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Biomedical subjects

Takashi Igarashi

Publications and source records attributed to Takashi Igarashi.

At least 19 recordsLinked to original sources
PubMed2007

Hyperostosis-hyperphosphatemia syndrome: a congenital disorder of O-glycosylation associated with augmented processing of fibroblast growth factor 23.

UNLABELLED: Two hyperphosphatemic patients with mutations in GALNT3 showed low intact FGF23 levels with marked increase of processed C-terminal fragments. FGF23 protein has three O-linked glycans and FGF23 with incomplete glycosylation is susceptible to processing. Silencing GALNT3 resulted in enhanced processing of FGF23. Decreased function of FGF23 by enhanced processing is the cause of hyperphosphatemia in patients with GALNT3 mutation. INTRODUCTION: Hyperostosis-hyperphosphatemia syndrome (HHS) is an autosomal recessive entity manifesting as severe hyperphosphatemia associated with episodic bone pain and radiological findings of cortical hyperostosis and periosteal reaction. Persistent hyperphosphatemia is not counterbalanced by PTH or 1,25-dihydroxyvitamin D, posing a mirror image of hypophosphatemic states attributed to increased fibroblast growth factor (FGF)23 activity. MATERIALS AND METHODS: We describe two children with HHS who were found to be homozygous for a mutation in GALNT3 encoding a peptide involved in mucin-type O-glycosylation (ppGaNTase-T3). FGF23 levels were evaluated by two ELISAs and Western blotting. FGF23 protein was analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Effect of silencing GALNT3 was evaluated using siRNA in cells transfected with expression vector for FGF23. RESULTS: Both patients had low levels of the full-length FGF23 with markedly augmented amounts of the inactive fragments. Biologically active FGF23 has three O-linked glycans. FGF23 with only one or two O-linked glycans is processed into inactive fragments. Decreasing the expression of the GALNT3 gene by RNA interference resulted in enhanced processing of FGF23. CONCLUSIONS: The primary defect in HHS is impairment of glycosylation of FGF23 resulting from mutations in GALNT3 and leading to augmented processing of FGF23. These changes in FGF23 abolish its phosphaturic effect and lead to severe persistent hyperphosphatemia. This study provides the pathogenetic mechanism of the first mucin-type O-glycosylation defect identified.

Amino Acid Sequence↗
PubMed2007

Regulation of human insulin, IGF-I, and multidrug resistance protein 2 promoter activity by hepatocyte nuclear factor (HNF)-1beta and HNF-1alpha and the abnormality of HNF-1beta mutants.

Mutations in hepatocyte nuclear factor-1beta (HNF-1beta) lead to type 5 maturity-onset diabetes of the young (MODY5). Moreover, mutations in the HNF-1beta gene might cause multiorgan abnormalities including renal diseases, genital malformations, and abnormal liver function. The objective of this study was to investigate the molecular mechanism of diabetes mellitus, intrauterine growth retardation, and cholestasis observed in MODY5 patients. We analyzed the transactivity of wild-type and three mutant HNF-1beta on native human insulin, IGF-I, and multidrug resistance protein 2 (MRP2) promoters in combination with HNF-1alpha, using a reporter-assay system in transiently transfected mammalian cells. In the human insulin gene promoter, we found that the cooperation of HNF-1alpha and HNF-1beta is prominent. Absence of this cooperation was observed in all of the HNF-1beta mutants. In the human IGF-I and MRP2 promoters, we found that the HNF-1beta His153Asn (H153N) mutant had a mutant-specific repressive effect on both HNF-1alpha and wild-type HNF-1beta transactivity. Absence of the cooperation of HNF-1beta mutants with HNF-1alpha in the human insulin gene promoter might be one cause of defective insulin secretion. The H153N mutant-specific repression of HNF-1alpha and HNF-1beta transactivity in human IGF-I and MRP2 promoters might explain the case-specific clinical features of growth retardation and cholestasis observed only in early infancy. We found differential property of HNF-1alpha/HNF-1beta activity and the effect of HNF-1beta mutants by the promoters. We consider that analyses of HNF-1beta mutants on the intended human native promoters in combination with HNF-1alpha may be useful in investigating the molecular mechanisms of the various features in MODY5.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2006

A case of Panayiotopoulos syndrome showing an atypical course.

We describe herein a patient with Panayiotopoulos syndrome (PS) showing an atypical course. The patient initially had seizures typical of this syndrome from 3 to 5 years of age. EEG showed right occipital high-amplitude sharp and slow-wave complexes followed by brief generalized discharges of slow waves. Sequential EEGs obtained from 5 to 11 years of age showed both multifocal discharges and generalized spike and wave complexes. With these changes in EEG findings, the patient experienced various types of seizures. The seizures were frequent and showed oculocephalic deviation followed by absence, atonic seizures, generalized tonic clonic convulsions and clonic seizures of the eyelids, which were observed between 7 and 10 years of age. Antiepileptic drugs were only partially effective for these seizures. Ictal EEG recorded at 8 years of age revealed high-voltage slow waves from the bilateral frontal and occipital regions prior to diffuse high-amplitude spike-wave bursts. At 9 years of age, magnetoencephalography (MEG) revealed the calculated dipoles of the preceding bifrontal spike-wave discharges to be in the frontal areas, while those of the following generalized spike-wave bursts were in the bilateral mid-temporal areas. In PS, reportedly, dipoles of multifocal epileptic discharges are usually located in the occipital and Rolandic areas. The unique clinical evolution in our case may be associated with the unusual frontal localization of dipoles detected by MEG.

Anticonvulsants↗
PubMed2006

[Dent's disease].

Explore the source record for details and available documents.

Chloride Channels↗
PubMed2006

Predominant contribution of OATP1B3 to the hepatic uptake of telmisartan, an angiotensin II receptor antagonist, in humans.

Telmisartan, a nonpeptide angiotensin II receptor antagonist, is selectively distributed to liver. In the present study, we have characterized the contribution of organic anion transporting polypeptide (OATP) isoforms to the hepatic uptake of telmisartan by isolated rat hepatocytes, human cryopreserved hepatocytes, and human transporter-expressing cells. Because it is difficult to evaluate the transport activity of telmisartan because of its extensive adsorption to cells and culture materials, we performed the uptake study in the presence of human serum albumin. The saturable uptake of telmisartan into isolated rat hepatocytes took place in a Na(+)-independent manner and was inhibited by pravastatin, taurocholate, and digoxin, which are Oatp substrates and inhibitors, but not by organic cation, tetraethylammonium, indicating the involvement of Oatp isoforms in its uptake into rat hepatocytes. To identify which human OATP transporters are important for the hepatic uptake of telmisartan, the uptake assay was carried out using OATP1B1- and OATP1B3-expressing human embryonic kidney 293 cells and cryopreserved human hepatocytes. The uptake of telmisartan by OATP1B3-expressing cells was saturable (K(m) = 0.81 microM) and significantly higher than that by vector-transfected cells. In contrast, no significant uptake was observed in OATP1B1-expressing cells. We also observed the saturable uptake of telmisartan by human hepatocytes. Thirty micromolar estrone-3-sulfate, which can selectively inhibit OATP1B1-mediated uptake compared with OATP1B3, did not inhibit the uptake of telmisartan in human hepatocytes, whereas it could inhibit the uptake of estradiol 17beta-d-glucuronide mediated by OATP1B1. These results suggest that OATP1B3 is predominantly involved in the hepatic uptake of telmisartan in humans.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2006

A novel compound heterozygous mutation in the thyroglobulin gene resulting in congenital goitrous hypothyroidism with high serum triiodothyronine levels.

Thyroglobulin abnormality is a rare cause of congenital hypothyroidism and only a limited number of mutations in the thyroglobulin gene have been reported. We analyzed the thyroglobulin gene in a patient with congenital goitrous hypothyroidism. This girl was identified with hyperthyrotropinemia in a neonatal mass-screening test. The patient had goiter, and her body weight gain was poor. Distal femoral epiphysis was absent on roentgenography. Her serum thyroxine level was low; however, her triiodothyronine level was high. Autoantibodies against triiodothyronine, thyroid peroxidase, and thyroglobulin were all negative. Her serum thyroglobulin level was undetectable. The thyroglobulin gene from the genomic DNA of the patient was analyzed by direct sequencing. Two novel heterozygous missense mutations, Cys1897Tyr (exon 31) and Arg2336Gln (exon 40), were found in the patient. The former mutation was derived from her mother, suggesting a compound heterozygous state. Normal triiodothyronine and low thyroxine concentrations are often observed in patients with thyroglobulin gene mutations. We considered that some patients with thyroglobulin abnormality might have high triiodothyronine levels. In cases of congenital goitrous hypothyroidism with normal-to-high triiodothyronine levels and low serum thyroglobulin levels, thyroglobulin abnormality should be considered.

Amino Acid Substitution↗
PubMed2006

Mutations of the PTPN11 and RAS genes in rhabdomyosarcoma and pediatric hematological malignancies.

PTPN11 has been identified as a causative gene in Noonan syndrome (NS), responsible for about 50% of cases of NS. Given the association between NS and an increased risk of some malignancies, notably leukemia and probably some solid tumors including neuroblastoma (NB) and rhabdomyosarcoma (RMS), recent studies have reported that gain-of-function somatic mutations in PTPN11 occur in some hematological malignancies, especially de novo juvenile myelomonocytic leukemia (JMML) and in some solid tumors such as NB, although at a low frequency. In a screen for mutations of PTPN11 in 7 cell lines and 30 fresh tumors of RMS and in 25 cell lines and 40 fresh tumors of NB, we identified a missense mutation (A72T) in an embryonal RMS patient. In the RMS samples, we also detected mutations of NRAS in 1 cell line and 1 patient; both mutations were in embryonal RMSs and had no PTPN11 mutations. No mutations of PTPN11 were detected in NB. In 95 leukemia cell lines and 261 fresh leukemia samples including 22 JMMLs, 9 kinds of missense mutations were detected in 17 leukemia samples, which included 11 (50.0%) mutations in JMML samples and lower frequencies in other hematological malignancies. Furthermore, we identified 4 (18.2%) NRAS mutations and 1 (4.5%) KRAS mutation in 5 JMML samples, 1 of which had a concomitant PTPN11 mutation. Our data suggest that mutations of PTPN11 as well as RAS play a role in the pathogenesis of not only myeloid hematological malignancies but also a subset of RMS malignancies.

Cell Line, Tumor↗
PubMed2006

Aggravation of laryngeal rheumatoid arthritis after use of a laryngeal mask airway.

We report a case of aggravation of laryngeal rheumatoid arthritis (RA) after the use of a laryngeal mask airway (LMA). The patient was a 55-year-old woman with severe RA who underwent wrist arthrodesis under general anesthesia using a size 3 LMA. A few days after the operation, she reported hoarseness. Inflammation of the arytenoid region and vocal cord immobility were observed by fiberoptic nasolaryngoscopy. Vocal function returned to normal by postoperative day 42 in response to prednisolone therapy. In this case, stridor was misdiagnosed preoperatively, and postoperative symptoms and local findings were probably caused by aggravation of laryngeal RA resulting from substantial compression of the arytenoid region by the LMA. For patients with RA referred for surgery, a careful search for cricoarytenoid arthritis is essential, particularly in those with laryngeal stridor, because it may be aggravated after general anesthesia.

Arthritis, Rheumatoid↗
PubMed2006

[Neuropathy in the upper extremity after anesthesia].

BACKGROUND: The purpose of this study was to demonstrate the frequency of neuropathy in the upper extremity after anesthesia. METHODS: We reviewed the postoperative courses of 5454 patients who had received surgical procedures at the Jichi Medical School Hospital from 2004 January to 2004 December. RESULTS: Neuropathy developed in 33 patients (0.7%). In 28 of 33 patients (0.6%), symptoms were minor and resolved within a few days. The remaining 5 patients (0.1%) who had complained the symptoms immediately after emergence from anesthesia had residual symptoms. CONCLUSIONS: In our hospital, the frequency of neuropathy in the upper extremities was 0.7%. The majority of the neuropathies, however, were minor. Neuropathies persisting for a long time were infrequent complications (0.1%).

Adult↗
PubMed2005

A compound heterozygous mutation in the BSND gene detected in Bartter syndrome type IV.

Bartter syndrome is a genetic disorder with hypokalemic metabolic alkalosis and is classified into five types. Type IV Bartter syndrome is a type of neonatal Bartter syndrome with sensorineural deafness and has been recently shown to be caused by mutations in the BSND gene. Owing to the rarity of this disease, only a limited number of mutations have been reported. We analyzed the BSND gene in a patient with type IV Bartter syndrome. The patient was delivered at 37 weeks, with normal body weight, and his neonatal course was uneventful. He was examined for developmental delay and polyuria at age 1 year 8 months and was found to have hypokalemia, metabolic alkalosis, hyperreninemic hyperaldosteronism, and sensorineural deafness. He developed end-stage renal failure at age 15 years, and renal transplantation was performed. We identified compound heterozygous mutations (Q32X and G47R) in the BSND gene. Each mutation was inherited from the parents. The Q32X mutation is a novel mutation and the first nonsense mutation identified in this gene. The mild perinatal clinical features of the patient were similar to those of a patient reported with a homozygous G47R mutation. However, the severity of renal failure suggested that factors other than this gene might affect the manifestation of renal abnormalities.

Bartter Syndrome↗
PubMed2005

Small amounts of achiral beta-amino alcohols reverse the enantioselectivity of chiral catalysts in cooperative asymmetric autocatalysis.

An asymmetric autocatalytic reaction has been catalyzed by a mixture of chiral and achiral beta-amino alcohols. The absolute configuration of the highly enantioenriched obtained product (>98% ee) was shown to depend not only on the absolute configuration of the chiral catalyst but also on the structure and the amount of achiral catalyst. Even in default versus the chiral catalyst, achiral catalysts were shown to be able to reverse the enantioselectivity of the reaction.

Journal Article↗
PubMed2005

Altered expression of junctional adhesion molecule 4 in injured podocytes.

Recent investigations have revealed the importance of glomerular podocytes with its diaphragm as the major filtration barrier. Junctional adhesion molecule 4 (JAM4) has been identified as a protein that interacts with membrane-associated guanyl kinase inverted (MAGI)-1 and is reported to be expressed on podocytes. To elucidate the role of JAM4 on podocytes, we examined the expression of JAM4 and MAGI-1 in normal and two different proteinuric rat models: puromycin aminonucleoside (PAN) nephropathy and anti-nephrin antibody-induced (ANA) nephropathy, one model with and one without effacement of podocyte foot processes. JAM4 was detected by immunomicroscopy at the apical membrane of normal podocytes. JAM4 immunostaining was focally increased in the podocytes in PAN nephropathy but not in ANA nephropathy. In proteinuric podocytes, the expression of JAM4 was distinct from that of MAGI-1 or other slit diaphragm molecules such as nephrin and ZO-1. Close colocalization of JAM4 and ezrin was maintained in PAN nephropathy. By immunoelectron microscopy, the signals for JAM4 were detected at the free apical membrane of the podocytes with effaced foot processes. Studies with selective detergent extract revealed that the subcellular localization of JAM4 was altered in PAN nephropathy. Thus the altered expression of JAM4 appears to be associated with morphological changes in podocytes and can be a useful marker of injured podocytes. JAM4 may have a different role at the apical membrane besides the role as a junctional molecule and is likely associated with the unique structure of this epithelium.

Amino Acid Sequence↗
PubMed2005

Functional characterization of rat organic anion transporter 5 (Slc22a19) at the apical membrane of renal proximal tubules.

A novel member of the organic anion transporter (OAT) family, Oat5 (Slc22a19), has been reported to transport a naturally occurring mycotoxin, ochratoxin A (OTA). However, neither its endogenous substrate and driving force nor physiological functions have been determined. Herein, we report the functional characterization of rat Oat5 (rOat5), as well as its intrarenal distribution and membrane localization. When expressed in Xenopus laevis oocytes, rOat5 mediated the transport of sulfate conjugates of steroids such as estrone-3-sulfate (E(1)S; K(m) = 18.9 +/- 3.9 microM) and dehydroepiandrosterone sulfate (K(m) = 2.3 +/- 0.2 microM) in a sodium-independent manner, in addition to OTA. The rOat5-mediated E(1)S transport was strongly inhibited by four-carbon (C4) dicarboxylate succinate and longer dicarboxylates (C7-C9). The uptake of [(3)H]E(1)S via rOat5 was significantly trans-stimulated by succinate, and the efflux of [(14)C]succinate was significantly trans-stimulated by E(1)S. A similar trans-stimulatory effect of preloaded succinate on E(1)S uptake was also detected in cells stably expressing rOat5 (S(2) rOat5). rOat5 interacted with chemically heterogenous anionic compounds. The rOat5-mediated E(1)S transport was inhibited by several sulfate conjugates, such as 4-methylumbelliferyl sulfate and beta-estradiol sulfate, but not by glucuronide conjugates. An immunohistochemical study showed that rOat5 was localized at the apical membrane of renal proximal tubules in the corticomedullary region. rOat5 mRNA was expressed in the late segments (S(2) and S(3)) of proximal tubules. These results indicate that rOat5 is renal organic anion/dicarboxylates exchanger and, under physiological conditions, may function as an apical reabsorptive pathway for organic anions in proximal tubules driven by an outward gradient of dicarboxylates.

Animals↗
PubMed2005

A novel mutation in fibroblast growth factor 23 gene as a cause of tumoral calcinosis.

CONTEXT: Tumoral calcinosis is a disease characterized by ectopic calcification and hyperphosphatemia due to enhanced renal tubular phosphate reabsorption. Fibroblast growth factor (FGF)23 was identified as a responsible factor in hypophosphatemic diseases caused by renal phosphate leak. OBJECTIVE: The objective of the study was to analyze the involvement of FGF23 in the development of tumoral calcinosis. DESIGN: Serum FGF23 level was evaluated in a patient with tumoral calcinosis by two kinds of ELISA: full-length assay that detects only full-length FGF23 with phosphate-lowering activity and C-terminal assay that measures full-length as well as C-terminal fragment of FGF23. FGF23 gene was analyzed by direct sequencing of PCR products, and mutant FGF23 was analyzed by Western blotting after expression in mammalian cells. PATIENTS: A family of tumoral calcinosis patients were studied. RESULTS: Serum FGF23 was extremely high when measured by C-terminal assay. In contrast, it was low normal by full-length assay. Analysis of FGF23 gene detected a serine to phenylalanine mutation in codon 129. No wild-type allele of this codon was found in the patient. The brother of the proband showed the same base change. When this mutant FGF23 was expressed in vitro, full-length and N-terminal fragments were barely detectable by Western blotting, whereas C-terminal fragment with the same molecular weight as that from wild-type FGF23 could be detected. CONCLUSION: The production and serum level of C-terminal fragment of FGF23 are increased in this patient with tumoral calcinosis. Together with the recent similar report of FGF23 mutation, impaired action of full-length FGF23 seems to result in tumoral calcinosis.

Adult↗
PubMed2005

A familial case of multicystic dysplastic kidney.

A familial case of multicystic dysplastic kidney (MCDK) is described. The proband is a one-year-old boy with left MCDK, and his father was also revealed to have unilateral MCDK. The mother had two abortions; the second pregnancy was terminated because of bilateral MCDK of the fetus (Potter anomaly). The two patients and the aborted male fetus did not have any malformations except for MCDK. Thus in this family MCDK occurs as an isolated phenomenon in three individuals within two generations, presumably as a result of autosomal dominant inheritance.

Adult↗