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Biomedical subjects

G K Brown

Publications and source records attributed to G K Brown.

At least 19 recordsLinked to original sources
PubMed1992

Mutations and polymorphisms in the pyruvate dehydrogenase E1 alpha gene.

We present an update on mutations and polymorphisms in the human X chromosome located pyruvate dehydrogenase E1 alpha gene. A total of 20 different mutations are tabulated. The mutations include deletions, insertions, and point mutations. Certain sequences seem particularly prone to mutation. Most of the mutations are found in exons 10 and 11. Furthermore, four of the mutations are seen in unrelated patients. Little is known about how the mutations affect the structure or function of the pyruvate dehydrogenase complex.

Amino Acid Sequence↗
PubMed1992

Pyruvate dehydrogenase E1 alpha deficiency.

Pyruvate dehydrogenase (PDH) deficiency has long been recognized as the most common defined cause of primary lactic acidosis in infancy and early childhood. More recently, it has also been described in patients with subacute/chronic neurodegenerative disease without significant metabolic acidosis. The great majority of cases of PDH deficiency result from a genetic defect in the E1 alpha subunit of the complex. PDH E1 alpha deficiency is an X-linked inborn error of metabolism in which a high proportion of heterozygous females manifest the condition. In this review of 29 patients with PDH E1 alpha deficiency, particular emphasis is given to those aspects of the disorder which are specifically related to the X chromosome location of the PDH E1 alpha gene. These include the broad spectrum of clinical presentations and problems of diagnosis, especially antenatal diagnosis, in females.

Acidosis, Lactic↗
PubMed1992

X-linked pyruvate dehydrogenase E1 alpha subunit deficiency in heterozygous females: variable manifestation of the same mutation.

Three female patients are described with pyruvate dehydrogenase (PDH) deficiency as a result of mutation in the X-linked gene for the E1 alpha subunit of the complex. Two of these patients illustrate typical presentations of PDH E1 alpha deficiency, with severe neurological dysfunction, degenerative changes and developmental anomalies in the brain, together with variable lactic acidosis. The third patient extends the known spectrum of the condition to include mild to moderate mental retardation and seizures in an adult. All three patients have the same mutation in the PDH E1 alpha gene. This mutation, a C-to-T substitution in a CpG dinucleotide in amino acid codon 302 (designated R302C), results in the replacement of arginine by cysteine at this position. The mildly affected adult was the mother of one of the other patient, making this the first described instance of mother-to-daughter transmission of a mutation causing PDH E1 alpha deficiency. The genetic basis of the variable expression of X-linked PDH E1 alpha deficiency in heterozygous females is discussed.

Adolescent↗
PubMed1991

Characterization of the mutations in three patients with pyruvate dehydrogenase E1 alpha deficiency.

The human pyruvate dehydrogenase complex catalyses the oxidative decarboxylation of pyruvate to acetyl-CoA. Defects in several of the seven subunits have been reported, but the majority of mutations affect the E1 component and especially the E1 alpha subunit. However, the clinical presentation of patients with pyruvate dehydrogenase E1 alpha deficiency is extremely variable. Dependency of the brain on pyruvate dehydrogenase activity and localization of the gene for the somatic form of the pyruvate dehydrogenase E1 alpha subunit to the X chromosome provide the basis for a better understanding of the variation in the clinical manifestations. Further understanding of the function and interaction of subunits and the pathophysiology of pyruvate dehydrogenase deficiency necessitates the characterization of mutations in the pyruvate dehydrogenase complex. We report the analysis of three patients with pyruvate dehydrogenase E1 alpha deficiency. One female has a three base pair deletion which affects dephosphorylation of the subunit. Of two males analysed, one has a two base pair deletion causing a shift in the reading frame. The other has a base change, resulting in an Arg to His substitution. All three mutations are located near the carboxyl terminus of the subunit.

Amino Acid Sequence↗
PubMed1990

Pyruvate dehydrogenase E1 alpha subunit genes in the mouse: mapping and comparison with human homologs.

Two gene loci for the E1 alpha subunit of the pyruvate dehydrogenase (PDH) complex have been mapped in the mouse by in situ hybridization. One locus maps to the X chromosome in the region F3-F4, the other to chromosome 19, in band B close to the centromere. This arrangement is exactly comparable to the situation in man where there is an X-linked PDH E1 alpha locus and an autosomal locus on chromosome 4. Comparison of the regional localization of the human and mouse X-linked PDH E1 alpha genes provides further information concerning sites of rearrangement of segments of the X chromosome during mammalian evolution. The human autosomal PDH E1 alpha gene is a "processed" gene, which lacks the introns that are present in the X-linked gene. It codes for a testis-specific E1 alpha subunit that is only expressed after the onset of spermatogenesis. The comparative mapping results in the mouse suggest that the genetic organization and pattern of expression of the two PDH E1 alpha genes is the same in the two species.

Animals↗
PubMed1990

A testis-specific form of the human pyruvate dehydrogenase E1 alpha subunit is coded for by an intronless gene on chromosome 4.

The pyruvate dehydrogenase (PDH) complex converts pyruvate to acetyl CoA, an essential step in aerobic glucose metabolism. We have previously shown that the gene for the E1 alpha subunit of this complex, expressed in somatic tissues, is located on band p22.1 of the human X chromosome. This gene, PDHA1, contains 10 introns and spans approximately 17 kb. An autosomal locus, PDHA2, showing significant cross-hybridization with a PDH E1 alpha cDNA probe, was detected on chromosome 4, in the region q22-q23. We here report the isolation of human testis-specific PDH E1 alpha cDNA clones. The similarity with the X chromosome-linked cDNA coding sequence at the nucleotide level is 84%. Specific amplification using the polymerase chain reaction confirmed the presence of a testis-specific mRNA and indicated that postmeiotic spermatogenic cells express this subunit. In situ hybridization with a unique probe from the 3' untranslated region of the testis-specific cDNA showed that the gene for this form of PDH E1 alpha is localized on chromosome 4 in the region q22-q23. The autosomal human gene was isolated from a chromosome 4-specific genomic library. The transcribed region of this gene is identical to the testis-specific cDNA sequence. It completely lacks introns and possesses characteristics of a functional processed gene.

Amino Acid Sequence↗
PubMed1990

Differential methylation of the hypervariable locus DXS255 on active and inactive X chromosomes correlates with the expression of a human X-linked gene.

Consistent differences in methylation of particular cytosine residues in the DNA of active and inactive X chromosomes can be used for rapid, direct analysis of X-inactivation patterns in different female tissues. We have studied methylation of the highly polymorphic DXS255 locus in tissues from patients with deficiency of the E1 alpha subunit of the pyruvate dehydrogenase complex in whom the results can be correlated directly with total enzyme activity, levels of immunoreactive protein, and patterns of cell mosaicism. The results confirm that methylation of the DXS255 locus correlates with X-chromosome expression. In patients and normal controls, the pattern of X inactivation varied widely from tissue to tissue and often deviated markedly from a 50:50 proportion. These deviations are likely to reflect small numbers of tissue-specific stem cells at the time of random X inactivation and cannot be taken alone as evidence for selection or "nonrandom" inactivation.

Dosage Compensation, Genetic↗
PubMed1990

A causal analysis of chronic pain and depression.

There is considerable controversy in the literature regarding the extent to which chronic pain and depression are associated and the possible causal relationship of such an association. The present study examines these issues with a sample of 243 patients diagnosed with rheumatoid arthritis (RA) who were mailed questionnaires for six waves of data collection. The results indicated that RA patients experience higher levels of depressive symptomatology than community samples. Using a two-latent-variable, cross-lagged design, covariance structural modeling was conducted on self-report measures of pain and depression over 6-month intervals. Results most strongly supported a causal model in which pain predicts depression during the last 12 months of the study.

Arthritis, Rheumatoid↗
PubMed1990

Pyruvate dehydrogenase deficiency caused by deletion of a 7-bp repeat sequence in the E1 alpha gene.

A 7-bp deletion in the X-chromosomal pyruvate dehydrogenase (PDH) E1 alpha gene was characterized in a female patient with the "cerebral" form of PDH deficiency. The mutation was localized using the chemical cleavage method and further characterized by application of the polymerase chain reaction and DNA sequencing. This 7-bp sequence is found in the normal gene as a direct tandem repeat. The deletion causes a change in the reading frame. Results have shown that the level of normal sized PDH E1 alpha in the fibroblast sample was approximately 30% of that of normal controls. This is consistent with normal transcription from the X chromosome carrying the nonmutated form of the E1 alpha subunit, as this chromosome is active in approximately 30% of this patient's cells. The severity of PDH E1 alpha deficiency in affected females is to a large extent dependent on the X-chromosome inactivation pattern in the brain. The clinical picture might therefore vary significantly between patients with the same mutation. We show that the 7-bp deletion must be a de novo mutation, because it is not present in the parent's X chromosomes. Furthermore, the deletion was not detected in chorionic villus samples in two subsequent pregnancies.

Chromosome Deletion↗
PubMed1989

Structural organization of the gene for the E1 alpha subunit of the human pyruvate dehydrogenase complex.

The structural organization of the X-linked gene for the E1 alpha subunit of the human pyruvate dehydrogenase complex has been determined by restriction endonuclease mapping and DNA sequence analysis of overlapping genomic clones. The gene is approximately 17 kilobase pairs long. It contains 11 exons ranging from 61 to 174 base pairs and introns ranging from 600 base pairs to 5.7 kilobase pairs. All the splice donor and acceptor sites conform to the GT/AG rule. The transcription initiation site was determined by S1 nuclease mapping. The DNA sequence around this site is very GC-rich. A "TATA box"-like sequence and a "CAAT box"-like sequence are present 24 and 113 bases upstream from the cap site, respectively. Also upstream from the cap site are several sets of inverted repeats, direct repeats, several sequences resembling the transcription factor Sp1 binding site, a glucocorticoid-responsive element, and two cAMP receptor binding sites.

Amino Acid Sequence↗
PubMed1989

Validity of the Center for Epidemiological Studies Depression Scale in arthritis populations.

Using data from 3 studies of patients with rheumatoid arthritis, we examined the extent to which responses to items in the Center for Epidemiological Studies Depression Scale (CES-D) are influenced by aspects of the disease process other than depression. Our findings suggested that 4 CES-D items (i.e., "I felt that everything I did was an effort," "I felt hopeful about the future," "My sleep was restless," and "I could not get going") may be influenced by aspects of the disease process and, thus, are not necessarily indicative of depression among persons with arthritis. The impact that these items have on the interpretation of CES-D scores was assessed in relation to 2 research issues: estimation of the prevalence and severity of depression in arthritis populations and identification of the determinants of depression among individuals with arthritis. Our results suggest that the original CES-D may overestimate the prevalence and severity of depression among patients with arthritis. The magnitude of this bias is modest, however. The results also suggest that in studies designed to identify the determinants of depression among individuals with arthritis, inclusion of the 4 items identified is unlikely to have any effect on study findings.

Adult↗
PubMed1989

Striatal degeneration in glutaric acidaemia type II.

A girl of first cousin parents presented in the 1st year of life with a progressive neurological disease with muscle weakness and hypotonia, accompanied later by dystonia. Investigations, including gas chromatography of urine, showed no abnormality. Autopsy showed marked neuronal loss and gliosis in the putamen and globus pallidus. The activity of glutaryl-CoA dehydrogenase in cultured fibroblasts was normal, but the activity of electron transfer flavoprotein was markedly diminished. Retrospective study of urine by capillary gas chromatography/mass spectrometry showed small amounts of glutaric and other organic acids. This is the first report of striatal degeneration in association with glutaric acidaemia type II. The neuropathological changes were milder than those in glutaric acidaemia type I.

Child, Preschool↗
PubMed1989

Cytochrome c oxidase deficiency in subacute necrotizing encephalopathy (Leigh syndrome).

Tissues and cultured fibroblasts from two patients with Leigh syndrome (subacute necrotizing encephalopathy) were examined. A systemic defect in cytochrome oxidase was identified by enzyme assay and estimation of cytochrome concentrations. Immunochemical analysis showed a reduction of most subunits of the cytochrome oxidase complex. The rate of synthesis of cytochrome oxidase subunits, determined by labelling experiments in cultured fibroblasts, was the same in the patients and normal controls. The reduced cytochrome oxidase content of the patients' tissues must therefore result from abnormal turnover of the protein subunits.

Animals↗
PubMed1989

X-chromosome localization of the functional gene for the E1 alpha subunit of the human pyruvate dehydrogenase complex.

The functional gene locus for the E1 alpha subunit of the human pyruvate dehydrogenase complex has been localized to the p22.1-22.2 region of the X chromosome by in situ hybridization and analysis of somatic cell hybrids with various human X-chromosome rearrangements. Another locus showing significant cross-hybridization with an E1 alpha cDNA probe was detected on chromosome 4, in the region q22. The X-chromosome localization of the pyruvate dehydrogenase E1 alpha subunit gene provides a number of possible explanations for the clinical and biochemical variability which is a major feature of human pyruvate dehydrogenase deficiency.

Animals↗
PubMed1989

Pain coping strategies and depression in rheumatoid arthritis.

A study was conducted to examine the role of pain episodes and the role of active and passive pain coping strategies in predicting depression in 287 patients with rheumatoid arthritis (RA). The independent effects of pain and pain coping strategies, as well as the interaction effects between pain and pain coping strategies on depression, were evaluated cross-sectionally and prospectively over a 6-month interval. The cross-sectional findings revealed that pain, passive coping, and the interaction between pain and passive coping contributed independent variance, all accounting for higher depression. Of principal interest was the finding that the frequent use of passive pain coping strategies in the face of high pain contributed to the most severe level of depression over time. These results were obtained after controlling for the potentially confounding effects of prior depression, functional disability, and medication status. These data imply that there may be a potential benefit of developing techniques to reduce the use of passive pain coping strategies to deal with chronic arthritis pain in cognitive-behavioral pain management programs.

Adaptation, Psychological↗
PubMed1989

Maple syrup urine disease in calves: a clinical, pathological and biochemical study.

The clinical, pathological and biochemical findings of a study of 30 Poll Hereford, Hereford, Poll Hereford cross or Hereford cross calves affected with branched chain ketoacid dehydrogenase (BCKAD) complex deficiency or maple syrup urine disease (MSUD) are presented. In breeding studies, 6 of 21 calves from obligate heterozygote matings were affected with MSUD, suggesting the disease is inherited in an autosomal recessive manner. Calves were clinically affected from birth, but there were variations in the subsequent course of progressive deterioration of central nervous system function. Concentrations of the branched chain amino acids and keto acids were elevated in pre-suckle plasma and cerebellar water content was higher in affected calves. Activity of BCKAD complex was minimal in fibroblasts cultured from an affected calf. Spongiform encephalopathy and elevated ratios of the branched to straight chain amino acids in formalin fixed cerebral tissue were found in a stillborn foetus and a 3-month-old Hereford calf. These findings suggest the disease occurs prenatally and that a delayed form may exist.

Alanine↗