Hazuki Samejima

National Center for Child Health and Development, Edo, Tōkyō, Japan

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Publications (7)9.29 Total impact

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    ABSTRACT: We report on wide phenotypic variations within a family with SALL1 mutations; the elder sister presented with a Townes-Brocks syndrome phenotype including external ear anomalies, preaxial polydactyly, and anteriorly placed anus, whereas the younger sister presented with a phenotype resembling Goldenhar syndrome, including atretic ear canals, mandibular hypoplasia, and right preaxial polydactyly as well as an epibulbar dermoid. The mother had abnormal external ears but was otherwise structurally normal, and the father was asymptomatic. Analysis of the SALL1 gene revealed that both daughters were heterozygous for nonsense mutation 1256T>A (L419X), that is present 5' to the region encoding the first double zinc finger. The mother was heterozygous for the L419X mutation. The younger daughter is the first patient with a SALL1 mutation to exhibit a classic Goldenhar syndrome-like phenotype with an epibulbar dermoid. The observation lends further support to the concept that Goldenhar syndrome is an etiologically heterogeneous disorder that may have a genetic basis in some cases.
    American Journal of Medical Genetics Part A 05/2007; 143A(10):1087-90. · 2.30 Impact Factor
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    ABSTRACT: Mutations in the JAG1 gene and the NOTCH2 gene cause Alagille syndrome. At present, however, genetic testing of Alagille syndrome is not commonly applied in clinical settings because the currently available assays are technically and financially demanding, mainly because of the size of the genes. In the present study, we optimized the highly sensitive and specific mutation scanning method automated denaturing high-performance liquid chromatography (DHPLC) to analyze the entire coding region of JAG1 and NOTCH2. The coding region was amplified by 69 primer pairs, all of which have the same cycling conditions, aliquoted on a 96-well format PCR plate. In this manner, all the exons were simultaneously amplified using a single block in a thermal cycler. We then wrote a computer script to analyze each segment of JAG1 and NOTCH2 by DHPLC in a serial manner using conditions that were optimized for each amplicon. The implementation of this screening method for JAG1 and NOTCH2 will help medical geneticists confirm their clinical impressions and provide accurate genetic counseling to the patients with Alagille syndrome and their families.
    Genetic Testing 02/2007; 11(3):216-27. · 1.17 Impact Factor
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    ABSTRACT: Many of the effects of dioxins, which are potent environmental pollutants and teratogens, are mediated through the aryl hydrocarbon receptor, also known as the dioxin receptor. The purpose of the present study was to characterize dioxin-responsive genes in a comprehensive manner using two complementary approaches: bioinformatic analysis and microarray analysis. First, we characterized the overall distribution of the cis-regulatory element for the dioxin-responsive element sequence (DRE) 'gcgtg' within putative promoter regions. We assembled the upstream sequences 10 kb from the transcription start site and evaluated their location and frequency in the human and mouse genomes. Second, we characterized the expression profile of mouse embryonic day 12 fetal brain exposed to 2,3,7,8-tetrarchlorodibenzo-p-dioxin. The distributions of 26,680 DREs among 2,843 human genes and 98,711 DREs among 18,541 mouse genes were examined. In both species, the DREs tended to be located close to the transcription start site. Forty genes exhibited significant induction or repression following dioxin exposure in fetal mice. The set of genes exhibited a strong functional coherence, with statistically significant enrichment in organogenesis and the DNA-dependent regulation of transcription, according to Gene Ontology annotations. In both humans and mice, DREs were preferentially distributed close to transcription start sites. Evolutionary conservation of this unique DRE distribution pattern suggests that DREs may be involved in transcriptional regulation. In mice, prenatal dioxin exposure altered the expression of 10 transcription factors, many of which have been documented to play a role in organogenesis. These genes may represent potential mediators of dioxin's effects in fetal tissues.
    Congenital Anomalies 10/2006; 46(3):135-43. · 1.00 Impact Factor
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    ABSTRACT: The authors investigated whether high-dose methotrexate-induced toxicity differed according to the presence of methylenetetrahydrofolate reductase (MTHFR) or reduced folate carrier 1 (RFC1) genetic polymorphism. The authors studied 15 children with acute lymphoblastic leukemia or lymphoblastic lymphoma who were treated using protocols that included high-dose methotrexate (3.0 g/m), for an overall total of 43 courses. Methotrexate-induced toxicities and the plasma methotrexate concentrations were evaluated retrospectively. Hematologic toxicity was the most frequently observed toxicity, appearing in 87% of the patients. In a subset of patients (47%), elevation of liver transaminase levels showed a repeated tendency to develop. High plasma methotrexate concentrations at 48 hours after the methotrexate infusion were not significantly related to methotrexate-induced toxicities except for mucositis. A generalized estimating equation analysis revealed that vomiting during the high-dose methotrexate treatment was more pronounced in patients who had a larger number of G alleles at the RFC1 80G>A polymorphism. No significant differences in the development of other toxicities or in the plasma methotrexate concentrations were observed for the different MTHFR 677C>T or RFC1 80G>A polymorphisms. This study suggests but does not prove that the RFC1 80G>A polymorphism may contribute to interindividual variability in responses to high-dose methotrexate.
    Journal of Pediatric Hematology/Oncology 02/2006; 28(2):64-8. · 0.97 Impact Factor
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    ABSTRACT: Mutations in the CHD7 (chromodomain helicase DNA binding protein 7) gene cause CHARGE syndrome. At present, however, genetic testing of the CHD7 gene is not commonly applied in clinical settings because the currently available assays are technically and financially demanding, mainly because of the size of the gene. In the present study, we optimized the highly sensitive and specific mutation scanning method automated denaturing high-performance liquid chromatography (DHPLC) to analyze the entire coding region of CHD7. The coding region was amplified by 39 primer pairs, all of which have the same cycling conditions, aliquoted on a 96-well format polymerase chain reaction (PCR) plate. In this manner, all of the exons were amplified simultaneously using a single block in a thermal cycler. We then wrote a computer script to analyze each segment of the CHD7 gene by DHPLC in a serial manner using conditions that were optimized for each amplicon. The implementation of this screening method for CHD7 will help medical geneticists confirm their clinical impressions and provide accurate genetic counseling to the patients with CHARGE syndrome and their families.
    Genetic Testing 02/2006; 10(4):244-51. · 1.17 Impact Factor
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    ABSTRACT: Mutations in the CREBBP (CREB-binding protein gene) cause Rubinstein-Taybi syndrome (RSTS). At present, however, genetic testing of CREBBP is not commonly applied in clinical settings because the currently available assays are technically and financially demanding, mainly because of the size of the gene. In the present study, we took advantage of a highly sensitive and specific, automated denaturing high-performance liquid chromatography (DHPLC) technique. First, we developed a DHPLC-based protocol to analyze the entire coding region of CREBBP. Second, we analyzed genetic samples from 21 RSTS patients using DHPLC. The coding region was amplified by 41 primer pairs, all of which have the same cycling conditions, aliquoted on a 96-well format PCR plate. In this manner, all the exons were simultaneously amplified using a single block in a PCR machine. We then wrote a computer script to analyze all the PCR amplicons generated from various portions of the CREBBP gene in a serial manner at optimized conditions determined individually for each amplicon. Heterozygous CREBBP mutations were identified in 12 of the 21 patients: five frameshift mutations, three nonsense mutations, two splice-site mutations, and two missense mutations. The resulting detection rate of 57% was comparable to the outcome of previous studies. The relatively high detection rate in the present study demonstrates the enhanced sensitivity of the DHPLC-based mutation analysis, as exemplified by mutation analyses of other genes. The implementation of similar methodologies for other dysmorphic syndromes will help medical geneticists to confirm their clinical impressions and to provide accurate genetic counseling for patients and their families.
    Congenital Anomalies 01/2006; 45(4):125-31. · 1.00 Impact Factor
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    ABSTRACT: N-desmethylclobazam (N-CLB), the major metabolite of clobazam (CLB), exerts a large influence on therapeutic and adverse effects of CLB. A substantial inter-individual variability has been observed in the ratios of N-CLB concentration/CLB dose and of the N-CLB/CLB concentration. We document here a genotype-phenotype correlation between CYP2C19 polymorphisms and those ratios. Patients with two mutated CYP2C19 alleles show significantly higher ratios than those with the wild type genotype: patients with one mutated allele exhibited intermediate trait. That is, the degree of elevation in the ratios was dependent on the number of mutated alleles of CYP2C19 (gene-dose effect). The N-CLB concentration/CLB dose ratio of patients with two mutated alleles was more than six fold higher than that of wild type patients. Thus, the serum N-CLB/CLB concentration ratio may be a valuable parameter to screen for patients at risk for side effects. Such precautions may be clinically relevant in populations where the mutant allele frequency is high, such as in Asian populations ( approximately 35%). Patients co-medicated with CYP3A4 inducer showed lower CLB concentration/CLB dose ratios and higher N-CLB/CLB concentration ratios. The overall effect of CYP3A4 inducer on N-CLB metabolism, however, was small and, thus, we conclude that the CYP2C19 genotype is the major determinant of the N-CLB concentration. For this reason it is crucial for the better management of epilepsy and other chronic illnesses in general to establish the correlation of genotype of CYP enzymes and pharmacokinetics/dynamics of drugs.
    Brain and Development 01/2005; 26(8):530-4. · 1.67 Impact Factor