[Maple syrup urine disease].
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3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
Biomedical subjects
I Matsuda
Publications and source records attributed to I Matsuda.
High concentration of L-arginine suppresses nitric oxide synthase activity and produces reactive oxygen species in NB9 human neuroblastoma cells.
Hereditary argininemia manifests as neurological disturbance and mental retardation, features not observed in other amino acidemias. The cytotoxic effect of a high concentration of L-arginine (L-Arg) was investigated using NB9 human neuroblastoma cells (NB9), which express neuronal nitric oxide synthase (nNOS). When the concentration of L-Arg in the medium increased from 50 microM to 2 mM after incubation for 48 hr, the intracellular concentration of L-Arg increased from 68.0 +/- 1 pmol/10(6) cells to 1310.0 +/- 5 pmol/10(6) cells and that of L-citrulline (L-Cit) from undetectable levels to 47.1 +/- 0.2 pmol/10(6) cells (mean +/- SD of three independent analyses). This increase in intracellular L-Arg levels caused a decrease in NOS activity by approximately 71%. Flow cytometric analysis showed that reactive oxygen species (ROS) are produced in NB9 exposed to 2 mM L-Arg. The production of ROS was abolished by a NOS inhibitor, NG-nitro-L arginine-methylester. Production of ROS was also observed when NB9 were treated with L-Cit for 48 hr. To investigate the effect of L-Cit on the activity of NOS, a kinetic study on nNOS was conducted using cellular extracts from NB9. The apparent Km value of nNOS for L-Arg was 8.4 microM, with a Vmax value of 8.2 pmol/min/mg protein. L-Cit competitively inhibited NOS activity, as indicated by an apparent Ki value of 65 nM. These results suggest that L-Cit formed by nNOS in L-Arg-loaded neuronal cells inhibits NOS activity and nNOS in these L-Arg-loaded cells functions as a NADPH oxidase to produce ROS, which may cause neurotoxicity in argininemia.
Arginine↗
[Standard versus long-term prednisolone with sairei-to for initial therapy in childhood steroid-responsive nephrotic syndrome: a prospective controlled study].
The most appropriate initial treatment for children with steroid-responsive nephrotic syndrome is controversial. Initial treatment with 18-week prednisolone and the Chinese herbal medicine. Sairei-to, may prevent subsequent relapse. To determine whether similar results can be obtained with a combination of just initial 8-week prednisolone and Sairei-to, we compared the effects of such treatment with those of treatment with 18-week prednisolone and Sairei-to in 196 children with steroid-responsive nephrotic syndrome. The patients were randomly assigned to receive 8-week (group 1) or 18-week (group 2) prednisolone for the initial therapy. All patients received Sairei-to for 2 years in addition to prednisolone. Eighty-eight of the 98 patients in group 1 and 83 of the 98 patients in group 2 completed their trial. At entry, the two groups of patients did not differ in their clinical and laboratory findings. During the 2-year trial, 62 group 1 patients (70%) and 54 group 2 patients (65%) had relapses, and 19 group 1 patients (21%) and 20 group 2 patients (24%) had frequent relapses. The present study demonstrates that a combination of initial 8-week prednisolone and 2-year Sairei-to is effective in children with steroid-responsive nephrotic syndrome.
Anti-Inflammatory Agents↗
Complete rescue of lethal albino c14CoS mice by null mutation of 4-hydroxyphenylpyruvate dioxygenase and induction of apoptosis of hepatocytes in these mice by in vivo retrieval of the tyrosine catabolic pathway.
Hereditary tyrosinemia 1 (HT1) is characterized by progressive liver damage, from infancy, and by a high risk for hepatocellular carcinoma. HT1 is due to mutations in the fumarylacetoacetate hydrolase gene Fah, encoding the last enzyme in the tyrosine catabolic pathway. Lethal albino deletion c14CoS mice and mice with target-disrupted Fah are models for HT1, but they die in the perinatal period, albeit with a different phenotype from that seen in HT1 in humans. We first asked whether homozygous null mutation of the 4-hydroxyphenylpyruvate dioxygenase gene Hpd could rescue the homozygous c14CoS mice (c14CoS/c14CoS or Fah-/-). The double mutant Fah-/- Hpd-/- mice appeared normal, at least until age 18 months, and there was no evidence of liver disease, findings that facilitated examination of the effect of Fah-/- on mature and unmodified hepatocytes in vivo. The hepatocytes of Fah-/- undergo rapid apoptosis, and acute death follows. Essentially the same phenomena were observed when Fah-/- Hpd-/- mice were administered homogentisate intraperitoneally. These changes in liver pathology in Fah-/- Hpd-/- mice after the administration of homogentisate were associated with massive urinary excretion of succinylacetone. These results suggest that accumulation of fumarylacetoacetate, maleylacetoacetate, or succinylacetone seems to trigger the endogenous process of apoptosis in hepatocytes that lack fumarylacetoacetate hydrolase activity. This apoptosis may be related to the development of hepatocellular carcinomas seen in HT1 patients and pharmaceutically treated fumarylacetoacetate hydrolase-deficient mice.
4-Hydroxyphenylpyruvate Dioxygenase↗
The ornithine transcarbamylase (OTC) gene: mutations in 50 Japanese families with OTC deficiency.
Mutations in the OTC gene in 50 Japanese families with OTC deficiency were reviewed in relation to the phenotype of the patients and predicted structure of the mutant enzyme. Similar to other X-linked diseases, mutant alleles in OTC deficiency are highly heterogeneous. Mutations observed in male patients with neonatal onset of the disease included base insertion/deletion, exon skipping, and nonsense and missense mutations in exon 4, 5, 6, or 7. OTC activity was essentially undetectable in this group of patients. These mutations possibly resulted in unstable mRNA or truncated protein, or involved the active site or core domain of the enzyme leading to structural changes. In male patients with late onset, abnormalities observed were missense mutations in exons 2, 4, 8, 9, and 10, and missense mutations plus donor site errors involving exons 4, 5, and 6. OTC activity in these patients was 8.1 +/- 6.3% of the control and most mutations occurred on the surface of the protein. In female patients, age at onset ranged from 19 months to 7 years, depending on residual OTC activities (4.5 to 33% of the control). Most mutations in this group were similar to those seen in male patients with neonatal onset, i.e., nonsense and missense mutations in exons 5 and 6, and exon skipping, leading to null enzyme activity. These collective data can serve for genetic counseling and monitoring in prenatal care.
Alternative Splicing↗
Simplified method for the determination of 25-hydroxy and 1alpha,25-dihydroxy metabolites of vitamins D2 and D3 in human plasma. Application to nutritional studies.
A simplified method for the determination of 25-hydroxy and 1alpha,25-dihydroxy metabolites of vitamins D2 and D3 in human plasma was developed. Plasma samples were deproteinizated and applied to a Bond Elut C18OH cartridge to separate 25-hydroxyvitamin D (25-OH-D) and 1alpha,25-dihydroxyvitamin D [1,25(OH)2D] fractions. The 25-OH-D fraction was purified by a Bond Elut C18 cartridge and 25-OH-D2 and 25-OH-D3 were assayed by HPLC using a Zorbax SIL column. The 1,25(OH)2D fraction obtained above was subsequently applied to HPLC using a Zorbax SIL column to separate 1,25(OH)2D2 and 1,25(OH)2D3 fractions which were determined by a radioreceptor assay (RRA) using calf thymus receptor. The method was applied to nutritional studies.
25-Hydroxyvitamin D 2↗
Familial lethal inheritance of a mutated paternal gene in females causing X-linked ornithine transcarbamylase (OTC) deficiency.
A Leu148Phe substitution of the ornithine transcarbamylase (OTC) gene was identified in a 2-year-old girl with OTC deficiency (14% of control). Her two elder sisters died in childhood of hyperammonemia, and the patient also died of OTC deficiency. Enzyme activity in Cos1 cells transfected by the mutant cDNA was undetectable, thereby indicating a definite pathogenic mutation. Familial gene analysis showed that the mother had wild-type OTC alleles on both X-chromosomes and the father was a mosaic for the mutant allele in his lymphocytes and spermatozoa. This clinical case shows that a somatic and germline mosaicism for a single-gene disorder led to an unusual pattern of X-linked inheritance in the family, and all three daughters in the family died of OTC deficiency. The possibility that inherited factors will lead to skewed X-inactivation needs to be considered.
Fatal Outcome↗
In vivo correction with recombinant adenovirus of 4-hydroxyphenylpyruvic acid dioxygenase deficiencies in strain III mice.
Tyrosinemia type 3, caused by a genetic deficiency of 4-hydroxyphenylpyruvic acid dioxygenase (HPD) in tyrosine catabolism, is characterized by convulsion, ataxia, and mental retardation. The III mouse is a model of tyrosinemia type 3. HPD activity and protein are defective in the liver and its blood tyrosine levels are elevated, the range being between 1,100 and 1,656 microM. We constructed a recombinant adenoviral vector bearing the human HPD cDNA (AdexCAGhHPD), which is expressed under the control of a potent CAG promoter. III mice were injected with 1.0 x 10(8) to 1.0 x 10(9) pfu of AdexCAGhHPD through the tail vein. When 3.0 x 10(8) - 1.0 x 10(9) pfu were injected, blood tyrosine levels decreased within 3 hr, reached a normal range (under 300 microM), and remained at a low level for 2-6 weeks. Hepatic HPD activities also increased as early as 3 hr after the injection of 5.0 x 10(8) pfu, reached the levels comparable to the control mice in 3-7 days, and then decreased, and correlated well to blood tyrosine. Hepatic HPD expression was confirmed by Northern blot and immunoblot analyses. Histology revealed no difference (gross or microscopic) between the liver injected with AdexCAGhHPD and the control. No significant changes in blood tyrosine levels were noted after the second injection of 5.0 x 10(8) pfu of AdexCAGhHPD. Thus, the intravenous administration of the adenoviral vector bearing a foreign gene seems suitable for transient, early gene transfer into the liver.
4-Hydroxyphenylpyruvate Dioxygenase↗
Structure and organization of the human TRKA gene encoding a high affinity receptor for nerve growth factor.
Nerve growth factor (NGF) induces neurite outgrowth and promotes survival of embryonic sensory and sympathetic neurons. TRKA, a receptor tyrosine kinase cloned from a human colon cancer was later found to be expressed in the nervous system and phosphorylated in response to NGF. Somatic rearrangement(s) of the TRKA gene (also designated NTRK1) are responsible for formation of some oncogenes. Genetic defects in TRKA are responsible for a human disorder, congenital insensitivity to pain with anhidrosis (CIPA). We report here isolation and characterization of the TRKA gene which spans at least 23 kb and is split into 17 exons. Exon sizes range from 18 to 394 bp and intron sizes range from 170 bp to at least 3.3 kb. Sizes and boundaries of the exons were determined, and all the splice donor and acceptor sites conformed to the GT/AG rule. Approximately 1.2 kb of the 5'-flanking regions was sequenced, and putative regulatory elements were identified. These results will be useful for studies on the developmental and biological regulation of the TRKA gene and for further characterization of mutations in CIPA patients as well as elucidation of mechanisms responsible for rearrangement(s) observed in human tumors.
Base Sequence↗
Depressed natural killer cell activity due to decreased natural killer cell population in a vitamin E-deficient patient with Shwachman syndrome: reversible natural killer cell abnormality by alpha-tocopherol supplementation.
UNLABELLED: Natural Killer (NK) cell activity was examined in a 16-month-old Japanese boy with Shwachman syndrome associated with severe vitamin E deficiency. As evaluated by 51Cr-release assay from K562 cells, NK cell activity was constantly decreased. After 8 weeks of oral alpha-tocopherol (alpha-Toc) supplementation (100 mg/day), NK cell activity had normalised. When alpha-Toc supplementation was interrupted for 16 weeks. NK cell activity again decreased. Flow cytometry of peripheral lymphocytes revealed a lowered number of CD16+ CD 56- fraction, which has the most potent NK cell activity. Single cell-in-agarose assay, to investigate the binding and cytolytic activity of NK cell at the single cell level, revealed that the number of NK cells which bind to K562 cell was decreased, but that the cytolytic activity of the individual binding cell was relatively unaffected. A second supplementation of alpha-Toc for 8 weeks successfully restored NK cell activity, the number of cells expressing NK cell markers and the number of K562-binding cells as compared to the age-matched normal range. CONCLUSION: These results indicate that severe vitamin E deficiency caused impaired NK cell activity due to a decrease in the number of CD16+ CD56- NK cells and that this abnormality is reversible with alpha-Toc supplementation.
Adolescent↗
The R40H mutation in a late onset type of human ornithine transcarbamylase deficiency in male patients.
Ornithine transcarbamylase (OTC) deficiency is an X-linked trait and is one of the most frequent of the inherited urea cycle enzyme deficiencies. Most male patients with OTC deficiency develop a hyperammonemic crisis and die in the neonatal period or in early infancy. In contrast to those patients, in some male patients the disease first becomes overt in adolescence or during the reproductive age period. In the present report, we describe six such male patients who first developed clinical signs at ages ranging from 6 to 58 years, all of whom came from a limited area of the northern part of Kyushu Island in southern Japan. The mutation analysis disclosed a R40H mutation in exon 2 of the OTC gene in each of these patients. Transmission of this mutant gene through paternal lineage as well as through maternal lineage was documented in one family. The levels of mRNA of the mutant OTC gene expressed in transfected Cos 1 cells and in the liver tissue obtained by biopsy in one patient were both similar to those of the wild-type gene. The activity of the mutant OTC was, however, decreased to a level of 28% of the wild-type OTC, and the levels of the mutant OTC protein expressed in Cos 1 cells were decreased, as assessed by western blot analysis. Apparent Km values of the mutant enzyme for ornithine (1.1 mM) and carbamylophosphate (2.0 mM) were similar to those of the wild-type enzyme. Both enzymes gave similar pH-dependency profiles, giving a maximal activity at pH 7.8-7.9. Activity of wild-type OTC expressed in Cos 1 cells did not change after five cycles of freezing and thawing, whereas that of the mutant OTC decreased to 17% by this treatment. These results suggest that deficiency is due to inactivation of the mutant OTC under certain conditions.
Adolescent↗
Fractional esterification rate of cholesterol in high density lipoprotein (HDL) can predict the particle size of low density lipoprotein and HDL in patients with coronary heart disease.
Fractional esterification rate of cholesterol in high density lipoprotein (HDL) (FER[HDL]) can predict the size distribution and physicochemical characteristics of HDL in plasma. In the present study, we investigated the correlation of FER(HDL) with the particle size of low density lipoprotein (LDL) (LDL-size) in 111 patients (81 males and 30 females) with coronary heart disease (CHD). The correlations of FER(HDL) and LDL-size with conventional lipid and lipoprotein parameters were also studied. FER(HDL) was closely associated with LDL-size (males: r = -0.618, females: r = -0.629, P < 0.001). Plasma levels of TG, HDL-cholesterol (HDL-C), HDL2-cholesterol (HDL2-C) and apo B were also associated with LDL-size in male CHD patients (r = -0.534, 0.314, 0.358, and -0.482, P < 0.01 or 0.001), while plasma levels of TG and apo B were associated with LDL-size in female patients (r = -0.350 and -0.348, P < 0.05). In a stepwise multiple regression analysis, FER(HDL) alone accounted for 38 and 40% of the variability in LDL-size in male and female CHD patients, respectively. Other parameters accounted for an additional 6-10%. With respect to the relation between FER(HDL) and HDL subfractions, FER(HDL) related only to HDL2-C (males: r = -0.640, females: r = -0.652, P < 0.001). This result suggests that FER(HDL) is better able to predict the presence (or absence) of large HDL, rather than that of small HDL. All these data taken together, suggest that FER(HDL) is a useful tool to predict the particle size of both LDL and HDL, even in CHD patients.
Aged↗
Mutations in the CLCN5 gene in Japanese patients with familial idiopathic low-molecular-weight proteinuria.
Familial idiopathic low-molecular-weight proteinuria (FILMWP) is a renal proximal tubulopathy that occurs predominantly in males. FILMWP is characterized by mild proteinuria consisting of low-molecular-weight proteinuria, aminoaciduria and relatively conserved renal function, but without rickets. To determine whether FILMWP is related to the CLCN5 gene, which is responsible for Dent's disease and two related disorders, we analyzed the CLCN5 gene from four Japanese families with FILMWP. We identified two novel mutations: one was a single base insertion at codon 520 serine in exon 10 and the other was a single base deletion at codon 403 tyrosine in exon 8. These mutations caused a shift in the reading frame, resulting in synthesis of truncated CLC5 proteins that lacked 220 (29%) and 314 (42%) amino acids, respectively. These mutations were demonstrated to cosegregate with the disease in two families, respectively. We conclude that the CLCN5 gene is responsible for this proximal renal tubulopathy in some Japanese families and that FILMWP is possibly a variant of Dent's disease.
Alleles↗
In situ expression and soluble form of P-selectin in human glomerulonephritis.
To clarify the early involvement of cellular adhesion molecules in human glomerulonephritis, we investigated P-selectin and high endothelial venules' (HEVs) marker MECA-79 expression in kidney specimens by immunohistochemical and in situ hybridization analyses, and measured serum and urinary soluble P-selectin levels by enzyme-linked immunosorbent assay. In normal controls, P-selectin and MECA-79 expression were negative in glomeruli (N = 4), and serum soluble P-selectin levels were 114.3 +/- 36.8 ng/ml (mean +/- SEM, N = 12). Soluble P-selectin was not detectable in urine of all cases. In proliferative glomerulonephritis involving rapidly progressive glomerulonephritis (N = 6), IgA nephropathy (N = 26), lupus nephritis (N = 7) and acute glomerulonephritis (N = 2), both glomerular and interstitial P-selectin expression were up-regulated. Glomerular P-selectin expression correlated positively with local cellular accumulation, endocapillary proliferation and CD41b (platelet) staining. Interstitial P-selectin expression showed a positive correlation with the grade of local cellular infiltrates. P-selectin mRNA signals detected by in situ hybridization were only observed on capillary or venous endothelium in the interstitium, but not in glomeruli. In addition, MECA-79 was expressed on the plump endothelial cells at the cortico-medullary junction (outer medulla). Serum soluble P-selectin levels were significantly higher in patients with proliferative glomerulonephritis, especially in glomerular and interstitial P-selectin positive staining, and correlated with glomerular endocapillary proliferation. These observations suggested that P-selectin was associated with both glomerular and interstitial leukocyte accumulation in human glomerulonephritis, and might be expressed by two distinct mechanisms that are the activated platelets in glomeruli and the de novo expression in the interstitial lesions that correlated with MECA-79 expression as HEVs like vessels, and serum soluble P-selectin may be a useful marker for predicting in situ P-selectin expression associated with glomerular endocapillary proliferation in nephritis.
Adult↗
Age-related changes of serum progastrin-releasing peptide levels during childhood.
Gastrin-releasing peptide (GRP) has attracted much attention in recent years because it has become recognized as a significant tissue-specific growth factor. To investigate the physiological significance of this peptide in growing children, the time course of serum ProGRP(31-98) level, a precursor hormone of GRP, in children was assessed. A total of 118 serum samples including cord blood was examined with informed consent by using a specific enzyme-linked immunosorbent assay (ELISA) system to measure serum ProGRP(31-98). The serum ProGRP(31-98) level was highest in cord blood and neonatal samples, rapidly declined by 1 year of age and then gradually declined to the adult level by 5 years of age. This time-dependent change of serum ProGRP(31-98) level suggests the importance of GRP as a physiological growth factor in fetal and neonatal tissues.
Adolescent↗
Comparative analysis of Pseudomonas syringae pv. actinidiae and pv. phaseolicola based on phaseolotoxin-resistant ornithine carbamoyltransferase gene (argK) and 16S-23S rRNA intergenic spacer sequences.
Pseudomonas syringae pv. phaseolicola, which causes halo blight on various legumes, and pv. actinidiae, responsible for canker or leaf spot on actinidia plants, are known as phaseolotoxin producers, and the former possesses phaseolotoxin-resistant ornithine carbamoyltransferase (ROCT) which confers resistance to the toxin. We confirmed that the latter is also resistant to phaseolotoxin and possesses ROCT, and we compared the two pathovars by using sequence data of the ROCT gene and the intergenic spacer region located between the 16S and 23S rRNA genes (16S-23S spacer region) as an index. It was found that the identical ROCT gene (argK) is contained not only in bean isolates of P. syringae pv. phaseolicola in Mexico and the United States but also in bean isolates in Japan and Canada, and that it is also distributed in the kudzu (Pueraria lobata) isolates of P. syringae pv. phaseolicola. Moreover, the kiwifruit and tara vine isolates of P. syringae pv. actinidiae were also found to possess the identical argK. On the contrary, the 16S-23S spacer regions showed a significant level of sequence variation between P. syringae pv. actinidiae and pv. phaseolicola, suggesting that these two pathovars evolved differently from each other in the phylogenetic development. The fact that even synonymous substitution has not occurred in argK among these strains despite their extreme differences in phylogenetic evolution and geographical distribution suggests that it was only recently in evolutionary time that argK was transferred from its origin to P. syringae pv. actinidiae and/or pv. phaseolicola.
Base Sequence↗
Medium chain 3-ketoacyl-coenzyme A thiolase deficiency: a new disorder of mitochondrial fatty acid beta-oxidation.
A Japanese male neonate died at 13 d of age after presenting at 2 d of age with vomiting, dehydration, metabolic acidosis, liver dysfunction, and terminal rhabdomyolysis with myoglobinuria. Multiple urine organic acid analyses consistently revealed a markedly elevated excretion of lactic acid, 3-hydroxybutyric acid, and saturated and unsaturated C6-C16 dicarboxylic acids, with predominant C12-C16 species. Oxidation of [1-14C]octanoic acid in cultured skin fibroblasts was significantly reduced (0.59 nmol/h/mg of protein; controls, 1.93 +/- 0.65), [1-14C]palmitic acid oxidation was 1.11 nmol/h/mg of protein (controls, 1.63 +/- 0.41). A systematic study of the catalytic activities of nine enzymes of the beta-oxidation cycle using the respective optimal substrate revealed a deficiency of a single enzyme not previously associated with a metabolic disorder, medium chain 3-ketoacyl-CoA thiolase (patient, 3.9 nmol/min/mg protein; controls (n = 6), 10.2 +/- 2.3). Immunoprecipitation with antibodies raised against medium chain 3-ketoacyl-CoA thiolase revealed a 60% decrease compared with controls.
Acetyl-CoA C-Acyltransferase↗
Magnetic resonance imaging of sequelae of temporal lobe herniation secondary to traumatic acute subdural hematoma: Kernohan's notch and posterior cerebral artery territory infarctions contralateral to the supratentorial lesion--case report.
A 16-year-old girl presented with left hemiparesis and right oculomotor nerve paresis due to temporal lobe herniation resulting from a traumatic acute subdural hematoma secondary to a head injury. Computed tomography revealed a subdural hematoma in the right frontotemporal regions and midline structures shifted to the left. She became comatose and underwent an emergency operation. The hemiparesis and newly manifested homonymous hemianopsia on the right side persisted after surgery. Postoperative magnetic resonance imaging showed Kernohan's notch in the cerebral peduncle and infarctions in the occipital lobe and posterolateral part of the thalamus on the left side, contralateral to the supratentorial lesion.
Adolescent↗