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Biomedical subjects

M Emi

Publications and source records attributed to M Emi.

At least 109 records · Page 6Linked to original sources
PubMed1999

Ret/PTC3 is the most frequent form of gene rearrangement in papillary thyroid carcinomas in Japan.

Rearrangements of the RET and TRK proto-oncogenes, which generate fusion oncogenes, are frequent in papillary thyroid carcinomas in Caucasian populations. To determine the spectrum of gene rearrangements in Japanese patients, we systematically examined 40 papillary thyroid carcinomas for all possible types of gene fusion events involving RET or TRK genes. RET rearrangements were found in ten tumors (25%): ret/PTC1 had occurred in two tumors, ret/PTC2 in one, ret/PTC3 in six, and a novel RET rearrangement in the remaining patient. In this last patient, the 5' novel sequence was fused in-frame to the RET amino acid sequence; thus, the fusion gene may encode a protein with a RET kinase domain at the carboxy terminus. The RET gene was fused to 5' donor sequences at the beginning of exon 12 in all ten tumors. No rearrangements involving the TRK gene were found in this panel of carcinomas. Our results indicated that constitutive activation of the RET by gene rearrangement is a frequent mechanism of papillary thyroid carcinogenesis in Japanese adults.

Adult↗
PubMed1999

Isolation and radiation hybrid mapping of a highly polymorphic CA repeat sequence at the human nuclear factor kappa-beta subunit 1 (NFKB1) locus.

The transcriptional factor nuclear factor kappa-beta (NFKB) consists of a multicomponent protein complex that plays a major role in the regulation of many viral and cellular genes. The NFKB complex has two alternative DNA binding subunits. We isolated a polymorphic dinucleotide (CA) repeat sequence from a genomic clone containing the NFKB subunit 1 (NFKB1) gene located at 4q23-24. High heterozygosity (0.813) makes this polymorphism a useful marker in the genetic study of disorders affecting the immune response and cell differentiation.

Base Sequence↗
PubMed1999

Association of radial bone mineral density with CA repeat polymorphism at the interleukin 6 locus in postmenopausal Japanese women.

Twin studies have shown strong correlations between bone mass and genetic factors. Some of the genes involved could regulate bone metabolism and bone formation and resorption, all processes that determine bone mass. One candidate gene, interleukin 6 (IL-6), has been implicated in the pathogenesis of bone loss because it stimulates osteoclasts. We investigated a possible association between the CA repeat polymorphism at the IL-6 gene locus and the bone mineral density (BMD) of radial bone in 472 postmenopausal Japanese women. Genotypes were classified into six groups according to the number of CA repeats present, from 13 to 18. BMD was expressed as adjusted BMD, which was the body mass index (BMI)- and age-adjusted average BMD. The 73 women who possessed an A1 allele (134 bp, containing 18 repeats of CA) had significantly lower adjusted BMD than those participants (n = 399) who did not carry an allele of that size (mean +/- SD values, 0.294 +/- 0.064 vs 0.312 +/- 0.061 g/cm2; P = 0.0221). This result suggests that genetic variation at the IL-6 gene locus is associated with some determinants of BMD in postmenopausal women.

Adenine Nucleotides↗
PubMed1999

Association of diffuse panbronchiolitis with microsatellite polymorphism of the human interleukin 8 (IL-8) gene.

Diffuse panbronchiolitis (DPB) is a distinctive chronic inflammatory lung disease predominantly found in Asian populations. Although its etiology is unknown, DPB is considered to be a multifactorial disease of whose susceptibility is determined by genetic predisposition unique to Asians. We and others have previously reported that the B*5401 allele of the human leukocyte antigen (HLA)-B gene or a closely linked gene in the HLA region on 6p21.3 is one of the major genetic factors in susceptibility to this disease. However, the association with B*5401 is not absolute and the contribution of other genetic or environmental factors should also be considered. Here, four candidate genes that are postulated to play a role in the pathophysiology of DPB, namely, RON-kinase, CYP3A4, motilin, and interleukin (IL)-8, were chosen, and association studies between microsatellite markers at these loci and DPB were conducted. We demonstrated the presence of a specific allele at the IL-8 locus was associated with the disease (c2 = 9.13; P = 0.0025; corrected P [Pc] < 0.05). Although further studies are needed to examine whether neutrophil accumulation in the airways of patients with DPB is controlled by a possible genetic variation of IL-8 or other chemokine genes located in the region 4q12-q13, our data suggest that genes other than those of the HLA system may also contribute to a genetic predisposition to DPB.

Asian People↗
PubMed1999

Isolation and radiation hybrid mapping of a highly polymorphic CA repeat sequence at the SREBP cleavage-activating protein (SCAP) locus.

Sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) is a central regulator of lipid synthesis and uptake in animal cells. A polymorphic dinucleotide (CA) repeat sequence was isolated from a genomic clone containing the SCAP gene and was mapped to chromosome 3p21.3. High heterozygosity (0.89) makes this polymorphism a useful marker in the genetic study of disorders affecting lipid metabolism.

CCAAT-Enhancer-Binding Proteins↗
PubMed1999

Two single nucleotide polymorphisms of the hSNF5/INI1 gene.

We found two single nucleotide polymorphisms at the hSNF5/INI1 gene located on 22q11.2, encoding a member of the chromatin-remodelling SWI/SNF multiprotein complexes. A guanine/adenine polymorphism at codon 299 in exon 7, and another guanine/adenine polymorphism at 39 bp upstream of exon 9 were identified. As the gene was recently identified as a tumor suppressor gene for malignant rhabdoid tumor, this polymorphism may be useful for the genetic study of susceptibility for human malignancies of various tissue origins.

Adenine↗
PubMed1999

A novel LDLR mutation, H190Y, in a Utah kindred with familial hypercholesterolemia.

Heterozygous familial hypercholesterolemia (FH) is a serious disorder causing twice normal low-density lipoprotein (LDL) cholesterol levels early in childhood and very early coronary disease in both men and women. Treatment with multiple medications together with diet can normalize cholesterol levels in many persons with FH and prevent or delay the development of coronary atherosclerosis. Previously published blood cholesterol criteria greatly under-diagnosed new cases of FH among members of known families with FH and over-diagnosed FH among participants of general population screening. Thus, there is a need for accurate and genetically validated criteria for the early diagnosis of heterozygous FH. In the course of investigations of coronary artery disease in Utah, we identified a family whose proband showed elevated plasma levels of LDL cholesterol. To carry out molecular genetic diagnosis of the disease, we screened DNA samples for mutations in all 18 exons and the exon-intron boundaries of the LDL receptor gene (LDLR). Novel point mutations were identified in the proband: a C-to-T transversion at nucleotide position 631, causing substitution of tyrosine for histidine at codon 190 in exon 4 of the LDLR gene. The mutant allele-specific amplification method was used to examine 12 members of the family recruited for the diagnosis. This method helped to unequivocally diagnose 7 individuals as heterozygous for this particular LDLR mutation, while excluding the remaining 5 individuals from carrier status with FH.

Adult↗
PubMed1999

Genomic structure and chromosomal mapping of the human sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) gene.

Sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) is a central regulator of lipid synthesis and uptake in mammalian cells. The entire genomic structure of the human SCAP gene was cloned in a 110-kb region covered by overlapping genomic clones. The SCAP gene was localized to chromosome 3p21.3 by fluorescence in situ hybridization. The human SCAP gene is over 30 kb in length and contains 23 exons and 22 introns. The transcription initiation site within exon 1 is separate from the initiation codon coded in exon 2. Analysis of exon/intron structure revealed that the gene consists of a mosaic of exons encoding functional protein domains. Exon 1 encodes the 5' non-coding region. Exons 2, 3, 7, 8, 9, 10, 11, 13, and 15, respectively, encode each of the eight transmembrane regions. Of these, exons 7-11 encode the sterol-sensing domain. Exons 15-23 encode the hydrophilic carboxyl-terminal domains containing four copies of a motif called the Trp-Asp (WD) repeats that interact with and regulate SREBP and the site-1 protease. Sequence analysis of the 5'-flanking region showed that it comprised a high G/C-rich region and contained adipocyte determination and differentiation-dependent factor 1 (ADD1)/SREBP-1 binding sites in addition to Sp1 and AP2 sites. This suggests that SCAP gene expression is under the control of SREBP-1, a key regulator of the expression of genes essential for intracellular lipid metabolism. Our data establish the basis of investigation for molecular variants in this gene that may result in alterations in plasma lipoprotein levels and/or derangement of intracellular lipid metabolism.

Base Sequence↗
PubMed1999

A common Ile796Val polymorphism of the human SREBP cleavage-activating protein (SCAP) gene.

We identified a new common amino acid polymorphism of isoleucine/valine at codon 796 in exon 16 of the gene for human sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP), a central regulator of lipid synthesis and metabolism in animal cells. It can be detected as an MslI restriction fragment length polymorphism. The allelic frequencies were: isoleucine (A) allele, 0.57 and valine (G) allele, 0.43. This polymorphism may be useful for genetic studies of disorders affecting intracellular lipid metabolism and hyperlipidemia.

Humans↗
PubMed1999

Inactivation of both alleles of the DPC4/SMAD4 gene in advanced colorectal cancers: identification of seven novel somatic mutations in tumors from Japanese patients.

Loss of heterozygosity (LOH) of loci on chromosome 18q occurs in a majority of colorectal cancers. The DPC4/SMAD4 gene, lying in close proximity to the DCC gene at 18q21.1, was recently identified as a candidate tumor suppressor for the genesis of pancreatic cancer as well as a predisposing gene for Juvenile Polyposis Syndrome (JPS). The gene product functions as a cytoplasmic mediator in the signaling pathway of transforming growth factor beta (TGF-beta). To investigate the potential role of DPC4/SMAD4 gene in colorectal cancers, we examined 73 tumors of clinical stages II or III from Japanese patients, for LOH at 18q21 and also for subtle mutations anywhere within the coding region of DPC4/SMAD4. LOH was identified in 50 (78%) of the 64 tumors that were informative for polymorphic markers in the region. Somatic mutations were identified in seven of those tumors: two frameshift mutations, a 1-bp deletion (326 del T) in exon 8 and a 1-bp insertion (50-51 ins A) in exon 1; two nonsense mutations, Arg445Ter in exon 10 and Glu538Ter in exon 11; and three missense mutations, Asn129Lys in exon 2, Tyr95Asn in exon 2, and Asp355Glu in exon 8. Three of the seven mutations were observed in the mad homology 1 (MH1) domain encoded by exons 1 and 2. In all of the tumors carrying intragenic mutations of one allele, LOH analysis had shown that the other allele was missing. The results demonstrated that inactivation of both alleles of the DPC4/SMAD4 gene occurs in a substantial proportion of advanced colorectal cancers, and that the DPC4/SMAD4 gene probably exerts a tumor-suppressor effect for colorectal carcinogenesis that fulfills the criterion of the two-hit concept proposed by Knudson [A.G. Knudson, Hereditary cancer, oncogenes, and anti-oncogenes, Cancer Res. 45 (1985) 1437-1443.].

Alleles↗
PubMed1999

Contribution of TAP genes to genetic predisposition for diffuse panbronchiolitis.

Diffuse panbronchiolitis is a chronic obstructive pulmonary disease found in Asian populations. Although diffuse panbronchiolitis is considered to be a multifactorial disease of unknown etiology, the disease susceptibility appears to be determined by a genetic predisposition unique to Asians. An earlier study showed that human leukocyte antigen (HLA)-B54 predominantly found in East Asians was strongly associated with the disease. A possible interpretation of this association is that the class I molecule or class I antigen presenting system is directly involved in its pathogenesis. Recent observations in which impaired expression of class I molecules causes a syndrome resembling diffuse panbronchiolitis further prompted us to test this possibility. Genes of the molecules implicated in the class I pathway, TAP1, TAP2 and LMP2, which are located in the HLA region of the sixth chromosome were analyzed in 76 patients with diffuse panbronchiolitis and 120 normal controls. The combination of Ala-665 and Gln-687 in exon 11 of the TAP2 gene was associated with the disease (P=0.0028, Pc<0.05). Although this positive association might be partly explained by linkage disequilibrium with HLA-B*5401, this TAP2 variation was associated with the disease even in the B*5401-negative subgroup. On the other hand, the His-60 substitution within the LMP2 gene exhibited a negative association with the disease. This negative association, however, could be explained by a strong linkage disequilibrium with HLA-B44 which showed a negative association with the disease in the previous study. These results support the notion that diffuse panbronchiolitis is influenced by genetic factors in the HLA region. Besides the class I gene itself, genes relevant to the class I antigen presenting system might contribute to its genetic predisposition.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

A highly polymorphic CA repeat marker at the interleukin-11 locus.

The interleukin-11 (IL-11) stimulates T cell-dependent development of immunoglobulin-producing B cells and collaborates with IL-3 in supporting murine megakaryocyte colony formation. The interleukin-11 (IL-11) also stimulates osteoclast formation and inhibits osteoclast function in vitro and has been implicated in estrogen deficiency-induced bone loss. We isolated a polymorphic dinucleotide (CA) repeat sequence from a genomic clone containing the IL-11 gene located at 19q13.3-q13.4. High heterozygosity (0.81) makes this polymorphism a useful marker in genetic study of disorders affecting immune response and bone metabolism.

Base Sequence↗
PubMed1999

Allelic variants in the interleukin-6 gene and essential hypertension in Japanese women.

Genes that can be implicated in hypertension in experimental animals are plausible candidates in the pathogenesis of human hypertension. A recent genome-wide search for quantitative-trait loci (QTL) in hypertensive rats revealed a strong correlation between the interleukin-6 (IL-6) locus on rat chromosome 4 and systolic, diastolic, and mean arterial pressure in this mammalian species. To investigate a possible association between genetic variations of the IL-6 gene and hypertension in humans, we identified two novel single-nucleotide sequence variations, a C/G substitution at -634 in the promoter region and a G/A substitution at 4391 in a 3' non-coding portion of exon 5, and a previous reported sequence variant, an A/T variation in the composition of the AnTn tract around -447 in the promoter region (Fishman D et al. J Clin Invest 1998; 102: 1369-1376), within a test population of 96 Japanese subjects. Allelic associations involving these variations were analyzed in 150 hypertensive and 143 normotensive Japanese women. The distribution of alleles of the three polymorphisms, as well as a dinucleotide repeat present at the IL-6 locus, was similar in the two groups. Therefore, the IL-6 gene appears to play a minimal role in the genetic etiology of essential hypertension in Japanese women.

Aged↗
PubMed1999

Frameshift mutations and a length polymorphism in the hMSH3 gene and the spectrum of microsatellite instability in sporadic colon cancer.

Mutations in the hMVSH3 gene in sporadic colon cancer with microsatellite instability (MSI) were investigated, since several mismatch repair genes were known to be mutated in cancers with MSI, but only deletions in the (A)8 region in the hMSH3 gene have been reported. We also analyzed the relationships between hMSH3 mutations and the spectrum of MSI. We screened MSI in 79 sporadic colon cancer samples using mono- and dinucleotide repeat markers and the samples with MSI were further analyzed for tri- and tetranucleotide repeat instability and mutations in the hMSH3 gene by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis. Five (6%) out of 79 tumors were MSI-H and 15 (19%) were MSI-L. Two MSI-H tumors showed insertion in the (C)8 region in the hMSH6 gene and one tumor showed insertion and deletion in the (A)8 region in the hMSH3 gene, and two of the three above tumors showed MSI in tri-and tetranucleotide repeats. One MSI-L tumor showed somatic alteration in a 9-bp repeat sequence in hMSH3. No frameshift mutations were found in the (A)7 and (A)6 regions in hMSH3. Thus, we confirmed that the (A)8 region in hMSH3 is a hot spot and mutations in the (A)7 and (A)6 regions in hMSH3 are not common. The hMSH3 mutation may enhance genomic instability in some colorectal cancers.

Base Pair Mismatch↗
PubMed1999

PTEN/MMAC1 mutations in hepatocellular carcinomas: somatic inactivation of both alleles in tumors.

Allelic loss of loci on chromosome 10q occurs frequently in hepatocellular carcinomas. Somatic mutations of the PTEN/MMAC1 gene on this chromosome at 10q23 were recently identified in sporadic cancers of the uterus, brain, prostate and breast. To investigate the potential role of PTEN/MMAC1 gene in the genesis of hepatocellular carcinomas, we examined 96 tumors for allelic loss on 10q and also for subtle mutations anywhere within the coding region of PTEN/MMAC1 gene. Allelic loss was identified in 25 of the 89 (27%) tumors that were informative for polymorphic markers in the region. Somatic mutations were identified in five of those tumors: three frameshift mutations, a 1-bp insertion at codon 83-84 in exon 4 and two 4-bp deletions, both at codon 318-319 in exon 8; two C-to-G transversion mutation, both at -9 bp from the initiation codon in the 5' non-coding region of exon 1. No missense mutation was observed in this panel of tumors. In most of the informative tumors carrying intragenic mutations of one allele, we were able to detect loss of heterozygosity as well. These findings suggest that two alleles of the PTEN/MMAC1 gene may be inactivated by a combination of intragenic point mutation on one allele and loss of chromosomal material on the other allele in some of these tumors.

Alleles↗
PubMed1999

Localization of a target region of allelic loss to a 1-cM interval on chromosome 16p.13.13 in hepatocellular carcinoma.

To identify the location of the putative tumor suppressor gene on chromosome 16p that may be involved in hepatocellular carcinoma (HCC), we examined 96 primary HCCs and evaluated their patterns of allelic loss at 10 microsatellite marker loci distributed along this chromosome arm. Allelic loss at one or more loci was observed in 46 (48%) of these tumors. Through detailed deletion mapping of tumors having partial or interstitial deletions, we identified a commonly deleted region at a 1-cM interval, flanked by D16S519 and D16S3078 at 16p13.13, defining the location of a putative tumor suppressor gene for HCC. This region contains the gene for JAB (JAK-binding protein), which is responsible for negative-feedback regulation of the JAK-STAT pathway induced by cytokine stimulation, raising the possibility that inactivation of this gene may participate in hepatocarcinogenesis via genetic and/or epigenetic changes.

Carcinoma, Hepatocellular↗