defects will be higher. It is probable that a high prevalence of a lethal recessive defect could occur within a particular livestock population and escape recognition. First, livestock producers accept a relatively high neonatal mortality rate without seeking a diagnosis. Second, few if any veterinary diagnostic facilities possess either the instrumentation or the analytic skills essential for investigating the vast range of potential inborn errors of metabolism. Third, national selection programs--e.g., those employed within the dairy industry--tend to use production data from adult progeny in selection. Consequently, the programs would not detect differences in fetal or neonatal mortality rates among descendants of specific sires until a deleterious defect had been widely disseminated.(ABSTRACT TRUNCATED AT 250 WORDS)
Subject(s)
Animals, Domestic , Enzymes/deficiency , Metabolism, Inborn Errors/veterinary , Animals , Argininosuccinate Synthase/deficiency , Cattle , Cattle Diseases/enzymology , Cattle Diseases/genetics , Citrulline/blood , Factor XI Deficiency/enzymology , Factor XI Deficiency/genetics , Factor XI Deficiency/veterinary , Maple Syrup Urine Disease/enzymology , Maple Syrup Urine Disease/genetics , Maple Syrup Urine Disease/veterinary , Metabolism, Inborn Errors/enzymology , Metabolism, Inborn Errors/genetics , Multienzyme Complexes/deficiency , Orotate Phosphoribosyltransferase/deficiency , Orotidine-5'-Phosphate Decarboxylase/deficiency , Porphyrias/enzymology , Porphyrias/genetics , Porphyrias/veterinaryABSTRACT
Five Devon cattle with suspected ceroid-lipofuscinosis and aged between 19 and 39 months of age were humanely slaughtered and subjected to post-mortem examination. There was severe atrophy of the cerebrum, particularly of the occipital cortex. Microscopy also showed severe atrophy of the retina with complete loss of photoreceptor cells, even in the youngest animal examined. Histopathologically the disease was characterised by accumulation of a fluorescent lipopigment in neurones, including those of the retina and a severe astrocytosis. The disease, which is characterised by the accumulation of subunit c of mitochondrial ATP synthase, is similar to that extensively described in South Hampshire sheep except that the retinal lesions were more severe. In contrast, tremors were not noted in the cattle. The clinical history and similarity to the disease in sheep and other species indicated inheritance was as an autosomal recessive trait.