Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Mitochondrial trifunctional protein (MTP) deficiency is a rare inherited metabolic disorder of mitochondrial fatty acid oxidation. We newly characterized three novel mutations in 2 Japanese patients with MTP deficiency, and investigated the clinical and molecular aspects of 5 Japanese patients including 3 previously reported cases. Herein, we describe the characterization of four missense mutations, R214C, H346R, R411K, and V422G, in the HADHB gene, which have been identified in Japanese patients, employing a newly developed, sensitive transient expression analysis. Co-transfection of wild-type HADHA and HADHB cDNAs in SV40-transfected fibroblasts from a MTP-deficient patient yielded sufficient enzyme activity to evaluate low-level residual enzyme activity, using two incubation temperatures of 30 degrees C and 37 degrees C. At 30 degrees C, residual enzyme activity was higher than that at 37 degrees C in V422G, R214C, and R411K. However, H346R, which was seen in the most severe case, showed no enzyme activity at both temperatures. Our results demonstrate that a defect of HADHB in MTP deficiency is rather common in Japanese patients, and the mutational spectrum is heterogeneous. The present findings showed that all missense mutations in this study were disease-causing. Although the number of patients is still limited, it is suggested that the phenotype is correlated with the genotype and a combination of two mutant alleles of the HADHB gene in MTP deficiency.
Mol Genet Metab 2009 Dec
PMID:Clinical and molecular aspects of Japanese patients with mitochondrial trifunctional protein deficiency. 1969 28

LET-721 is the Caenorhabditis elegans ortholog of electron-transferring flavoprotein dehydrogenase (ETFDH). We are studying this protein in C. elegans in order to establish a tractable model system for further exploration of ETFDH structure and function. ETFDH is an inner mitochondrial membrane localized enzyme that plays a key role in the beta-oxidation of fatty acids and catabolism of amino acids and choline. ETFDH accepts electrons from at least twelve mitochondrial matrix flavoprotein dehydrogenases via an intermediate dimer protein and transfers the electrons to ubiquinone. In humans, ETFDH mutations result in the autosomal recessive metabolic disorder, multiple acyl-CoA dehydrogenase deficiency. Mutants of let-721 in C. elegans are either maternal effect lethals or semi-sterile. let-721 is transcribed in the pharynx, body wall muscle, hypoderm, intestine and somatic gonad. In addition, the subcellular localization of LET-721 agrees with predictions that it is localized to mitochondria. We identified and confirmed three cis-regulatory sequences (pha-site, rep-site, and act-site). Phylogenetic footprinting of each site indicates that they are conserved between four Caenorhabditis species. The pha-site mapped roughly 1,300 bp upstream of let-721's translational start site and is necessary for expression in pharyngeal tissues. The rep-site mapped roughly 830 bp upstream of the translational start site and represses expression of LET-721 within pharyngeal tissues. The act-site mapped roughly 800 bp upstream of the translational start site and is required for expression within spermatheca, body wall muscle, pharynx, and intestine. Taken together, we find that LET-721 is a mitochondrially expressed protein that is under complex transcriptional controls.
Mol Genet Genomics 2009 Dec
PMID:Characterizing the transcriptional regulation of let-721, a Caenorhabditis elegans homolog of human electron flavoprotein dehydrogenase. 1977 99

Sex hormone-binding globulin (SHBG) is the main transport binding protein for sex steroid hormones in plasma and regulates their accessibility to target cells. Plasma SHBG is secreted by the liver under the control of hormones and nutritional factors. In the human hepatoma cell line (HepG2), thyroid and estrogenic hormones, and a variety of drugs including the antioestrogen tamoxifen, the phytoestrogen, genistein and mitotane (Op'DDD) increase SHBG production and SHBG gene promoter activity. In contrast, monosaccharides (glucose or fructose) effectively decrease SHBG expression by inducing lipogenesis, which reduces hepatic HNF-4alpha levels, a transcription factor that play a critical role in controlling the SHBG promoter. Interestingly, diminishing hepatic lipogenesis and free fatty acid liver biosynthesis also appear to be associated with the positive effects of thyroid hormones and PPARgamma antagonists on SHBG expression. This mechanism provides a biological explanation for why SHBG is a sensitive biomarker of insulin resistance and the metabolic syndrome, and why low plasma SHBG levels are a risk factor for developing hyperglycemia and type 2 diabetes, especially in women. These important advances in our knowledge of the regulation of SHBG expression in the liver open new approaches for identifying and preventing metabolic disorder-associated diseases early in life.
Mol Cell Endocrinol 2010 Mar 05
PMID:Sex hormone-binding globulin gene expression in the liver: drugs and the metabolic syndrome. 1978 70

Polycystic ovary syndrome (PCOS) is an endocrine-metabolic disorder associated with insulin resistance and compensatory hyperinsulinemia. Scarce information is available on the expression of molecules involved in the insulin pathway in endometria from women with PCOS. Therefore, we examined the protein levels of insulin-signaling molecules, like insulin receptor, insulin-receptor substrate (IRS)-1, pIRS-1Y612, Akt, AS160, pAS160T642 and GLUT4 in endometria from PCOS women with or without hyperinsulinemia. Protein levels were assessed by Western blot and immunohistochemistry in 21 proliferative-phase endometria from control women (CE = 7), normoinssulinemic PCOS women (PCOSE-NI = 7) and hyperinsulinemic PCOS women (PCOSE-HI = 7). The data show no differences in the expression of insulin receptor between all groups as assessed by Western blot; however, IRS-1 and pIRS-1Y612 were lower in PCOSE-HI than controls and PCOSE-NI (P < 0.05). AS160 was detected in all analyzed tissues with similar expression levels between groups. Importantly, PCOSE-HI exhibited lower levels of pAS160T642 (P < 0.05) and of GLUT4 (P < 0.05) compared with CE. The immunohistochemistry for insulin receptor, IRS-1, Akt, AS160 and GLUT4 showed epithelial and stromal localization; IRS-1 staining was lower in PCOSE-HI (P < 0.05). In conclusion, human endometrium has the machinery for glucose uptake mediated by insulin. The diminished expression of GLUT4, as well as the lower level of pIRS-1Y612 and pAS160T642 exhibited by PCOSE-HI, suggests a disruption in the translocation of vesicles with GLUT4 to the cell surface in these patients.
Mol Med 2010 Mar
PMID:Changes in the expression of insulin signaling pathway molecules in endometria from polycystic ovary syndrome women with or without hyperinsulinemia. 2001 Dec 49

Nonketotic hyperglycinemia (NKH), a metabolic disorder due to defects in the glycine cleavage system, leads to the accumulation of toxic levels of glycine. Glycine levels in these patients may be lowered by sodium benzoate treatment. Benzoic acid binds to glycine to form hippurate, which is subsequently eliminated through the kidneys. At high concentrations, hippuric acid can crystallize in the kidneys and cause renal failure. Therefore, it is desirable to have benzoic acids concentrations within a therapeutic range. In the gas chromatography method described, the drug from the acidified serum or plasma sample is extracted using ethyl acetate. The organic phase containing drug is separated and dried under a stream of nitrogen. After trimethylsilyl derivatization, benzoic acid analysis is done on a gas chromatograph mass spectrometer. Quantitation of the drug in a sample is achieved by comparing responses of the unknown sample to the responses of the calibrators using selected ion monitoring. Benzoic acid D(5) is used as an internal standard.
Methods Mol Biol 2010
PMID:Determination of benzoic acid in serum or plasma by gas chromatography-mass spectrometry (GC/MS). 2007 64

Phenylketonuria (PKU) is a metabolic disorder that results in significant brain dysfunction if untreated. Although phenylalanine restricted diets instituted at birth have clearly improved PKU outcomes, neuropsychological deficits and neurological changes still represent substantial problems. The specific mechanisms by which Phe affects the brains of individuals with PKU are yet fully determined. The use of animal models in PKU research significantly broadens the possibilities for investigating these mechanisms. This report presents an overview of findings from animal studies on the mechanisms of Phe action in the PKU brain, discussing the importance of changes in protein synthesis, transport of large neutral amino acids across the blood-brain barrier, synthesis of monoamine neurotransmitters, activity of glutamate receptors, animal behavior, and translation of animal behavioral data to patients with PKU. This report shows that great progress has been made in past years and demonstrates the importance of further animal research to understand the neuropathological mechanisms underlying brain dysfunction in PKU. A better understanding of these mechanisms will guide the development of optimal treatment strategies for PKU.
Mol Genet Metab 2010
PMID:Animal models of brain dysfunction in phenylketonuria. 2012 63

Psychological and psychiatric problems are well documented across the lifespan of individuals with early-treated phenylketonuria (PKU). Early-treated children and adolescents tend to display attentional problems, school problems, lower achievement motivation, decreased social competence, decreased autonomy, and low-self-esteem. As they enter adulthood, early-treated individuals may carry forward low self-esteem and lack of autonomy but also tend to develop depressed mood, generalized anxiety, phobias, decreased positive emotions, social maturity deficits, and social isolation. The correlation between level of metabolic control and severity of symptoms suggests a biological basis of psychiatric dysfunction. Additionally, psychosocial factors such as the burden of living with a chronic illness may contribute to psychological and psychiatric outcomes in PKU. The lack of a PKU-specific psychiatric phenotype combined with the observation that not everyone with PKU is affected highlights the complexity of the problem. More research on psychiatric and psychological outcomes in PKU is required. Of particular importance is the routine monitoring of emotional, behavioral, and psychosocial symptoms in individuals with this metabolic disorder. Longitudinal studies are required to evaluate the impact of new and emerging therapies on psychiatric and psychosocial functioning in PKU. Unidentified or untreated emotional and behavioral symptoms may have a significant, lifelong impact on the quality of life and social status of patients.
Mol Genet Metab 2010
PMID:Psychiatric symptoms and disorders in phenylketonuria. 2012 72

Maple syrup urine disease (MSUD) is an inherited metabolic disorder caused by mutations in the branched chain alpha-keto acid dehydrogenase complex. Worldwide incidence of MSUD is 1:225,000 live births. However, within Old Order Mennonite communities, the incidence is 1:150 live births and results from a common tyrosine to asparagine substitution (Y438N) in the E1alpha subunit of branched chain alpha-keto acid dehydrogenase. We developed a new DNA diagnostic assay utilizing TaqMan technology and compared its efficacy, sensitivity, and duration with an existing polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Carrier testing was performed by both TaqMan technology and PCR-RFLP on DNA isolated from buccal swabs of 160 individuals as well as from buccal swabs and blood spots of nine at-risk newborns; assay time, sensitivity, and reliability were also evaluated. The TaqMan assay, like the PCR-RFLP assay, accurately determined Y438N E1alpha allele status. However, the TaqMan assay appeared (1) more sensitive than the PCR-RFLP assay, requiring 10-fold less DNA (10 ng) to reliably determine genotype status and (2) faster, reducing the assay time required for diagnosis from approximately 12 to 5 h. TaqMan technology allowed more rapid DNA diagnoses of MSUD in the neonate, thereby reducing the likelihood of neurological impairment while enhancing health and prognosis for affected infants.
Genet Test Mol Biomarkers 2010 Apr
PMID:DNA carrier testing and newborn screening for maple syrup urine disease in Old Order Mennonite communities. 2013 25

Type 2 diabetes mellitus (T2DM) is a highly complicated metabolic disorder for which there is worldwide effort for the identification of susceptibility genes. Polymorphisms of the Apolipoprotein E (ApoE) gene are associated with plasma lipid and lipoprotein levels and influence cardiovascular risk. Since insulin resistance is known to be strongly associated with metabolic dyslipidemia, ApoE polymorphisms have been implicated in predisposition to diabetes but the results of the individual studies were inconclusive. We present here a meta-analysis of population-based case-control genetic-association studies relating ApoE polymorphisms and T2DM. We included in the analysis 30 studies, which reported data of ApoE genotypes in 5423 T2DM patients and 8197 healthy unrelated controls. Multivariate and univariate methods suggest a significant role played by the E2 allele, since carriers of the E2 allele were at elevated risk for T2DM (Odds Ratio=1.18, 95% CI: 1.02, 1.35). There was no evidence for publication bias or other small-study related bias or significant heterogeneity in the analyses. Cumulative meta-analysis revealed no trend of the effect estimates over time and influential analysis excluded the possibility of a single influential study. E2 allele of ApoE seems to be a moderate risk factor for T2DM. Meta-regression analysis provided some weak evidence that the risk conferred by E2 allele is mediated through altering serum lipid levels (Total Cholesterol, LDL and HDL). Further studies are needed in order to elucidate the metabolic mechanism of this association as well as to study its effects on larger populations.
Mol Genet Metab 2010 Jul
PMID:Apolipoprotein E polymorphisms and type 2 diabetes: a meta-analysis of 30 studies including 5423 cases and 8197 controls. 2038 92

Reactive oxygen species are generated within peroxisomes during peroxisomal metabolism. However, due to technological difficulties, the intraperoxisomal redox state remain elusive, and the effect of peroxisome deficiency on the intracellular redox state is controversial. A newly developed, genetically encoded fluorescence resonance energy transfer (FRET) probe, Redoxfluor, senses the physiological redox state via its internal disulfide bonds, resulting in a change in the conformation of the protein leading to a FRET response. We made use of Redoxfluor to measure the redox states at the subcellular level in yeast and Chinese hamster ovary (CHO) cells. In wild-type peroxisomes harboring an intact fatty acid beta-oxidation system, the redox state within the peroxisomes was more reductive than that in the cytosol, despite the fact that reactive oxygen species were generated within the peroxisomes. Interestingly, we observed that the redox state of the cytosol of cell mutants for peroxisome assembly, regarded as models for a neurological metabolic disorder, was more reductive than that of the wild-type cells in yeast and CHO cells. Furthermore, Redoxfluor was utilized to develop an efficient system for the screening of drugs that moderate the abnormal cytosolic redox state in the mutant CHO cell lines for peroxisome assembly without affecting the redox state of normal cells.
Mol Cell Biol 2010 Aug
PMID:A novel fluorescent sensor protein for visualization of redox states in the cytoplasm and in peroxisomes. 2049 74


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