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Biomedical subjects

I Matsuda

Publications and source records attributed to I Matsuda.

At least 145 records · Page 8Linked to original sources
PubMed1994

Homologous dinucleotide (GT or TG) deletion in Japanese patients with chronic granulomatous disease with p47-phox deficiency.

The cytosolic 47-kDa protein designated as p47-phox (phagocyte oxidase) is one of the essential components of the superoxide-generating system in phagocytes, and its defect is known to cause chronic granulomatous disease (CGD). Five unrelated CGD patients with p47-phox deficiency were found among 82 CGD patients in Japan. We sequenced the cDNAs and the genomic DNAs corresponding to p47-phox derived from these patients. In all cases examined, the defect was identified to be a GT (or TG) dinucleotide deletion at bases 75/76 (or 74/75, respectively) in the coding sequence for the protein. The same mutation was reported previously for a total of 9 alleles from 5 CGD patients in England and in the United States. It seems, therefore, that the dinucleotide GT deletion is the common mutation in 47-phox deficient CGD due to certain structural issues.

Adolescent↗
PubMed1994

Characterization of NF(P), the nuclear factor that interacts with the regulatory P sequence (5'-CGAAAATTTCC-3') of the human interleukin-4 gene: relationship to NF-kappa B and NF-AT.

The P sequence of the human interleukin-4 (IL-4) gene, which was defined as a responsive element for phorbol 12-myristate 13-acetate and calcium ionophore (A23187) in Jurkat T cells, shares sequence similarity with the NF-kappa B and the NF-AT binding sites. We examined whether NF(P), a nuclear factor specific for the P sequence, is related to NF-kappa B and NF-AT. NF-kappa B (P65 or P65/P50 heterodimer) bound to the P sequence in electrophoretic mobility shift assays (EMSA) and activated transcription through the P sequence when expression plasmids were cotransfected with P sequence-driven reporter plasmids in Jurkat T cells. In EMSAs, NF(P) binding was inhibited by the unlabeled NF-AT binding site but not by the unlabeled AP1 binding site and purified NF-AT contained an activity that bound to the P sequence. Both mobility shift and sequence specificity of NF-AT were similar to those of NF(P) and only a small amount of P65 was detected in NF(P) in crude nuclear extracts. These results indicate that the component(s) of NF-AT has the potential to reconstitute NF(P) whereas NF-kappa B alone cannot account for NF(P) in crude extracts. Unlike NF-AT, NF(P) does not contain AP1 as its DNA binding component.

Base Sequence↗
PubMed1994

Deficiency of the E1 beta subunit in the branched-chain alpha-keto acid dehydrogenase complex due to a single base substitution of the intron 5, resulting in two alternatively spliced mRNAs in a patient with maple syrup urine disease.

A patient with maple syrup urine disease (MSUD) associated with a E1 beta subunit deficiency of the branched-chain alpha-keto acid dehydrogenase (BCKDH) complex was investigated at the molecular level. The defect responsible for the deficiency of the E1 beta subunit protein was identified by analysis of cDNA and genomic DNA by polymerase chain reaction. Total RNA isolated from lymphoblastoid cells was transcribed into cDNA and amplified using a set of primers located within exon 3 and exon 9 of the E1 beta gene. Agarose gel electrophoresis of cDNA amplification products revealed two shortened bands as well as a faint band of normal size. Nucleotide sequencing of the shortened cDNA amplification products showed that sequences corresponding to exon 5 and both exons 5 and 6 were absent. Nucleotide sequencing of the proband's amplified genomic DNA corresponding to this region of the E1 beta gene revealed a single base substitution from G to T of the invariant GT dinucleotides at 5' splice site of the intron 5. Analysis of family members using primer-specified restriction map modification showed that the patient is homozygous for this mutation. We postulate that this mutation leads to the skipping of either exon 5 or both exons 5 and 6, thus producing two shortened E1 beta mRNA. The percentage of normal and two shortened transcripts was estimated to be 9, 71 and 20%, respectively. To our best knowledge, this is the first documented example of exon skipping in the E1 beta gene as the cause of MSUD and the novel mutation of the invariant G at the 5' splice site which results in two alternatively spliced mRNA due to the skipping of the preceding exon as well as both preceding and following exon.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1994

Structure of the human 4-hydroxyphenylpyruvic acid dioxygenase gene (HPD).

4-Hydroxyphenylpyruvic acid dioxygenase (HPD) is an important enzyme in tyrosine catabolism in most organisms. The activity of this enzyme is expressed mainly in the liver and developmentally regulated in mammals, and a genetic deficiency in this enzyme in humans and mice leads to hereditary tyrosinemia type 3. Using human HPD cDNA as a probe, a chromosomal gene related to HPD was isolated from human gene libraries. The human HPD gene is over 30 kb long and is split into 14 exons. The extract size and boundaries of exon blocks were determined, and all of the splice donor and acceptor sites conformed to the GT/AG rule. Analysis of the 5' flanking sequence of the gene suggests that expression of the gene is regulated by hepatocyte-specific and liver-enriched transcription factors, as well as by hormones. These features of the 5' flanking region of the gene are similar to those of other genes that are specifically expressed in hepatocytes and that are developmentally regulated.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed1994

Expression of four mutant human ornithine transcarbamylase genes in cultured Cos 1 cells relates to clinical phenotypes.

Ornithine transcarbamylase (OTC) deficiency is an X-linked disease with a heterogeneous phenotype, even in affected males. To detect mutations in the OTC gene using genomic DNA, we have developed a method in which all exons and adjacent introns are amplified and sequenced. Although this approach detected mutations in many cases, the relationship between a mutation and the OTC phenotype was not firmly established. Therefore, we investigated the issue by expression analysis of mutant OTC cDNA in cultured cells. Four mutant OTC cDNAs were constructed, based on the reported cases, using our newly developed method. The normal (wild-type) human OTC cDNA was reproducibly expressed at high levels in these Cos 1 cells. Predicted OTC activities of mutant OTC cDNAs ranged from 0% to 8.9% of the normal level together with variable amounts of the enzyme protein. The predicted enzyme activities account for the clinical phenotype of the disease. Our observations confirm that these mutations are responsible for OTC deficiency in these patients.

Amino Acid Metabolism, Inborn Errors↗
PubMed1994

Characterization of a point mutation in the pyruvate dehydrogenase E1 alpha gene from two boys with primary lactic acidaemia.

We report here a novel mutation in the codon for amino acid 263 resulting in the change from arginine to glutamine in the pyruvate dehydrogenase (PDH) E1 alpha gene, in two boys with primary lactic acidaemia, from independent families. The mutation changes an amino acid located between the two serine residues which are the sites of phosphorylation of the subunit protein. In one family, the mutation was de novo and in the other it was transmitted from mother to son. The amino acid substitution may affect function of the PDH complex via phosphorylation and dephosphorylation of the E1 alpha subunit. Derangement in the regulation of activity of the PDH complex may explain the primary lactic acidaemia in the patients.

Acidosis, Lactic↗
PubMed1994

A family of selective immunodeficiency with normal immunoglobulins: possible autosomal dominant inheritance.

We report here our findings in two Japanese siblings who experienced recurrent bacterial and viral infections since early infancy. Recent symptoms included diarrhoea, conjunctivitis, rashes, headache, sore throat, joint pain, vomiting and vertigo, all similar to those seen in toxic shock syndrome, except for shock. These symptoms improved following gammaglobulin treatment. Staphylococcus aureus with coagulase type IV was continuously isolated from nasal smears producing toxic shock syndrome toxin-1 (TSST-1). Serum antibodies did not or only poorly responded to TSST-1, diphtheria toxoid, varicella virus and rubella virus, whereas total and subclass levels of serum immunoglobulin and in vitro DNA synthesis of lymphocytes stimulated by TSST-1, Staph. aureus, varicella vaccine and mitogens were normal. In the family, ten other members in three generations (five males: five females) including the mother had similar clinical symptoms. Thus, the disease may be inherited in an autosomal dominant fashion.

Antibodies, Bacterial↗
PubMed1994

Signals and nuclear factors that regulate the expression of interleukin-4 and interleukin-5 genes in helper T cells.

Mouse thymoma line EL-4 cells produce cytokines such as interleukin (IL)-2, IL-3, IL-4, IL-10, and granulocyte-macrophage colony-stimulating factor in response to phorbol 12-myristate 13-acetate (PMA). EL-4 cells also produce low levels of IL-5 when stimulated by PMA alone; however, cAMP greatly augments PMA-dependent IL-5 production. A transient transfection assay revealed that two signals, PMA and cAMP, are required for optimal activation of the IL-5 promoter. In contrast, cAMP almost completely inhibited the PMA-dependent activation of the endogenous IL-2 gene, as well as the transfected IL-2 promoter. These results indicate that the IL-5 gene is positively regulated by cAMP in a manner opposite to that for the IL-2 gene. One of the nuclear factors (NFs) that regulates the response of the IL-5 promoter to cAMP and PMA has properties similar to NF for activated t cell. The P sequence of the IL-4 gene, defined as a responsive element for PMA and calcium ionophore (A23187), shares sequence similarity with the NF kappa B and the NF-activated T cell binding sites. We attempted to determine whether NF(P), a nuclear factor specific for the P sequence, is related to NF-kappa B and nuclear factor for activated T cell (NF-AT). In electromobility shift assays both NF-kappa B (P65 or P65/P50 heterodimer) and NF-AT bound to the P sequence. However, sequence specificity of NF-AT was more similar to that of NF(P), and only a small amount of P65 was detected in NF(P). These results indicate that a component or components of NF-AT have the potential to reconstitute NF(P), whereas NF-kappa B alone does not account for NF(P) in Jurkat crude extract. Taken together, these results suggest that NF-AT-like factors are involved in the regulation of IL-4 and IL-5 genes.

Animals↗
PubMed1994

Constitutive production of multiple colony-stimulating factors in patients with lung cancer associated with neutrophilia.

Production of colony-stimulating factor (CSF) was examined in three patients with lung cancer associated with neutrophilia. All three patients presented a marked increase in neutrophil count (26,000-39,000 microliters-1) that continued at least for 3 weeks and rapidly disappeared after surgical removal of the tumours. Culture media (CM) incubated with the excised tumour tissues stimulated the colony formation of bone marrow myeloid progenitor cells in vitro. Northern blot analysis of poly(A)+ RNA from the tumour tissues revealed a constitutive expression of granulocyte (G), macrophage (M), and granulocyte-macrophage (GM) CSF genes in all tumours. Immunoassay specific for these CSFs revealed that G- and M-CSF immunoreactivity was detected in all CM and GM-CSF protein in two out of three CM. The plasma CSF levels also increased before operation and decreased to normal or near-normal range after operation. In contrast, tumour cell CM obtained from two lung cancer patients without leucocytosis neither stimulated haematopoietic colony formation nor contained immunoreactive CSFs. These results indicated that the neutrophilia found in the three patients was probably caused by constitutive production of multiple CSFs by lung cancer cells.

Aged↗
PubMed1994

Mutations in the COL4A5 gene in Alport syndrome: a possible mutation in primordial germ cells.

Using a combination of gene amplification with single strand conformation polymorphisms analysis and sequencing, we examined the COL4A5 gene in 37 patients with Alport syndrome. In patient A8, a single base insertion was noted at codon 1,597 tyrosine in exon 49. The premature terminal signal appeared and 89 amino acids (approximately one-third) of the non-collagenous domain were lost. The mutation was present in the mother, hence she is heterozygous. In patient A12, the nucleotide changed from C to T at codon 1,679 glutamine in exon 51, which created a termination codon, and 7 amino acids at the carboxyl terminus were lost. Gene tracking using peripheral leukocytes revealed that the parents did not carry the mutant allele, while the sister was heterozygous. DNA samples from hair roots and skin fibroblasts of the mother were normal and immunological examination of the epidermis of the mother indicated that the alpha 5(IV) chain was normally expressed. As these results suggest that somatic cells of the mother do not carry the mutant allele, the primordial germ cells possibly carry a fresh mutation in the mother of patient A12.

Adolescent↗
PubMed1994

Zinc supplementation alters thyroid hormone metabolism in disabled patients with zinc deficiency.

OBJECTIVE: We examined zinc (Zn) status in relation to thyroid function in disabled persons, because the association between Zn deficiency and thyroid function remains controversial. METHODS: After measuring serum free 3,5,3'-triiodothyronine (T3) and free thyroxine (T4) in 134 persons, TSH-releasing hormone (TRH) injection test and estimation of Zn status were conducted in persons with low free T3. RESULTS: Thirteen had low levels of serum free T3 and normal T4. Patients with elevated levels of serum 3,3',5'-triiodothyronine (rT3) showed an enhanced reaction of serum thyrotropin (TSH) after TRH injection. Nine of 13 patients had mild to moderate Zn deficiency evaluated by body Zn clearance and increased urinary Zn excretion. After oral supplementation of Zn sulphate (4-10 mg/kg body weight) for 12 months, levels of serum free T3 and T3 normalized, serum rT3 decreased, and the TRH-induced TSH reaction normalized. Serum selenium concentration (Type 1 T4 deionidase contains selenium in the rat) was unchanged by Zn supplementation. CONCLUSION: Zn may play a role in thyroid hormone metabolism in low T3 patients and may in part contribute to conversion of T4 to T3 in humans.

Adolescent↗
PubMed1994

Rat argininosuccinate lyase promoter: the dyad-symmetric CCAAT box sequence CCAATTGG in the promoter is recognized by NF-Y.

The gene for rat argininosuccinate lyase (AL), which catalyzes the last step of arginine biosynthesis, is expressed in many tissues, though its expression is much higher in the liver where the enzyme is involved in the ornithine cycle (urea cycle), and moderately higher in the kidney. In transient transfection analysis using various cell lines, the AL promoter exhibited considerable levels of activity in all tested cell lines, with no apparent liver cell specificity, presumably reflecting the ubiquitous expression of this gene. Analysis of 5'-deletion mutants of the promoter region revealed several cis-regulatory elements, whose contribution to the promoter activity seemed to vary according to cell type. The most prominent positive regulatory region was detected around the position -80 base pairs, and it overlapped with a dyad-symmetric CCAAT box sequence CCAATTGG. A factor(s) interacting with this sequence element was found to be present ubiquitously. Gel shift competition analysis and antibody double shift analysis showed that this factor was identical or highly similar to a transcription factor, nuclear factor-Y (NF-Y), which consists of two different subunits and recognizes CCAAT motifs in various promoters. Point mutagenesis at each half site of the palindrome CCAATTGG and the introduction of a space between the half-site motifs abolished the binding with NF-Y. Thus, it seems that NF-Y recognizes the correctly spaced dyad-symmetric CCAAT box.

Animals↗
PubMed1994

Can renal handling of phosphate predict response to growth hormone therapy in normal variant short children by short-term treatment?

We investigated if renal handling of phosphate could predict height velocity in 28 normal variant short children (16 boys and 12 girls). Before and after human growth hormone was given for four consecutive days, the ratio of maximum tubular reabsorption rate for phosphorus to glomerular filtration rate (TmP/GFR) was calculated. Based on increments in TmP/GFR (delta TmP/GFR) with growth hormone administration, the patients were divided into two groups; children in whom the levels of delta TmP/GFR were 0.8 mg/dl GF or more (group A, n = 7) and those with levels less than 0.8 mg/dl GF (group B, n = 21). All children in group A and some in group B (n = 9) were injected with 0.5 IU/kg/week of recombinant human growth hormone for over one year. Height velocity during therapy was significantly greater in treated children in group A than in group B and was similar among treated (n = 9) and untreated (n = 12) children in group B. The present study suggests that change in renal handling of phosphate during short-term growth hormone administration can serve to select normal variant short children who will respond well to growth hormone therapy.

Age Determination by Skeleton↗
PubMed1994

Characterization of subspecies of apolipoprotein A-I-containing lipoprotein in homozygotes for familial lecithin:cholesterol acyltransferase deficiency.

We characterized the two species of lipoproteins containing apolipoprotein A-I (apoA-I), one containing only apoA-I (LpA-I) and the other containing apoA-I and apoA-II (LpA-I/A-II), in four homozygotes for familial lecithin: cholesterol acyltransferase (LCAT) deficiency. Two homozygotes lacked both LCAT mass and activity, whereas the other two had some residual LCAT mass and activity. In these patients, the amount of all apoA-I-containing lipoproteins was one fourth that of normal control subjects, and > 60% was LpA-I. The chemical composition of both LpA-I and LpA-I/A-II is characterized by markedly decreased ratios of neutral to polar lipids compared with those of normals and the sizes of LpA-I and LpA-I/A-II particles are shifted to smaller and larger diameter ranges when compared with those of normal particles. Changes in particle diameter are also reflected in slower electrophoretic mobilities of both LpA-I and LpA-I/A-II particles. All of these abnormalities were more evident in the two homozygotes who lacked LCAT activity. Incubation of LCAT-deficient plasma with LCAT markedly corrected the chemical and physical abnormalities in both LpA-I and LpA-I/A-II particles. These data, taken together, emphasize the importance of LCAT in modifying the chemical composition, size, and shape of LpA-I and LpA-I/A-II particles.

Adult↗
PubMed1994

Recovery from rheumatoid cerebral vasculitis by low-dose methotrexate.

We report the successful management of cerebral vasculitis in a 46-year-old woman with longstanding rheumatoid arthritis with low-dose methotrexate. She suddenly developed dysarthria and left hemiparesis. Magnetic resonance imaging disclosed ischemia of the right pons, and angiography demonstrated cerebral vasculitis of vertebro-basilar arteries. The vasculitis was refractory with high-dose steroid therapy, which had only transient clinical benefit, and evolution to the pontine infarction followed. Her clinical status showed marked improvement in association with recovery of the vascular abnormalities after the initiation of the methotrexate therapy.

Arthritis, Rheumatoid↗
PubMed1994

[A case of ANCA-associated rapidly progressive glomerulonephritis with oral aphtha and erythema nodosum].

We reported a case of a 22-year old female with a microscopic form of polyarteritis nodosa (PN) who initially manifested Behçet's disease-like symptoms, such as fever, arthralgia, oral aphtha and erythema nodosum, and rapidly progressive glomerulonephritis (RPGN). On admission, her urinalysis showed active nephritic syndrome and her renal function rapidly deteriorated; serum creatinine levels elevated from 1.2 to 3.9 mg/dl within 2 weeks. Skin biopsy specimens from erythema showed panniculitis. Accordingly, she was treated with daily 30 mg of oral prednisolone and three-day intravenous pulse therapy of 1000 mg of methylprednisolone twice. After treatment, skin eruption and oral aphtha disappeared, and the serum creatinine level improved to 1.2 mg/dl. Percutaneous renal biopsy performed on the 28th day showed focal necrotizing glomerulonephritis and hyalinosis of small arteries. Immunofluorescence studies showed only trace stainings for IgG, IgA and beta lc. Electron microscopic findings revealed fusion of the foot process and swelling of endothelial cells, but no dense deposits. Anti-neutrophil cytoplasmic antibody (ANCA) was positive for IgG class with a 40-fold titer by indirect immunofluorescence test and showed a cytoplasmic pattern combined with high urinary IL-8 level (280.1 pg/ml). We diagnosed this case as a microscopic form of PN. ANCA titer and urinary IL-8 correlated positively with the disease activity, and were finally below 8-fold and 58.6 pg/ml, respectively after resolution of RPGN for 42 months. In this case, ANCA was useful not only for differential diagnosis of the patients with systemic vasculitis and crescentic glomerulonephritis, but also for evaluation of the disease activity.

Adult↗