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Biomedical subjects

N Kamatani

Publications and source records attributed to N Kamatani.

At least 127 records · Page 7Linked to original sources
PubMed1996

[Abnormalities in urate metabolism: concept and classification].

Most of the primates, unlike other mammals, have mutations in urate oxidase gene and cannot catabolize urate in the bodies. In addition to the genetic defects, some human subjects have various abnormalities in urate metabolism. Urate metabolism abnormalities are classified into two categories, hyperuricemia and hypouricemia. Usually, the urate pool size of an adult male is about 1,200 mg, and 700 mg urate is produced daily. The production is balanced by the excretion of urate into urine (500 mg) and intestine (200 mg). If this balance is disturbed, either hyperuricemia or hypouricemia occurs. According to the mechanisms, hyperuricemia is classified into overproduction and underexcretion, and hypouricemia into underproduction and overexcretion. Overproduction of ruate is caused by PRPP synthetase superactivity, HPRT deficiency, leukemia and alcohol ingestion. Underexcretion of urate is caused by renal insufficiency and treatment by diuretics. Underproduction of urate is caused by xanthine dehydrogenase deficiency, purine nucleoside deficiency and allopurinol treatment. Overexcretion of urine is caused by familial renal hypouricemia, Fanconi's syndrome, diabetes mellitus and treatments with benzbromarone and probenecid. All of these conditions are classified, according to other aspects, into primary and secondary, and genetic and non-genetic abnormalities.

Adult↗
PubMed1996

[Adenine phosphoribosyltransferase(APRT) deficiency].

Adenine phosphoribosyltransferase(APRT) deficiency is an autosomal recessive disorder and the homozygotes develop 2,8-dihydroxyadenine(DHA) urolithiasis and, in severe cases, renal failure. The prevalence is higher among the Japanese than other ethnic groups. So far 120 cases have been reported among the Japanese. The disease is classified into 2 types; type I and II are associated with complete and partial deficiencies, respectively. While all non-Japanese cases were of type I, about 78% of the Japanese patients were of type II. Each of the type II patients has at least one APRT*J allele with a ATG(Met) to ACG(Thr) base substitution at codon 136. All APRT*J alleles were derived from a single ancestor. All type I patients and some type II patients possess APRT*QO alleles with various point mutations or large gene abnormality. Type II patients tend to develop first symptoms later than the type I patients. The diagnoses of homozygotes and heterozygotes can be done by the cell culture methods. Both enzyme assay and molecular diagnostic methods are useful but not as reliable as the cell culture methods Excessive water intake, restriction of foods with high adenine contents and administration of allopurinol are useful treatments.

Adenine↗
PubMed1995

Differential cytotoxic effects of mizoribine and its aglycone on human and murine cells and on normal and enzyme-deficient human cells.

The growth inhibitory mechanisms of mizoribine, an immunosuppressive imidazole nucleoside used clinically to inhibit rejection reactions after renal transplantation and in the treatment of systemic lupus erythematosus and rheumatoid arthritis, were studied in human and murine cells. We found that (a) human cells were 20- to 60-fold more resistant than murine cells to both mizoribine and its aglycone, (b) adenine phosphoribosyltransferase (APRT)-deficient human cells were resistant to aglycone but not to mizoribine, (c) hypoxanthine phosphoribosyltransferase (HPRT)-deficient human cells were at least 100-fold more sensitive to both mizoribine and aglycone, and (d) the decrease in intracellular GTP broadly paralleled the cytotoxicity in each case. Therefore, data obtained from studies using non-human tissues should be interpreted carefully before clinical application. Results indicate that the growth inhibitory effect of the aglycone but not of mizoribine is mediated by APRT, and depletion of guanine nucleotides is responsible for the effects of both drugs. Our data also suggest that the drugs may reduce mutant HPRT-deficient somatic cells in vivo, and may cause enhanced adverse reactions in HPRT-deficient individuals. The drug may have altered effects in patients receiving other purine or pyrimidine analogs.

Adenine Phosphoribosyltransferase↗
PubMed1995

Selection against blood cells deficient in hypoxanthine phosphoribosyltransferase (HPRT) in Lesch-Nyhan heterozygotes occurs at the level of multipotent stem cells.

Lesch-Nyhan syndrome is caused by a severe genetic deficiency of hypoxanthine phosphoribosyltransferase (HPRT) and is characterized by central nervous system disorders, gout, and in some cases, macrocytic anemia. Women heterozygous for HPRT deficiency are healthy but their somatic cells are mosaic for enzyme deficiency owing to random inactivation of the X chromosome. Frequencies of red blood cells and T cells deficient in HPRT are significantly lower than the expected 50% in heterozygotes, suggesting that HPRT-negative blood cells are selected against in heterozygotes. To determine at which stage of hematopoiesis such selection occurs, we determined the frequencies of HPRT-negative T, B and erythroid precursor cells in three heterozygotes. Since the cloning efficiencies of T and B cells and colony forming efficiency of burst-forming unit erythroid (BFU-E) for sample from Lesch-Nyhan patients were similar to those of normal cells, HPRT deficiency does not seem to render the differentiated cells less efficient for proliferation. However, the frequencies of HPRT-negative T and B cells, and BFU-E were all less than 10% in each of the three heterozygotes. Although the frequencies of HPRT-negative cells showed tenfold variations between the heterozygotes, each heterozygote had similar frequencies of HPRT-negative cells in the three cell types. These results suggest that HPRT is important at early stages of hematopoiesis, but less so after the cells have differentiated into T cells, B cells and erythroid precursor cells.

Adult↗
PubMed1995

Adenine phosphoribosyltransferase deficiency identified by urinary sediment analysis: cellular and molecular confirmation.

Adenine phosphoribosyltransferase deficiency is an autosomal recessive purine enzyme defect that causes urolithiasis and, in severe cases, renal failure. Most homozygotes with this disorder were identified by analyses of excreted or surgically removed urinary stones, but some were identified only because they were family members of symptomatic individuals. We report here the detection of adenine phosphoribosyltransferase deficiency in two cases by routine analysis of urinary sediments. 2,8-Dihydroxyadenine-like spherical crystals were observed in the urinary sediment, and a diagnosis of homozygous adenine phosphoribosyltransferase deficiency was confirmed by cellular and molecular methods. A molecular diagnostic system using the polymerase-chain reaction and single-strand conformational polymorphism analysis proved to be a rapid and sensitive method to identify the APRT*J allele, a common mutant allele among the Japanese people. These methods will facilitate identification of symptomatic and asymptomatic individuals with homozygous adenine phosphoribosyltransferase deficiency.

Adenine↗
PubMed1994

Molecular basis for the interaction between human IgM and staphylococcal protein A.

To examine the relationship between VH gene usage and reactivity of immunoglobulins, we cloned B cells from peripheral blood from adults and from human neonatal cord blood by EBV transformation. Nearly one-third of the B cell clones from both sources produced IgM reactive with staphylococcal protein A (SPA). None of such IgM reacted with other antigens, except for the crude extract of Staphylococcus aureus. All of 22 B cell clones producing IgM reactive with SPA expressed VH3 genes, while none of the control 15 clones secreting IgM nonreactive with SPA expressed VH3. The IgM proteins reactive with SPA could be clearly divided into two subjects based on the differential binding avidity to solid-phase SPA. Both kappa and lambda light chains were used in each subset of SPA-reactive IgM. Sequence analysis of the PCR products from seven VH3-IgM clones revealed that the VH3 genes were used in nearly germline configuration. The D and J gene usage was diverse. Comparison of amino acid sequences between antibodies with high and low avidity to SPA suggests that the differential avidity is related to amino acid sequence differences in the complementarity determining region 2 and framework region 3. The high frequencies of B cells committed to the production of SPA-reactive IgM in normal blood and the restricted use of VH3 heavy chain genes in nearly germline configuration in these cells support the notion that SPA behaves like a superantigen toward human B cells.

Adult↗
PubMed1994

Analysis of the genotypes for aldehyde dehydrogenase 2 in Japanese patients with primary gout.

Alcoholic ingestion is one of the major factors for increasing serum uric acid levels. Genotypes of aldehyde dehydrogenase 2 (ALDH2, E.C.1.2.1.3), which regulates the sensitivity of an individual to ethanol, were determined in Japanese patients with gout and control subjects by allele specific oligonucleotide hybridization using PCR amplified gene. The most common allele ALDH2*1 codes for normal ALDH2 activity, while the less common allele ALDH2*2 codes for a lower enzyme activity. The frequency of homozygotes of ALDH2*2 was significantly lower in patients with gout than those with rheumatoid arthritis or a normal population. Plasma and urinary hypoxanthine levels were strikingly increased after ethanol drinking in homozygotes for ALDH2*1 but not in heterozygotes for ALDH2*1/ALDH2*2, indicated extensive purine nucleotide degradation in homozygote for ALDH2*1. These data indicated that alcohol ingestion may not be the requisite factor but is deeply involved in the pathogenesis of gout and hyperuricemia.

Alcohol Drinking↗
PubMed1994

Sjögren's syndrome in one of two sisters with idiopathic renal hypouricemia.

Concomitance of idiopathic hypouricemia and Sjögren's syndrome is reported. A 37-year-old Japanese woman with Sjögren's syndrome and her 39-year-old sister without this syndrome both had extremely low levels of serum uric acid. Markedly increased urinary excretion of uric acid and poor response to the pyrazinamide suppression test revealed that the hypouricemia in these sisters was caused by a defect in the pre-secretory reabsorption of uric acid. It is categorized as idiopathic renal hypouricemia than hypouricemia rather secondary to Sjögren's syndrome. Thus, idiopathic renal hypouricemia should be considered even in cases with autoimmune diseases.

Adult↗
PubMed1994

Intermittent treatment with D-penicillamine is effective in lower doses and with fewer adverse effects in patients with rheumatoid arthritis.

OBJECTIVE: To determine whether intermittent rather than daily administration of D-penicillamine (D-Pen) would effectively reduce the incidence of adverse effects without significantly diminishing the clinical benefits. METHODS: We conducted an open prospective trial comparing daily and intermittent schedules. Among 76 Japanese patients with rheumatoid arthritis (RA), 37 underwent daily treatment with D-Pen while 39 were given D-Pen intermittently (every Monday, Wednesday, and Friday). RESULTS: The mean D-Pen dose was 166.8 and 99.4 mg/day for daily and intermittent groups, respectively, the difference being highly significant (p < 0.0001, Mann-Whitney's U test). The incidence of adverse effects was significantly lower in the intermittent group. Both schedules significantly reduced the activity of RA, as evaluated by clinical and laboratory variables. No significant differences were observed in the degree of improvement between the 2 schedules. CONCLUSION: Intermittent therapy with D-Pen is an effective treatment for patients with RA and its higher degree of flexibility can lead to maximum efficacy for management of patients with RA.

Adult↗
PubMed1993

Selective infiltration of B cells committed to the production of monoreactive rheumatoid factor in synovial tissue of patients with rheumatoid arthritis.

B cells were directly cloned using EBV transformation fron the synovial tissue of patients with rheumatoid arthritis (RA), the objective being to investigate the B cell repertoire at the site of inflammation. The frequency of clones producing antibodies with rheumatoid factor (RF) activity was approximately 10% in those from the RA synovial tissue. Similar percentages of B cell clones from the peripheral blood of both RA patients and healthy controls also produced RF. However, almost all of these clones from the peripheral blood produced RF reactive not only with rabbit IgG or human IgG Fc but also with several other antigens (polyreactive). Only one of 654 clones (0.15%) from the RA peripheral blood produced RF specific to rabbit IgG or human IgG Fc (monoreactive). On the other hand, the frequency of clones producing monoreactive RF was approximately 30 times higher in RA synovial tissue. Furthermore, these B cells were activated in vivo to produce antibodies, since monoreactive RF was spontaneously produced from synovial tissue cells without the addition of B cell stimulators. No clones producing monoreactive RF were obtained from the synovial tissue of patients with osteoarthritis. These results suggest selective infiltration and/or proliferation of B cells committed to the production of monoreactive RF in RA synovial tissue.

Antibody Specificity↗
PubMed1993

Analysis of germline and in vivo somatic mutations in the human adenine phosphoribosyltransferase gene: mutational hot spots at the intron 4 splice donor site and at codon 87.

We have characterized 18 germline and 10 in vivo somatic mutations in the human adenine phosphoribosyltransferase (APRT) gene. Both germline and in vivo somatic mutations were clustered at the intron 4 splice donor site and at codon 87. In vitro somatic mutations in human APRT do not appear to show this clustering. These findings suggest that the spectrum of germline mutations in APRT may be similar to that incurred by somatic cells in vivo, but different from that seen in cultured cells. Thus, in vivo, rather than in vitro, somatic mutations in this gene may be more representative of mutational events occurring in the germline.

Adenine Phosphoribosyltransferase↗
PubMed1992

A germ line mutation within the coding sequence for the putative 5-phosphoribosyl-1-pyrophosphate binding site of hypoxanthine-guanine phosphoribosyltransferase (HPRT) in a Lesch-Nyhan patient: missense mutations within a functionally important region probably cause disease.

Lesch-Nyhan syndrome caused by a complete deficiency of hypoxanthine guanine phosphoribosyltransferase (HPRT) is the result of a heterogeneous group of germ line mutations. Identification of each mutant gene provides valuable information as to the type of mutation that occurs spontaneously. We report here a newly identified HPRT mutation in a Japanese patient with Lesch-Nyhan syndrome. This gene, designated HPRT Tokyo, had a single nucleotide change from G to A, as identified by sequencing cDNA amplified by the polymerase chain reaction. Allele specific oligonucleotide hybridization analysis using amplified genomic DNA showed that the mutant gene was transmitted from the maternal germ line. This mutation would lead to an amino acid substitution of Asp for Gly at the amino acid position 140 located within the putative 5-phosphoribosyl-1-pyrophosphate (PRPP) binding region. Missense mutations in human HPRT deficient patients thus far reported tend to accumulate in this functionally active region. However, a comparison of the data suggested that both missense and synonymous mutations can occur at any coding sequence of the human germ line HPRT gene, but that a limited percentage of all the missense mutations cause disease. The probability that a mutation will cause disease tends to be higher when the missense mutation is within a functionally important sequence.

Amino Acid Sequence↗
PubMed1992

Accelerated purine nucleotide degradation by anaerobic but not by aerobic ergometer muscle exercise.

The exact conditions under which exercise causes purine nucleotide degradation are not well understood. We determined plasma hypoxanthine and uric acid levels serially in eight individuals during ergometer muscle exercise. When the load was increased gradually by 15 W/min, plasma hypoxanthine was elevated only after the status exceeded the anaerobic threshold (AT), as determined by analysis of expired gas. Nonstrenuous ergometer exercise, which kept the status continuously below the AT, induced neither blood lactic acid nor plasma hypoxanthine elevation. These results suggest that the AT is also the threshold for the acceleration of purine nucleotide degradation. Muscle exercise to a degree that does not exceed the AT does not cause major purine nucleotide degradation, and, therefore, is expected to be beneficial for patients with gout and/or hyperuricemia.

Adult↗
PubMed1992

Only three mutations account for almost all defective alleles causing adenine phosphoribosyltransferase deficiency in Japanese patients.

We analyzed mutant alleles of adenine phosphoribosyltransferase (APRT) deficiency in Japanese patients. Among 141 defective APRT alleles from 72 different families, 96 (68%), 30 (21%), and 10 (7%) had an ATG to ACG missense mutation at codon 136 (APRT*J allele), TGG to TGA nonsense mutation at codon 98, and duplication of a 4-bp sequence in exon 3, respectively. The disease-causing mutations of only four (3%) of all the alleles among Japanese remain to be elucidated. Thus, a diagnosis can be made for most of the Japanese APRT-deficient patients by identifying only three disease-causing mutations. All of the different alleles with the same mutation had the same haplotype, except for APRT*J alleles, thereby suggesting that alleles with the same mutation in different families were derived from the same ancestral gene. Evidence for a crossover or gene conversion event within the APRT gene was observed in an APRT*J mutant allele. Distribution of mutant alleles encoding APRT deficiency among the Japanese was similar to that seen in cystic fibrosis genes among Caucasians and Tay-Sachs genes among the Ashkenazi Jews.

Adenine Phosphoribosyltransferase↗