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Biomedical subjects

Naomi Kondo

Publications and source records attributed to Naomi Kondo.

At least 19 recordsLinked to original sources
PubMed2006

Single-base substitution at the last nucleotide of exon 6 (c.671G>A), resulting in the skipping of exon 6, and exons 6 and 7 in human succinyl-CoA:3-ketoacid CoA transferase (SCOT) gene.

Succinyl-CoA:3-ketoacid CoA transferase (SCOT, EC 2.8.3.5) is the key enzyme for ketone body utilization. Hereditary SCOT deficiency (MIM 245050) causes episodes of severe ketoacidosis. We identified a homozygous point mutation (c.671G>A) , which is a single-base substitution at the last nucleotide of exon 6, in a Turkish patient (GS12) with SCOT deficiency. This point mutation resulted in the skipping of exon 6, and exons 6 and 7 in human SCOT genes. To understand why the c.671G>A causes exons 6 and 7 skipping, nuclear RNA was separated from cytoplasmic RNA and both were analyzed by RT-PCR. In nuclear RNA, SCOT mRNA with exon 6 skipping was predominant and mRNA with exons 6 and 7 skipping was hardly detected, whereas the latter became one of major mRNA species in cytoplasmic RNA. This discrepancy was interpreted as follows: exon 6 skipping causes a frameshift and nonsense-mediated RNA decay in the cytosol, so mRNA with exon 6 skipping was unstable. On the other hand, SCOT mRNA with exons 6 and 7 is a minor transcript but it retains the reading-frame and is stable in cytosol. As a result, the latter mRNA is more abundant under steady-state conditions as compared to the former mRNA.

Acidosis↗
PubMed2006

Interstitial deletion of 1q42.13-q43 with Duane retraction syndrome.

Duane retraction syndrome is a congenital eye movement disorder characterized by failure of the sixth cranial nerve or nucleus to develop properly, resulting in restriction of abduction, narrowing of the palpebral fissure, and retraction of the globe on attempted adduction and/or restricted adduction. The gene loci of Duane syndrome have been mapped on 8q and 2q, indicating a heterogeneity. We report here a patient with interstitial deletion of 1q with Duane syndrome. The karyotype of our patient suggests another possible locus of the Duane syndrome, and the mapped genes around the deleted region, 1q42.13-43, contain possible candidate genes such as a homeobox gene. However, further clinical descriptions of patients with Duane syndrome and genetic investigations of the deleted regions are needed for a more accurate delineation.

Child↗
PubMed2006

The common phospholipid-binding activity of the N-terminal domains of PEX1 and VCP/p97.

PEX1 is a type II AAA-ATPase that is indispensable for biogenesis and maintenance of the peroxisome, an organelle responsible for the primary metabolism of lipids, such as beta-oxidation and lipid biosynthesis. Recently, we demonstrated a striking structural similarity between its N-terminal domain and those of other membrane-related AAA-ATPases, such as valosine-containing protein (p97). The N-terminal domain of valosine-containing protein serves as an interface to its adaptor proteins p47 and Ufd1, whereas the physiologic interaction partner of the N-terminal domain of PEX1 remains unknown. Here we found that N-terminal domains isolated from valosine-containing protein, as well as from PEX1, bind phosphoinositides. The N-terminal domain of PEX1 appears to preferentially bind phosphatidylinositol 3-monophosphate and phosphatidylinositol 4-monophosphate, whereas the N-terminal domain of valosine-containing protein displays broad and nonspecific lipid binding. Although N-ethylmaleimide-sensitive fusion protein, CDC48 and Ufd1 have structures similar to that of valosine-containing protein, they displayed lipid specificity similar to that of the N-terminal domain of PEX1 in the assays. By mutational analysis, we demonstrate that a conserved arginine surrounded by hydrophobic residues is essential for lipid binding, despite very low sequence similarity between PEX1 and valosine-containing protein.

ATPases Associated with Diverse Cellular Activitie↗
PubMed2006

Identification of Alu-mediated, large deletion-spanning exons 2-4 in a patient with mitochondrial acetoacetyl-CoA thiolase deficiency.

Mitochondrial acetoacetyl-CoA thiolase (T2) deficiency is a rare inherited metabolic disorder affecting isoleucine catabolism and ketone body metabolism. So far, more than 39 different mutations have been identified in 60 T2-deficient patients. However, no large deletions have been reported. We herein report the first case of a large T2 gene deletion from intron 1 to intron 4 in a T2-deficient patient (GK41). cDNA analysis revealed that an aberrant cDNA with exons 2-5 skipping was a major transcript, associated with a minor transcript of exons 2-4 skipping with a 94-bp insertion composed of an intron 1 sequence. Genomic analysis indicated an absence of PCR amplification of exons 2-4 and gene deletion was revealed by Southern blot analysis. Cloning and sequencing long range PCR products revealed a 6.4kb deletion. Alu element-mediated unequal homologous recombination between an Alu-Sx in intron 1 and another Alu-Y in intron 4 appears to be responsible for this deletion.

Acetyl-CoA C-Acetyltransferase↗
PubMed2006

Selective utilization of nonhomologous end-joining and homologous recombination DNA repair pathways during nervous system development.

The repair of DNA double-strand breaks (DSBs) occurs via nonhomologous end-joining (NHEJ) or homologous recombination (HR). These mechanistically distinct pathways are critical for maintenance of genomic integrity and organismal survival. Although inactivation of either pathway leads to embryonic lethality, here we show selective requirements for each DNA DSB repair pathway at different stages of mammalian nervous system development. DNA damage-induced apoptosis resulting from inactivation of HR (Xrcc2 deficiency) only occurred in proliferating neural precursor cells, whereas disruption of NHEJ (DNA ligase IV deficiency) mainly affected differentiating cells at later developmental stages. Therefore, these data suggest that NHEJ is dispensable for a substantial portion of early development because DSB repair during this period utilizes HR. Moreover, DNA damage-induced apoptosis required the ataxia telangiectasia mutated (Atm) kinase after disruption of NHEJ, but not HR, during neurogenesis. However, embryonic lethality arising from disruption of either repair pathway was rescued by loss of p53 and resulted in specific tumor types reflective of the particular DSB repair pathway inactivated. Thus, these data reveal distinct tissue- and cell-type requirements for each DNA DSB repair pathway during neural development and provide insights for understanding the contributions of DNA DSB responses to disease.

Animals↗
PubMed2006

A 6-bp deletion at the splice donor site of the first intron resulted in aberrant splicing using a cryptic splice site within exon 1 in a patient with succinyl-CoA: 3-Ketoacid CoA transferase (SCOT) deficiency.

Succinyl-CoA: 3-ketoacid-CoA transferase (SCOT; locus symbol OXCT, EC 2.8.3.5) deficiency is a rare genetic disorder affecting ketone body utilization in extra-hepatic tissues. A 6-bp deletion at the splice donor site of intron 1 resulted in the absence of a full-length mature SCOT mRNA with faint amounts of aberrantly spliced transcripts using a cryptic splice donor site within exon 1, which was located just 7 bases upstream from the authentic site in a SCOT deficient patient.

Base Pairing↗
PubMed2006

Aberrant peroxisome morphology in peroxisomal beta-oxidation enzyme deficiencies.

Peroxisomes are ubiquitous organelles in eukaryotic cells and surrounded by a single membrane, and undergo considerable changes in size, shape and number. Peroxisomal disorders are classified into two categories: peroxisome biogenesis disorders (PBDs) and single-enzyme deficiencies (SEDs). Morphologically aberrant peroxisomes called 'peroxisomal ghosts' in PBDs are well known, however, a morphological approach to the study of peroxisomes in SEDs has been rarely reported. Here, we investigated the morphology of peroxisomes in cultured fibroblasts from patients lacking peroxisomal beta-oxidation enzymes, including acyl-CoA oxidase (AOX) or D-3-hydroxyacyl-CoA dehydratase/D-3-hydroxyacyl-CoA dehydrogenase bifunctional protein (D-BP). Morphological analysis by immunofluorescence examination using an antibody against catalase revealed a smaller number of large peroxisomes in fibroblasts from these patients. Moreover, immunoelectron microscopy using an antibody against the 70-kDa peroxisomal membrane protein (PMP70) showed large peroxisomes with various horseshoe-shaped membrane structures. These results give an important clue to elucidating the division of peroxisomes and how peroxisomes change in size, shape, number and position within cells, which are subjects for future study.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed2006

Regulation of the Atm promoter in vivo.

While ATM, the protein defective in the human genetic disorder ataxia-telangiectasia (A-T), is primarily activated as a preexisting protein by radiation, there is also evidence that expression of the protein can be regulated at the transcriptional level. Activation of the ATM promoter by ionizing radiation has been reported only in quiescent cells in culture. To investigate how the Atm promoter is regulated in vivo, we generated transgenic mice that express the luciferase reporter gene under the control of the murine Atm promoter. Using a biophotonic imaging system luciferase activity was monitored in vivo. Strong promoter activity was detected throughout the transgenic animals with particularly high signals from the thymus, abdominal region, and reproductive organs. This activity further increased in response to both ionizing radiation and heat stress in a time dependent manner. Luciferase activity, measured in vitro in extracts from different tissues, showed highest activities in testes, ovaries, and cerebellum. Subjecting these mice to a single dose of 4 Gy total body radiation led to a time-dependent activation of the promoter with the strongest response observed in the peritoneal membrane, skin, and spleen. For most tissues tested, maximal promoter activity was reached 8 hr after radiation. The observed changes in promoter activity largely correlated with levels and activity of Atm protein in tissue extracts. These results demonstrate that, in addition to activation by autophosphorylation, Atm can also be regulated in vivo at the transcriptional level possibly ensuring a more sustained response to radiation and other stimuli.

Animals↗
PubMed2006

Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity.

Tyrosine kinase 2 (Tyk2) is a nonreceptor tyrosine kinase that belongs to the Janus kinase (Jak) family. Here we identified a homozygous Tyk2 mutation in a patient who had been clinically diagnosed with hyper-IgE syndrome. This patient showed unusual susceptibility to various microorganisms including virus, fungi, and mycobacteria and suffered from atopic dermatitis with elevated serum IgE. The patient's cells displayed defects in multiple cytokine signaling pathways including those for type I interferon (IFN), interleukin (IL)-6, IL-10, IL-12, and IL-23. The cytokine signals were successfully restored by transducing the intact Tyk2 gene. Thus, the Tyk2 deficiency is likely to account for the patient's complex clinical manifestations, including the phenotype of impaired T helper 1 (Th1) differentiation and accelerated Th2 differentiation. This study identifies human Tyk2 deficiency and demonstrates that Tyk2 plays obligatory roles in multiple cytokine signals involved in innate and acquired immunity of humans, which differs substantially from Tyk2 function in mice.

Adolescent↗
PubMed2006

Autologous peripheral blood stem cell transplantation in a patient with relapsed pleuropulmonary blastoma.

Pleuropulmonary blastoma (PPB) is a rare and aggressive primary intrathoracic neoplasma of children. The prognosis is extremely poor with frequent metastasis to the brain and bone. We present a 4-year-old girl with a tumor mass in the right hemithorax initially diagnosed as pneumoniae. Tumor resection was performed and the histologic report indicated the diagnosis of PPB. The patient received chemotherapy comprising vincristine, actinomycin D, doxorubicin, cisplatin, and cyclophosphamide. Irradiation was performed with total 45 Gy at the right lower pulmonary lobe. She relapsed 29 months later at the pleura between the right middle and lower pulmonary lobe. Tumor resection and total 45 Gy of irradiation were performed again. High-dose chemotherapy comprising cisplatin, adriamycin, and cyclophosphamide was performed followed by autologous peripheral blood stem cell transplantation (PBSCT). The patient achieved complete hematologic recovery. Thirty-one months after PBSCT, no signs of relapse have been observed. Although it might be that the patient could have been cured with second surgery alone or by the surgery and subsequent chemotherapy, high-dose chemotherapy and PBSCT should be considered for the treatment of relapsed PPB.

Antineoplastic Agents↗
PubMed2006

Age-related changes in intracellular cytokine profiles and Th2 dominance in allergic children.

The unbalanced T helper response has been pointed out in allergic diseases. Especially in childhood, it is important to consider the development of acquired immunity. We investigated the relationship between age and Th1, Th2, Tc1 or Tc2 cells. In addition, Th1, Th2, Tc1 or Tc2 cells in allergic diseases were compared with control subjects. Thirty-four healthy controls (0-40 years old), 200 samples of cord blood, nine patients with atopic dermatitis (AD) (1-3 years old) and five patients with bronchial asthma (BA) (2-6 years old) were studied. Surface staining with CD4, CD8 and intracellular staining with anti-interferon-gamma (IFN-gamma) and anti-interleukin (IL)-4 were carried out, and analyzed by using flow cytometry. In the healthy controls, the percentages of Th1, Tc1 or Th2 showed positive correlation with age. The absolute numbers of Th1 or Tc1 also correlated with age. Cord blood with a family history of allergic disease showed no significant difference compared to that without a family history. The percentage of Th2 in AD and BA patients was significantly higher than in the age-matched healthy controls. The increase in Th1, Th2 and Tc1 with age might reflect on the development of acquired immunity. Age matching is important when evaluating the cytokine profiles of T cells. In allergic diseases, although cord blood showed a Th1-dominant pattern, it changed to Th2 dominance in childhood, and this may reflect on some genetic background.

Adult↗
PubMed2006

Suppression of IFN-gamma production in atopic group at the acute phase of RSV infection.

Several studies have suggested that respiratory syncytial virus (RSV) bronchiolitis induced the change of cytokine production profile in childhood. We sought to determine whether the RSV-induced cytokine production was affected by the patient's atopic background. We quantified interferon-gamma (IFN-gamma) and interleukin (IL)-4 in the supernatant of peripheral blood mononuclear cells (PBMCs) cultured for 24 h and in the presence of phytohemaglutinin (PHA), IL-12, or IL-18, from 14 infants who were divided into two groups, those who are non-atopic and an atopic group. In RSV-infected infants with atopic diseases, IFN-gamma production from IL-12- or especially IL-18-stimulated PBMCs was subtotally suppressed in the acute phase, whereas in RSV-infected infants without atopic diseases IFN-gamma production was not suppressed on acute phase. The IFN-gamma suppression observed in the atopic group is not caused by the immaturity of an infant's immune system since reduced IFN-gamma production to RSV is not observed in the infants of non-atopic group. IFN-gamma suppression in regard to RSV infection might be caused by some genetic factor involved in the development of atopic disease such as IL-18 signal cascade.

Acute-Phase Reaction↗
PubMed2006

Inosiplex affects the spectra of proton magnetic resonance spectroscopy in subacute sclerosing panencephalitis.

In vivo magnetic resonance techniques such as magnetic resonance imaging (MRI) and magnetic resonance spectroscopy have been some of the most useful tools for evaluation of neurologic diseases. In subacute sclerosing panencephalitis, magnetic resonance spectroscopy can be an additional tool for evaluation of disease progression or the efficacy of the treatment, such as interferon or inosiplex, compared with MRI. Inosiplex is one of the effective drugs for subacute sclerosing panencephalitis, but our in vivo and in vitro magnetic resonance spectroscopic study indicated that inosiplex affects the spectra, suggesting a possible failure of neurologic evaluation in a patient with subacute sclerosing panencephalitis treated with inosiplex.

Adolescent↗
PubMed2006

Neuroradiologic findings in Sotos syndrome.

Sotos syndrome is a well-known anomaly syndrome characterized by overgrowth, characteristic facial gestalt, and developmental delay, and haploinsufficiency of the NSD1 gene has been revealed as one of the major genetic causes. However, there have been only a few reports on neuroradiologic findings by computed tomography (CT) or magnetic resonance imaging (MRI), and functional examination of the brain has not been reported. We examined three cases with typical Sotos syndrome, which also were confirmed by genetic analysis with a specific probe for the NSD1 gene. The results of MRI showed the characteristic features that have been reported previously. The findings obtained by using single-photon emission computed tomography and magnetic resonance spectroscopy suggested an association between mental delay and behavioral tendency in Sotos syndrome and immaturity in frontal brain function.

Brain↗
PubMed2006

Effects of dioxins on the quantitative levels of immune components in infants.

Dioxins (polychlorinated dibenzo-p-dioxin (PCDD)+polychlorinated dibenzofuran (PCDF)) and polychlorinated biphenyls (PCBs) are potentially hazardous compounds and have structural similarity with thyroid hormones. Animal studies have demonstrated that PCDDs, PCDFs and PCBs can alter immune functions. However, in humans it is not yet elucidated whether dioxins contained in breast milk have any effects on the immune functions in infants. To investigate the effects of dioxins on the immune system, we compared the quantitative levels of immune components between a breast-fed group and bottle-fed group, in which dioxin concentration is almost zero. Ratios of immune cells, such as CD4+ and CD8+ T-lymphocytes, as well as B-lymphocytes (CD19+ and/or CD20+) and NK cells (CD16+, CD56+) in peripheral blood lymphocytes, serum immunoglobulin level, and level of specific IgE antibody to allergens in the venous blood at 12 months of age were assessed in a subgroup of 281 infants. The relationship of post-natal dioxin exposure via breast feeding with the ratio of immunological markers and the level of humoral antibodies up to 12 month of age was not demonstrated. In conclusion, it would appear that the content of dioxins in breast milk in the Japanese general population is not enough to induce any change in theses-examined immunological parameters during the first year of life, although long-term effects remain to be evaluated.

Adult↗
PubMed2006

A randomized open-label comparative study of montelukast versus theophylline added to inhaled corticosteroid in asthmatic children.

BACKGROUND: Inhaled corticosteroids (ICSs) are widely used in combination with other classes of drugs for treatment of childhood asthma. The efficacy and the safety of montelukast added to low-dose ICS therapy were compared with those of sustained-release theophylline added to low-dose ICS therapy in asthmatic children in the present study. METHODS: Following the 2-week run-in period, 6-to 14-year old patients receiving treatment with ICSs were randomized to treatment for 4 weeks with either montelukast 5 mg once daily or sustained release theophylline 5-8 mg/kg (dry syrup) or 100-200 mg (tablet) twice daily. Patients also received a fixed dose of ICS throughout the run-in and treatment periods. The primary efficacy endpoint was the change from baseline in peak expiratory flow (PEF) at Week 2. RESULTS: A significant increase in morning PEF was observed in the add-on montelukast group as compared with the add-on theophylline group at Week 2 (change from baseline of 22.8 L/minvs. 8.7 L/min; p = 0.041 for between-group difference) and at Week 4 (31.0 L/minvs. 9.8 L/min; p = 0.012). A significant increase in evening PEF was observed in the add-on montelukast group as compared with the add-on theophylline group at Week 4 (24.7 L/minvs. 8.7 L/min; p = 0.027). There were no significant differences between the treatment groups in incidences of clinical and laboratory adverse experiences. CONCLUSIONS: The results indicate that montelukast added to low-dose ICS is an effective and safe option for the treatment of asthma in children.

Acetates↗