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Biomedical subjects

N Kondo

Publications and source records attributed to N Kondo.

At least 181 records · Page 10Linked to original sources
PubMed1998

Molecular heterogeneity in mucopolysaccharidosis IVA in Australia and Northern Ireland: nine novel mutations including T312S, a common allele that confers a mild phenotype.

Mucopolysaccharidosis IVA (MPS IVA) is an autosomal recessive lysosomal storage disorder caused by a genetic defect in N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Previous studies of patients from a British-Irish population showed that the I113F mutation is the most common single mutation among MPS IVA patients and produces a severe clinical phenotype. We studied mutations in the GALNS gene from 23 additional MPS IVA patients (15 from Australia, 8 from Northern Ireland), with various clinical phenotypes (severe, 16 cases; intermediate, 4 cases; mild, 3 cases). We found two common mutations that together accounted for 32% of the 44 unrelated alleles in these patients. One is the T312S mutation, a novel mutation found exclusively in milder patients. The other is the previously described I113F that produces a severe phenotype. The I113F and T312S mutations accounted for 8 (18%) and 6 (14%) of 44 unrelated alleles, respectively. The relatively high residual GALNS activity seen when the T312S mutant cDNA is overexpressed in mutant cells provides an explanation for the mild phenotype in patients with this mutation. The distribution and relative frequencies of the I113F and T312S mutations in Australia corresponded to those observed in Northern Ireland and are unique to these two populations, suggesting that both mutations were probably introduced to Australia by Irish migrants during the 19th century. Haplotype analysis using 6 RFLPs provides additional data that the I113F mutation originated from a common ancestor. The other 9 novel mutations identified in these 23 patients were each limited to a single family. These data provide further evidence for extensive allelic heterogeneity in MPS IVA in British-Irish patients and provide evidence for their transmission to Australia by British-Irish migrants.

Australia↗
PubMed1998

Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency: two pathogenic mutations, V133E and C456F, in Japanese siblings.

Succinyl-CoA:3-ketoacid CoA transferase (SCOT; EC 2.8.3.5; locus symbol OXCT) is the key enzyme of ketone body utilization. Hereditary SCOT deficiency (MIM 245050) causes episodes of severe ketoacidosis. We developed a transient expression system for mutant SCOT cDNAs, using immortalized SCOT-deficient fibroblasts. This paper describes and characterizes three missense mutations in two SCOT-deficient siblings from Japan. They are genetic compounds who inherited the mutation C456F (c1367 G-->T) from their mother. Their paternal allele contains two mutations in cis, T58M (c173 C-->T) and V133E (c398T-->A). Expression of SCOT cDNAs containing either V133E or C456F produces no detectable SCOT activity, whereas T58M is functionally neutral. T58M is a rare sequence variant not detected in 100 control Japanese alleles. In fibroblasts from the proband (GS02), in whom immunoblot demonstrated no detectable SCOT peptide, we measured an apparent residual SCOT activity of 20-35%. We hypothesize that the high residual SCOT activity in homogenates may be an artifact caused by use of the substrate, acetoacetyl-CoA by other enzymes. Expression of mutant SCOT cDNAs more accurately reflects the residual activity of SCOT than do currently available assays in cell or tissue homogenates.

Cell Line, Transformed↗
PubMed1998

Characterization of N93S, I312T, and A333P missense mutations in two Japanese families with mitochondrial acetoacetyl-CoA thiolase deficiency.

Mitochondrial acetoacetyl-CoA thiolase (T2) deficiency is an inborn error of ketone body and isoleucine catabolisms. Japanese patients, GK01 and GK19, were found to be compound heterozygotes of 149delC and A333P, and N93S and I312T, respectively. The latter three missense mutations were individually characterized by analyses of transient expression of the cDNAs and heat stability. A333P and I312T subunits showed aberrant electrophoretic mobility on SDS-PAGE. T2 protein was destabilized by A333P and existed as an insoluble form in the mitochondria. I312T mutation also destabilized T2 protein; however, some T2 protein was retained in soluble form and reduced residual activity was apparent. N93S mutation did not change the heat stability of T2 activity and the reduced residual activity was retained, however a considerable amount was observed in an insoluble form. The effects of mutations were interpreted based on a tertiary structural model of a subunit of the human T2. This model was constructed from the X-ray crystal structure of the homologous peroxisomal 3-ketoacyl-CoA thiolase of Saccharomyces cerevisiae. On the basis of this model, the positions of Ala333 and Ile312 were far from the active site and the mutations would be expected to destabilize the tertiary structure of T2 subunit. By contrast, Asn93 is located near the active site and may function to maintain a local loop structure. The mutation of Asn93 could directly disrupt disposition of the active site.

Acetyl-CoA C-Acetyltransferase↗
PubMed1998

Ataxia-telangiectasia in the Japanese population: identification of R1917X, W2491R, R2909G, IVS33+2T-->A, and 7883del5, the latter two being relatively common mutations.

We analyzed the data regarding six Japanese ataxia-telangiectasia (A-T) patients from four unrelated families, at the DNA level, to search for possible common mutations in the Japanese population. Among eight mutant alleles in the four families, c. 4612del165 (exon 33 skipping) was identified in two alleles, and c. 5749A to T (R1917X), c. 7471T to C (W2491R), c.7883de15, and c. 8725A to G (R2909G) were identified in one allele each. We found no mutations in the other two alleles. The IVS33 + 2T-->A mutation was identified at the genomic level as the cause of exon 33 skipping. We also identified the IVS33 + 2T-->A mutation in a Japanese patient ATL105 who was previously found to be a homozygote of c. 4612del165. W2491R and R2909G mutations were not detected in more than 100 control Japanese alleles. The latter is located in a highly conserved PI-3 kinase domain and is a completely conserved residue among ATM-related proteins. Taken together with previously documented mutations in five other Japanese A-T patients, IVS33 + 2T-->A and 7883del5 were identified in four and five alleles, respectively, in a total of 18 mutant alleles of Japanese A-T patients. These results suggest that these two mutations are relatively common mutations in the Japanese population.

Adolescent↗
PubMed1998

Changes of monoamines in post-mortem brains from patients with diffuse Lewy body disease.

1. In the present study, we measured the concentrations of 5-hydroxytryptamine (5-HT), norepinephrine and dopamine in post-mortem brains from five patients with diffuse Lewy body disease (DLBD), in comparison with five brains from patients with Alzheimertype dementia (ATD), and five brains from normal controls. 2. They were measured by means of high-performance liquid chromatography fluorometric detection. 3. Compared with the ATD and normal control brains, the DLBD ones showed decreased concentrations of 5-HT, norepinephrine and dopamine in the putamen, and lower 5-HT and norepinephrine concentrations, and almost equal dopamine ones in the neocortex.

Aged↗
PubMed1998

Amino acid and nucleotide sequences of human peroxisomal enoyl-CoA hydratase: 3-hydroxyacyl-CoA dehydrogenase cDNA.

Deficiency of enoyl-CoA hydratase: 3-hydroxyacyl-CoA dehydrogenase (peroxisomal bifunctional enzyme), one of the enzymes of the peroxisomal beta-oxidation system, leads to clinical manifestations resembling Zellweger syndrome with hypotonia, psychomotor delay, hepatomegaly, typical facial appearance and accumulation of very long-chain fatty acids. The nucleotide sequence of the human peroxisomal enoyl-CoA hydratase: 3-hydroxyacyl-CoA dehydrogenase cDNA has been reported by Hoefler and colleagues; however, we have found some amino acid differences from our originally isolated cDNA. Contrary to the findings described in a previous paper, we report here the cDNA sequence of human peroxisomal enoyl-CoA hydratase: 3-hydroxyacyl-CoA dehydrogenase in which there are 9 authenticated amino acid alterations.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1998

Mutation analysis in the iduronate-2-sulphatase gene in 43 Japanese patients with mucopolysaccharidosis type II (Hunter disease).

Our series of studies on Hunter disease in Japanese patients showed allelic heterogeneity of IDS gene mutations, genotype/phenotype correlation and racial differences in distribution of mutations. Twenty-five different small mutations have been characterized. Small mutations in the Japanese population are widely distributed through the IDS gene, although some mutations were unevenly concentrated on exon 5 (28%) and on exon 9 (24%). Mutations were seen at the same codon 468 in exon 9 in 5 patients. These findings are in good agreement with data on other ethnic groups. Two unique mutations linked to a severe phenotype were apparently associated with aberrant splicings; one was a point mutation within exon 3 (P86L), partially activating a cryptic splice acceptor site at 28 bp downstream from the mutation site within exon 3 and producing a 44-base truncated mRNA, and the other was a point mutation at the consensus sequence of the splice donor site of intron 2, causing exon 2 skipping.

Base Sequence↗
PubMed1998

Positional cloning of the gene for Nijmegen breakage syndrome.

Nijmegen breakage syndrome (NBS), also known as ataxia-telangiectasia (AT) variant, is an autosomal recessive disorder characterized by microcephaly, growth retardation, severe combined immunodeficiency and a high incidence of lymphoid cancers. Cells from NBS patients display chromosome instability, hypersensitivity to ionizing radiation and abnormal cell-cycle regulation after irradiation, all of which are characteristics shared with AT. Recently, the NBS locus was mapped at 8q21 by two independent approaches, complementation studies and linkage analysis. Here, we report the positional cloning of the NBS gene, NBS1, from an 800-kb candidate region. The gene comprises 50 kb and encodes a protein of 754 amino acids. The amino-terminal region of the protein shows weak homology to the yeast XRS2, MEK1, CDS1 and SPK1 proteins. The gene is expressed at high levels in the testes, suggesting that it might be involved in meiotic recombination. We detected the same 5-bp deletion in 13 individuals, and conclude that it is likely to be a founder mutation.

Amino Acid Sequence↗
PubMed1998

Treatment of MPS VII (Sly disease) by allogeneic BMT in a female with homozygous A619V mutation.

A 12-year-old girl with Sly disease (mucopolysaccharidosis VII; beta-glucuronidase deficiency), who is homozygous for the A619V mutation, had a successful allogeneic BMT, donored by an HLA-identical unrelated female to replace the deficient enzyme. Within 5 months after BMT, the enzyme activity of the recipient's lymphocytes increased to normal range. No signs of acute or chronic GVHD were observed. For the successive 31 months post-BMT, beta-glucuronidase activity in her lymphocytes was maintained at almost normal levels and excretion of glycosaminoglycans in the urine was greatly diminished. Ultrastructural findings demonstrated no abnormal vacuoles and inclusion bodies in the cytoplasm of her rectal mucosal cells. Coincident with the restoration of the enzyme activity, clinical improvement was dramatic. Especially notable were improvements in motor function. The patient was able to walk alone for a long time without aid, and she even became able to ride a bicycle and take a bath. In addition, recurrent infections of the upper respiratory tract and the middle ears decreased in frequency and severity, and dyspnea on exertion, severe snoring and vertigo have substantially improved. Thus, allogeneic BMT in this patient produced a better quality of life and provided a more promising outlook.

Bone Marrow Transplantation↗
PubMed1998

Regional differences in the effect of exercise intensity on thermoregulatory sweating and cutaneous vasodilation.

To investigate regional body differences in the effect of exercise intensity on the thermoregulatory sweating response, nine healthy male subjects (23.2 +/- 0.4 year) cycled at 35, 50 and 65% of their maximal O2 uptake (VO2max) for 30 min at an ambient temperature of 28.3 +/- 0.2 degrees C and a relative humidity of 42.6 +/- 2.4%. Local sweating rate (msw) on the forehead, chest, back, forearm and thigh increased significantly with increases in the exercise intensity from 35 to 50% VO2max and from 50 to 65% VO2max (P < 0.05). The mean values for the density of activated sweat glands (ASG) at 50 and 65% VO2max at the five sites were significantly greater than at 35% VO2max. The mean value of the sweat output per gland (SGO) also increased significantly with the increase in exercise intensity (P < 0.05). The patterns of changes in ASG and SGO with an increase in exercise intensity differed from one region of the body to another. Although esophageal temperature (Tes) threshold for the onset of sweating at each site was not altered by exercise intensity, the sensitivity of the sweating response on the forehead increased significantly from 35 to 50 and 65% VO2max (P < 0.05). The threshold for cutaneous vasodilation tend to increase with exercise intensity, although the exercise intensity did not affect the sensitivity (the slope in the relationship Tes vs. percentage of the maximal skin blood flow) at each site. Tes threshold for cutaneous vasodilation on the forearm was significantly higher at 65% VO2max than at either 35 or 50% VO2max, but this was not observed at the other sites, such as on the forehead and chest. These results suggest that the increase in msw seen with an increasing intensity of exercise depends first on ASG, and then on SGO, and the dependence of ASG and SGO on the increase in msw differs for different body sites. In addition, there are regional differences in the Tes threshold for vasodilation in response to an increase in exercise intensity.

Adult↗
PubMed1998

Serum IgE level is negatively correlated with the ability of peripheral mononuclear cells to produce interferon gamma (IFNgamma): evidence of reduced expression of IFNgamma mRNA in atopic patients.

BACKGROUND: In patients with atopic diseases such as bronchial asthma and atopic dermatitis, an elevated serum IgE level is common. Several studies showed that interleukin-4(IL-4) and interferon-gamma (IFNgamma) are important for regulation of IgE production. OBJECTIVES: The study was designed to examine the pathogenesis of an elevated serum IgE level at the production levels of TH1-type and TH2-type cytokines. METHODS: The production of interleukin-2 (IL-2), IL-4, interleukin-5 (IL-5) and IFNgamma by peripheral blood mononuclear cells (PBMCs) stimulated with phytohemagglutinin (PHA) was analysed in 20 individuals with various serum IgE levels. The amount of IFNgamma mRNA in the stimulated PBMCs was analysed using a quantitative polymerase chain reaction method. RESULTS: Cytokine production was analysed simply as a function of serum IgE level. The serum IgE level was negatively correlated with the amount of IFNgamma secreted by PBMCs (n = 20, R = -0.724, P<0.005) when logarithmically transformed data were analysed, but were not or were only weakly correlated with those of IL-4, IL-2, or IL-5 secreted by these cells (n = 20). For investigation of the cause of reduced IFNgamma production in individuals whose serum IgE level are high, the amount of IFNgamma mRNA was determined. The levels of IFNgamma mRNA expression in the stimulated PBMCs correlated well with the amount of IFNgamma secreted by the PBMCs (n = 8, R = 0.947, P < 0.001). CONCLUSIONS: Reduced IFNgamma production ability due to reduced IFNgamma mRNA expression in PBMCs is associated with an elevated serum IgE level in atopic patients.

Adolescent↗