Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phenylketonuria (PKU) is a metabolic disorder secondary to a deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH). The recent creation of a mouse strain for PAH deficiency has provided an excellent model system to explore the possibility of its phenotypic correction by hepatic gene therapy. A recombinant retrovirus containing the mouse PAH cDNA under the transcriptional control of the human CMV promoter was constructed and used to transduce hepatocytes isolated from PAH-deficient mice. Viral-transduced hepatocytes produced dramatically higher levels of mouse PAH mRNA as compared to control mock-infected hepatocytes. The PAH mRNA was translated efficiently into PAH protein that is capable of converting phenylalanine to tyrosine in vitro. These results demonstrate that the PAH-deficient mouse hepatocytes can be readily reconstituted by retroviral-mediated gene transduction, which is a crucial step towards somatic gene therapy for PKU.
Somat Cell Mol Genet 1992 Jan
PMID:Reconstitution of enzymatic activity in hepatocytes of phenylalanine hydroxylase-deficient mice. 131 61

The rare hereditary metabolic disorder alcaptonuria is characterized by the inability to metabolize homogentisic acid, an intermediary compound in the catabolism of the aromatic amino acids phenylalanine and tyrosine. The essentially complete deficiency of homogentisic acid oxidase causes a striking accumulation of homogentisic acid and a derived melanin-like pigment in the connective tissues; the latter is termed ochronosis. Urinary homogentisic acid is oxidized rapidly and becomes a brown or black pigment if alkali is added. Older alcaptonurics have intensely pigmented (ochronotic) connective tissues, primarily the cartilaginous joint surfaces, ribs, intervertebral disks, ear cartilage, etc. They also have an unusual type of arthritis affecting the large weight-bearing joints, i.e. hips, knees and spine, but not the small joints of the hands and feet, as in rheumatoid arthritis. A mechanistic explanation for ochronotic arthritis has not been worked out, but it is clear that accumulation of homogentisic acid in the connective tissues directly or indirectly leads to the arthritic changes. A detailed analysis of the events leading to alcaptonuric arthritis should be worthwhile since it is a model form of arthritis secondary to a well-defined metabolic disorder that must persist for many years before the arthritic complications appear. Possibly other, more common types of arthritis, develop secondarily to metabolic disturbances that involve chemical mediators less obvious, or less easily detected, than homogentisic acid.
Mol Biol Med 1991 Feb
PMID:Alcaptonuria and ochronotic arthritis. 194 88

The eyes of 200 rats (Mol:SPRD, Moellegaard Ltd., Skensvet, Denmark), 8 weeks of age and of both sexes, were examined routinely with a photo-slitlamp microscope (Zeiss) and opthalmoscope (Heine) 3-4 times in the course of four different 12-week toxicity studies. The animals were kept under constant lighting conditions at a room temperature of 20 +/- 2 degrees C and 55 +/- 5% humidity on a standard diet. More than 70% of the animals were found to have more or less prominent corneal opacities already at the beginning of the study. These were morphologically characterized as meshwork-like alterations of the deeper corneal epithelium, mostly located in the central and nasal region. The temporal, upper and lower periphery remained always unaffected. Male animals were more frequently and more intensively affected than the females. The occurrence of the opacity was totally independent of the treatment scheme (controls and drug dosages, respectively), showing a slight increase in density in some of the animals of all groups and remaining stable in others. Regression was rarely observed. Light and electron microscopical investigations demonstrated focal degenerations of the basal epithelial cell layer as well as alterations of its basement membrane. The lesion was not associated with inflammation or irritation. Therefore, we considered that a genetically determined metabolic disorder of the basal epithelial cells might have led to the impairment of basement membrane synthesis. Further screenings performed in conjunction with the breeder evidenced that these opacities are probably caused by a spontaneous mutation with a complex, not X-linked genetic background.
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PMID:Clinical, histological and ultrastructural characteristics of a spontaneous corneal opacity in Sprague-Dawley rats. 787

Electron transfer flavoprotein (ETF) is a heterodimeric enzyme composed of an alpha-subunit and a beta-subunit and contains a single equivalent of FAD per dimer. ETF deficiency can be demonstrated in individuals affected by a severe metabolic disorder, glutaric acidemia type II (GAII). In this study, we have investigated for the first time the molecular basis of beta-ETF deficiency in three GAII patients: two Japanese brothers, P411 and P412, and a third unrelated patient, P485. Molecular analysis of the beta-ETF gene in P411 and P412 demonstrated that both these patients are compound heterozygotes. One allele is carrying a G to A transition at nucleotide 518, causing a missense mutation at codon 164. This point mutation is maternally derived and is not detected in 42 unrelated controls. The other allele carries a G to C transversion at the first nucleotide of the intron donor site, downstream of an exon that is skipped during the splicing event. The sequence analysis of the beta-ETF coding sequence in P485 showed only a C to T transition at nucleotide 488 that causes a Thr154 to Met substitution and the elimination of a HgaI restriction site. HgaI restriction analysis on 63 unrelated controls' genomic DNA demonstrated that the C488T transition identifies a polymorphic site. Finally, transfection of wild-type beta-ETF cDNA into P411 fibroblasts suggests that wild-type beta-ETF cDNA complements the genetic defect and restores the beta-oxidation flux to normal levels.
Hum Mol Genet 1994 Mar
PMID:Mutations and polymorphisms of the gene encoding the beta-subunit of the electron transfer flavoprotein in three patients with glutaric acidemia type II. 791 28

X-linked hypophosphatemic rickets in humans is caused by mutations in the PEX gene which codes for a protein homologous to neutral endopeptidases. Hyp and Gy mice both have X-linked hypophosphatemic rickets, although genetic data and the different phenotypic spectra observed have previously suggested that two different genes are mutated. In addition to the metabolic disorder observed in Hyp mice, male Gy mice are sterile and show circling behavior and reduced viability. We now report the cloning of the mouse homolog of PEX which is highly conserved between man and mouse. The 3' end of this gene is deleted in Hyp mice. In Gy mice, the first three exons and the promotor region are deleted. Thus, Hyp and Gy are allelic mutations and both provide mouse models for X-linked hypophosphatemia.
Hum Mol Genet 1997 Feb
PMID:Pex gene deletions in Gy and Hyp mice provide mouse models for X-linked hypophosphatemia. 906 36

Carbohydrate-deficient glycoprotein syndrome type I (CDGS) is an inherited metabolic disorder with multisystemic abnormalities resulting from a failure to add entire N-linked oligosaccharide chains to many glycoproteins. Fibroblasts from these patients also abnormally glycosylate proteins, but this lesion is corrected by providing 250 microM mannose to the culture medium. This correction of protein glycosylation suggests that providing dietary mannose to elevate blood mannose concentrations might also remedy some of the underglycosylation observed in these patients. We find that ingested mannose is efficiently absorbed and increases blood mannose levels in both normal subjects and CDGS patients. Blood mannose levels increased in a dose-dependent fashion with increasing oral doses of mannose (0.07-0.21 g mannose/kg body weight). Peak blood mannose concentrations occurred at 1-2 h following ingestion and the clearance half-time was approximately 4 h. Doses of 0.1 g mannose/ kg body weight given at 3-h intervals maintained blood mannose concentrations at levels 3- to 5-fold higher than the basal level in both normal controls (approximately 55 microM) and CDGS patients. No side effects were observed for this dosage regimen. These results establish the feasibility of using mannose as a potential therapeutic dietary supplement (nutraceutical) to treat CDGS patients.
Biochem Mol Med 1997 Apr
PMID:Oral ingestion of mannose elevates blood mannose levels: a first step toward a potential therapy for carbohydrate-deficient glycoprotein syndrome type I. 916 93

Glycerol kinase is an X chromosome-encoded enzyme involved in the metabolism of endogenous and dietary glycerolipids. The physiological significance of its activity in mammals is not well understood. Glycerol kinase deficiency in humans occurs as an isolated enzyme deficiency or as part of a contiguous gene deletion syndrome in variable association with Duchenne muscular dystrophy and adrenal hypoplasia congenita. Isolated glycerol kinase deficiency has an inconstant phenotype, ranging from asymptomatic hyperglycerolemia to a severe metabolic disorder with growth and psychomotor retardation. Although intragenic mutations were reported recently, the pathophysiological basis for the phenotypic variability remains unknown. To understand better the physiological significance of glycerol kinase and the pathophysiology of its deficiency, we generated glycerol kinase-deficient mice by gene targeting. Mutant male mice appear normal at birth, but exhibit postnatal growth retardation, altered fat metabolism with profound hyperglycerolemia and elevated free fatty acids, autonomous glucocorticoid synthesis and death by 3-4 days of age. Heterozygous females are healthy and biochemically normal. The biochemical features observed in glycerol kinase-deficient mice provide the basis for further investigations into the pathogenesis of the human disorder.
Hum Mol Genet 1997 Oct
PMID:X-linked glycerol kinase deficiency in the mouse leads to growth retardation, altered fat metabolism, autonomous glucocorticoid secretion and neonatal death. 930 56

Two mouse mutations gyro (Gy) and hypophosphatemia (Hyp) are mouse models for X-linked hypophosphatemic rickets and have been shown to be deleted for the 5' and 3' end of the mouse homolog of PHEX (phosphate regulating gene with homologies to endopeptidases on the X chromosome; formerly called PEX), respectively. In addition to the metabolic disorder observed in Hyp mice, male Gy mice are sterile and show circling behavior and reduced viability. The human SMS (spermine synthase) gene maps approximately 39 kb upstream of PHEX and is transcribed in the same direction. To elucidate the complex phenotype of Gy mice, we characterized the genomic region upstream of Phex. By establishing the genomic structure of mouse Sms, a 160-190 kb deletion was shown in Gy mice, which includes both Phex and Sms. There are several pseudogenes of SMS / Sms in man and mouse. Northern analysis revealed three different Sms transcripts which are absent in Gy mice. Measurement of polyamine levels revealed a marked decrease in spermine in liver and pancreas of affected male Gy mice. Analysis of brain tissue revealed no gross or histological abnormalities. Gy provides a mouse model for a defect in the polyamine pathway, which is known to play a key role in cell proliferation.
Hum Mol Genet 1998 Mar
PMID:Spermine deficiency in Gy mice caused by deletion of the spermine synthase gene. 946 15

Dihydropyrimidine dehydrogenase (DPD) deficiency with a defect of the pyrimidine catabolic pathway has recently become the focus of considerable attention, due to the severe 5-fluorouracil (5-FU) toxicities occurring in DPD deficiency patients. Studies also suggest that 5-FU toxicities could occur in another pyrimidine metabolic disorder, dihydropyrimidinuria (DHPuria). This study shows that urinary dihydrothymine (DHT) and thymine (THY) are useful indexes for detection of DPD deficiency and DHPuria. We measured urinary DHT and THY in 276 Japanese adults to establish reference ranges. When males and females were compared, both DHT and THY levels were found to be significantly higher in females. The reference ranges (mean +/- SD with logarithmic values) for males were found to be 1.56-5.70 micromol/g of creatinine for DHT and 0.40-1.47 micromol/g of creatinine for THY. The reference ranges for females were found to be 1.89-8.33 micromol/g of creatinine for DHT and 0.58-2.30 micromol/g of creatinine for THY. In addition to this study we analyzed a DPD deficiency case and a DHPuria case. In the DPD deficiency case, the THY concentrations of all urine samples were out of the reference range. However, uracil levels in most of the samples were within the normal range. The DHPuria case excreted large amounts of DHT and dihydrouracil, both out of the normal range.
Int J Mol Med 1998 Oct
PMID:Possible prediction of adverse reactions to fluorouracil by the measurement of urinary dihydrothymine and thymine. 985 38

Mevalonic aciduria is a rare autosomal recessive metabolic disorder, characterized by psychomotor retardation, failure to thrive, hepatosplenomegaly, anemia and recurrent febrile crises. The disorder is caused by a deficient activity of mevalonate kinase due to mutations in the encoding gene. Thus far, only two disease-causing mutations have been identified. We now report four different missense mutations including three novel ones, which were identified by sequence analysis of mevalonate kinase cDNA from three mevalonic aciduria patients. All mutations affect conserved amino acids. Heterologous expression of the corresponding mutant mevalonate kinases as fusion proteins with glutathione S -transferase in Escherichia coli showed a profound effect of each of the mutations on enzyme activity. In addition, immunoblot analysis of fibroblast lysates from patients using specific antibodies against mevalonate kinase identified virtually no protein. These results demonstrate that the mutations affect not only the activity but also the stability of the mutant proteins.
Hum Mol Genet 1999 Aug
PMID:Identification and characterization of three novel missense mutations in mevalonate kinase cDNA causing mevalonic aciduria, a disorder of isoprene biosynthesis. 1040 Oct 1


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