Biomedical subjects

M Emi

Publications and source records attributed to M Emi.

At least 55 records · Page 3Linked to original sources

PubMed2000

Association of estrogen receptor beta gene polymorphism with bone mineral density.

Chromosomal mapping of the human estrogen receptor beta (ERbeta) gene by fluorescence in situ hybridization (FISH) reveals that ERbeta is located at human chromosome 14, region q23-24.1, where the aberration of DNA copy number in the bone disorders is frequently involved. Then, we investigated the association between dinucleotide (cytosine-adenine; CA) repeat polymorphism located in the flanking region of ERbeta gene and bone mineral density (BMD) in 204 healthy postmenopausal Japanese women. The genotype was classified into "A" through "O" according to the number of the repeats, from 18 to 32. BMD was expressed in Z score (a deviation from the weight-adjusted average BMD of each age using the standard deviation as a unit). When we separate the subjects into two groups bearing at least one I allele (26 CA repeats) and those who did not, the former subjects had significantly higher Z score of L2-4 BMD (mean +/- standard deviation; 0.674 +/- 1.53 vs 0.128 +/- 1.38; P = 0.027). These data suggest that genetic variation at the ERbeta locus may be associated with some determinants for BMD and the possible involvements of this polymorphism in the cause of postmenopausal osteoporosis in Japanese women.

Base Sequence↗

PubMed2000

Allelic loss at the 8p22 region as a prognostic factor in large and estrogen receptor negative breast carcinomas.

BACKGROUND: Allelic losses of tumor suppressor genes, or the chromosomal regions harboring them, in the DNA of tumor cells may become useful postoperative prognostic indicators. The authors studied frequent loss of heterozygosity (LOH) on chromosome 8p22 and its association with disease progression that occurred later in patients with breast carcinoma. METHODS: To examine whether allelic losses at 8p22 might correlate with postoperative survival during a 5-year period of prospective follow-up, the authors tested tumors from a cohort of 298 breast carcinoma patients informative for 8p22 markers. The tumors were tested for allelic losses of microsatellite markers D8S136 and D8S1106 located at 8p22, a chromosomal region where genetic alterations are frequent in breast carcinomas. RESULTS: Among the 298 breast carcinoma patients, 154 (52%) lost alleles in tumors. Patients whose tumors had lost an allele at 8p22 had a significantly higher risk of postoperative mortality than those whose tumors retained both alleles at those loci; their 5-year mortality rates were 18% (26 patients died among 154 with losses at 8p22) versus 7% (10 patients died among 144 with retentions at 8p22) (P = 0.017). The 8p22 LOH was a significant independent prognostic factor for postoperative survival in a group of patients with large tumors (>2.1 cm) and in a group of patients with estrogen receptor negative tumors in both univariate and multivariate analyses. These data show that 8p22 LOH was a significant prognostic factor for the postoperative survival of certain clinical groups of patients who underwent surgery for breast carcinoma. CONCLUSIONS: Allelic loss on chromosome 8p22 can serve as a negative prognostic indicator to guide the postoperative management of patients, especially patients with large tumors (>2.1 cm) and those with estrogen receptor negative tumors.

Adult↗

PubMed2000

Novel gene fusion of COX6C at 8q22-23 to HMGIC at 12q15 in a uterine leiomyoma.

Cytogenetic analyses have shown that aberrations involving 12q13-15 are frequent chromosomal changes in a variety of human benign mesenchymal tumors, e.g., pleomorphic adenomas of the parotid gland, pulmonary chondroid hamartomas, lipomas, and uterine leiomyomas. Recently, the high-mobility group protein gene HMGIC was identified as the target gene affected by the 12q13-15 aberrations. Using 3' rapid amplification of cDNA ends experiments, we isolated novel ectopic sequences fused to HMGIC in a uterine leiomyoma. Cloning of the fusion cDNA identified the human cytochrome c oxidase subunit VIc (COX6C) gene on 8q22-23 as the fusion partner of HMGIC. Nucleotide sequences of the fusion transcript revealed that the first 3 exons of the HMGIC gene, encoding the 3 DNA binding domains, was fused to the exon 2 of the COX6C gene. The identification of a gene rearrangement suggests a role for HMGIC in tumorigenesis of uterine leiomyoma and suggests a possible involvement of HMGIC in mesenchymal differentiation. Genes Chromosomes Cancer 27:303-307, 2000.

Chromosomes, Human, Pair 12↗

PubMed2000

Identification of a 1-Mb common region at 16q24.1-24.2 deleted in hepatocellular carcinoma.

To identify the location of one or more putative tumor suppressor genes that may be involved in hepatocellular carcinoma (HCC), we examined 96 such tumors for their patterns of allelic loss at 21 microsatellite marker loci distributed along chromosome arm 16q. Allelic loss at one or more loci was observed in 58 (60%) of these tumors. Detailed deletion mapping identified a distinct commonly deleted region located within an interval flanked by D16S534 and D16S3091 at 16q24.1-24.2. By constructing a physical map consisting of a YAC contig across the region, the extent of the deleted region was determined to be less than 1 Mb. Among the tumors for which clinical data were available, allelic loss at 16q24.1-24.2 was more frequent in tumors arising from liver cirrhosis compared to HCCs arising from chronic hepatitis (30/42, 71%, vs. 13/33, 39%; P = 0. 0054). Additionally, allelic loss at 16q24.1-24.2 was frequently observed in small tumors and early-stage tumors as well as in tumors of more advanced phenotype.

Carcinoma, Hepatocellular↗

PubMed2000

Association of bone mineral density with polymorphism of the human calcium-sensing receptor locus.

A strong correlation between bone mass and genetic factors has been shown in twins and family studies. Some of the genes involved would regulate bone metabolism, bone formation, and resorption, all processes that determine bone mass. One candidate genes, calcium-sensing receptor (CASR) in the parathyroid gland, regulates calcium homeostasis by sensing decreases in extracellular calcium level and effecting an increase in secretion of parathyroid hormone (PTH) and calcium (Ca) reabsorption in the kidney. We have investigated a possible association between the CA-repeat polymorphism at the human CASR gene locus and the bone mineral density (BMD) of radial bone in 472 postmenopausal Japanese women. Genotypes were classified into nine groups according to the number of CA repeats present, from 20 to 12. BMD was expressed as the adjusted BMD, which was the body mass index (BMI), and age-adjusted average BMD. The 247 women who had an A3 allele (228 bp, containing 18 repeats of CA) had significantly lower adjusted BMD (mean +/- SD: 0.303 +/- 0.059 versus 0.316 +/- 0.063 g/cm(2); P = 0.0308) than the participants (n = 201) who did not carry an allele of that size. This result suggests that genetic variation at the CASR gene locus is associated with some determinants for BMD in postmenopausal women.

Aged↗

PubMed2000

Identification of a gene disrupted by inv(11)(q13.5;q25) in a patient with left-right axis malformation.

An inv(11)(q13.5;q25) inversion was previously identified in a 9-month-old male patient with complex cyanotic heart defects, altered lung lobation, symmetric liver, and abnormally lobulated spleen (polysplenia). This chromosomal rearrangement was inherited from the phenotypically normal father. We termed these regions DHTX-A (disrupted in heterotaxy)-- A at 11q13.5 and DHTX-B at 11q25. Here, we report the isolation and characterization of the inversion breakpoints and the gene that is disrupted by the DHTX-A breakpoint. The putative DHTX is identical to the UVRAG gene, which was originally identified as a gene that complements the UV sensitivity of xeroderma pigmentosum complementation group C. The 4-kb mRNA was found to be encoded by a large gene, at least 300 kb long, composed of 15 exons. The function of the gene product remains largely unknown. However, the near central portion of the UVRAG protein is predicted to contain a coiled-coil domain, which has been implicated in mediating protein-protein interactions. Southern analyses and fluorescence in situ hybridization (FISH) revealed that the DHTX-A breakpoint in the patient and his father lies within the intron between exons 6 and 7 of UVRAG. Northern blot analysis indicated strong expression in human fetal and adult tissues and in mouse embryonic day-7 and adult tissues, respectively. Whole mount in situ hybridization also showed that the Uvrag gene is expressed in the presomite-stage embryo. Several hypotheses are discussed to explain the relationship between the chromosomal inversion and the accompanying phenotypes.

Amino Acid Sequence↗

PubMed2000

Association of bone mineral density with polymorphism of the human matrix Gla protein locus in elderly women.

The contribution of genetic factors has been implicated in the determination of bone mass in twin and family studies. Some of the genes involved would regulate bone metabolism, bone formation, and resorption, all processes that determine bone mass. One candidate gene matrix Gla protein gene (MGP), has been implicated in the pathogenesis of bone loss through a repression of bone formation. To analyze the genetic background for osteoporosis in elderly women, we have investigated a possible association between the CA repeat polymorphism at the human MGP gene locus and bone mineral density (BMD) of radial bone in 460 elderly Japanese women. Genotypes were classified into six groups according to the number of CA repeats present, from 13 to 18 (alleles A1 through A6). BMD was expressed as the adjusted BMD (ADJBMD), which was the body mass index (BMI)- and age-adjusted average BMD. The 214 women who lacked an A2 allele (212 bp, containing 17 repeats of CA) had significantly lower adjusted BMD than the participants (n = 246) who possessed an allele of that size (mean +/- SD; 0.303 +/- 0.062 vs 0.315 +/- 0.062 g/cm2; P = 0.0382). This result suggests that genetic variation at the MGP locus is associated with some determinants for BMD in elderly women. Therefore, this locus should serve as one of the genetic markers for osteoporosis.

Aged↗

PubMed2000

Genomic organization and chromosomal mapping of ELKS, a gene rearranged in a papillary thyroid carcinoma.

We recently isolated a novel cDNA, designated ELKS, that was fused to RET cDNA in a papillary thyroid carcinoma. Its encoded polypeptide sequence was rich in glutamic acid (E), leucine (L), lysine (K), and serine (S), and was characterized by the presence of nine alpha-helical coiled-coil domains consisting of periodic heptad repeats. We have now cloned the entire structure of the human ELKS gene from within a 700-kb genomic region represented by overlapping bacteriophage P1-derived artificial chromosome (PAC) and bacterial artificial chromosome (BAC) clones, and localized it to chromosomal band 12p13.3 by fluorescence in situ hybridization. The gene is approximately 500 kb long, with 19 exons and 18 introns; the transcription initiation site within exon 1 is separate from the initiation codon (in exon 2). Analysis of the exon/intron structure revealed that introns interrupt the coding sequence in such a way that many functional segments of the protein are encoded by distinct exons. Exon 1 encodes the 5' non-coding region; exons 2, 3, 6, 7, 8, 9, 11, 14, and 15 encode the nine coiled-coil domains. Exons 17-19 constitute the 3' non-coding region. Analysis of the region immediately upstream of exon 1 showed that it was extremely rich in G/C nucleotides and contained multiple Sp-1 and AP2 binding sequences. The ELKS-RET gene fusion rearrangement we had observed in a papillary thyroid carcinoma occurred between intron 10 of the ELKS gene and intron 11 of RET.

Adaptor Proteins, Signal Transducing↗

PubMed2000

A family with hydrocephalus as a complication of cerebellar hemangioblastoma: identification of Pro157Leu mutation in the VHL gene.

Various mutations in the VHL gene on chromosome 3p25-26 are responsible for von Hippel-Lindau (VHL) syndrome. We report on a Japanese VHL family in which two of the three affected members developed acute occlusive hydrocephalus that necessitated emergency surgery for ventricular shunt or drainage. Direct sequencing and restriction fragment length polymorphism analysis identified a germline missense mutation, Proline-to-Leucine, caused by a C-to-T transition at the second nucleotide of codon 157.

Acute Disease↗

PubMed2000

Co-segregation of elevated LDL with a novel mutation (D92K) of the LDL receptor in a kindred with multiple lipoprotein abnormalities.

Factors predisposing to the phenotypic features of familial combined hyperlipidemia have not been clearly defined. In the course of investigating familial coronary artery disease in Utah, we identified a three-generation family in which multiple members were affected with type IIa hyperlipoproteinemia (HLP IIa), type IIb hyperlipoproteinemia (HLP IIb), or type IV hyperlipoproteinemia (HLP IV). Because several family members had relatively severe low-density lipoprotein (LDL) cholesterol elevation, in order to dissect the possible contribution to the plasma lipoprotein abnormalities in this pedigree, we identified a novel point mutation in the low-density lipoprotein receptor (LDLR) gene, a G-to-A transition at nucleotide position 337 in exon 4. This change substituted lysine for glutamic acid at codon 92 (D92K) of the LDL receptor. By means of mutant allele-specific amplification we determined that the mutation co-segregated with elevated cholesterol and LDL cholesterol in the plasma of family members with HLP IIa and HLP IIb, but not with the elevated plasma triglycerides seen in HLP IIb and HLP IV patients. Thus, in families with apparent familial combined hyperlipidemia, a defective LDLR allele and other genetic or environmental factors that elevate plasma triglycerides may account for the multiple lipid phenotypes observed in this kindred.

Adult↗

PubMed2000

Association of estrogen receptor beta (ESR2) gene polymorphism with blood pressure.

We investigated the association between a dinucleotide (cytosine-adenine; CA) repeat polymorphism located in the flanking region of the human estrogen receptor beta (ESR2) gene and systemic blood pressure in 187 healthy postmenopausal Japanese women. The genotype was classified as "A" through "O" according to the number of these repeats from 18 to 32. When we separated the subjects into two groups-- bearing at least one "I" allele (26 CA repeats) and those who did not--we found that the former subjects had significantly higher systolic blood pressure than the latter (mean +/- SD, 146.0 +/- 25.0 vs 136.6 +/- 23.4; P = 0.032). These data suggest that genetic variation at the ESR2 locus may be associated with some determinants of blood pressure, and that there is a possible involvement of this polymorphism in causing hypertension in Japanese women.

Aged↗

PubMed2000

Association of bone mineral density with a dinucleotide repeat polymorphism at the calcitonin (CT) locus.

Calcitonin (CT), a calcium-regulating hormone, lowers the calcium level in serum by inhibiting bone resorption. Because CT may play a role in the pathogenesis of osteoporosis, genetic variations in or adjacent to the CT gene may be associated with variations in bone mineral density (BMD). The present study examined the correlation between a dinucleotide (cytosine-adenine; CA) repeat polymorphism at the CT locus and BMD in 311 Japanese postmenopausal women (mean age, 64.1 years). Seven alleles were present in this population; each allele contained 10, 11, 16, 17, 18, 19, or 20 CA repeats. Thus, we designated the respective genotypes A10, A11, A16, A17, A18, A19, and A20. The A10 and A17 alleles were the predominant alleles in the population studied. Z scores (a parameter representing deviation from the age-specific weight-adjusted average BMD) were compared between individuals that possessed one or two alleles of each genotype and those that did not possess the allele. Subjects who possessed one or two A10 alleles had lower BMD Z scores than those who did not (lumbar 2-4 BMD Z score; -0.148 +/- 1.23 vs 0.182 +/- 1.54; P = 0.04). No significant relationships were observed between allelic status and background data or biochemical parameters. The significant association observed between BMD and genetic variations at the CT locus implies that polymorphism at this locus may be a useful marker for the genetic study of osteoporosis.

Aged↗

PubMed2000

Genomic structure of the gene encoding human 3-hydroxy-3-methyl-glutaryl coenzyme A reductase: comparison of exon/intron organization of sterol-sensing domains among four related genes.

We determined the genomic structure of the human gene encoding 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which catalyzes the conversion of HMG-CoA to mevalonate and is the rate-limiting and major regulatory enzyme in sterol biosynthesis. The gene is more than 21 kb long, about five times the size of its corresponding cDNA. It consists of 20 exons, ranging in size from 68 to 1809bp. An amino-terminal hydrophobic membrane-bound domain is encoded by exons 2-10, a flexible linker domain by exons 10 and 11, and the catalytic domain by exons 11-20. Exons 3-7 encode a sterol-sensing domain. We compared its genomic structure in this region with the sterol-sensing domains of three related genes, sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP), Niemann-Pick type C1 protein (NPC1), and a morphogen receptor, Patched. Two of the five positions of introns in the sterol-sensing domain of the HMG-CoA reductase gene were identical to the exon/intron organization of this domain in the related human genes, but these positions of introns were not conserved in homologues from lower organisms, except in one instance. The data suggested that exon-shuffling may have occurred during relatively recent evolution: this would account for the structural similarity of this domain in four quite different human proteins.

Amino Acid Sequence↗

PubMed2000

Genomic structure and chromosomal mapping of the human site-1 protease (S1P) gene.

Site-1 protease (S1P) is a subtilisin-related enzyme that cleaves sterol regulatory element-binding proteins (SREBPs) in the lumen of endoplasmic reticulum, thereby initiating the release of transcriptionally active NH2-terminal fragments of SREBPs from membranes. In the experiments reported here, we localized the human S1P gene to chromosome 16q24 by fluorescent in situ hybridization and radiation-hybrid mapping, and determined its genomic structure. This gene is more than 60 kb long and contains 23 exons and 22 introns. Its transcription-initiation site within exon 1 is separate from the initiation codon in exon 2. Analysis of the exon/intron structure revealed that the S1P gene consists of a mosaic of functional units: exon 1 encodes the 5' non-translated region; exon 2 encodes the NH2-terminal signal sequence; and exons 2 and 3 encode the pro-peptide sequence that is released when S1P is self-activated by intramolecular cleavage. Exons 5-10 encode the subtilisin-homology domain that is critical for catalytic activity, and exon 23 encodes the transmembrane region. Analysis of the putative promoter region revealed a highly G/C-rich region containing a binding site for ADD1/SREBP-1, as well as Sp1 and AP2 sites. Therefore, expression of the S1P gene may be under the control of SREBP-1, a key regulator of the expression of genes essential for intracellular lipid metabolism. Our data establish a basis for investigations to detect molecular variants in this gene that may alter levels of plasma lipoproteins and/or otherwise disrupt intracellular lipid metabolism.

Base Sequence↗

PubMed2000

Association between single nucleotide polymorphisms in the hMSH3 gene and sporadic colon cancer with microsatellite instability.

The association between three single nucleotide polymorphisms (SNPs) in the hMSH3 gene and sporadic colon cancer with microsatellite instability (MSI) was analyzed. Of the three SNPs observed in this population, SNPs at residues 235 and 693 were novel, while that at residue 3133 was previously described. The SNPs at residues 235 and 3133 caused amino acid substitutions, V79I and T1045A, respectively. We analyzed the allele frequencies of the three SNPs in samples from 19 patients with sporadic colon cancer with MSI and 90 healthy controls. We found that the V79 allele frequency was significantly higher in the tumor samples than in controls. In addition, the frequency of the G693 allele showed a higher trend in the tumor samples than in controls. These results indicated that some SNPs in the hMSH3 gene were associated with colon cancer with MSI.

Alleles↗

PubMed2000

New target region of allelic loss in hepatocellular carcinomas within a 1-cM interval on chromosome 6q23.

BACKGROUND/AIMS: Frequent allelic losses on the long arm of chromosome 16 in several types of human cancers have suggested that 16q harbors one or more genes that are important for suppressing tumorigenesis in the tissues in question. METHODS: To identify the locations of putative tumor suppressor genes involved in hepatocellular carcinoma, we examined 96 primary hepatocellular carcinomas for their patterns of allelic loss at 18 microsatellite marker loci distributed along this chromosome arm. RESULTS: Allelic loss at one or more loci was observed in 48 (50%) of these tumors. The highest frequency of loss of heterozygosity (42%) was observed with marker D6S311 on chromosome 6q23. Through detailed deletion mapping of tumors having partial or interstitial deletions, we identified two commonly deleted regions at 6q23 and at 6q26-27. CONCLUSIONS: The common region at 6q23 lay within a 1-cM interval, flanked by D6S977 and D6S311. The previously documented deletion region that includes the M6P/IGF2R locus was confined to a 20-cM region at band 6q26-27 in our panel of tumors. The location we defined at 6q23 for a putative suppressor of hepatocellular carcinoma has not been reported before.

Adult↗

PubMed2000

Linkage of human tumor necrosis factor-alpha to human osteoporosis by sib pair analysis.

Osteoporosis as well as osteopenia are common human conditions considered to result from the interplay of multiple genetic and environmental factors. Twin and family studies have yielded strong correlation between measures of bone mass and a number of genetic factors. Certain genes (e.g., cytokines such as interleukin-1, interleukin-6, or tumor necrosis factor-alpha) are capable of regulating metabolism, formation, and resorption of bone; all processes that determine bone mass. We tested 192 sib-pairs of adult Japanese women from 136 families for genetic linkage between osteoporosis and osteopenia phenotypes and allelic variants at the tumor necrosis factor-alpha (TNFA) locus, using a dinucleotide-repeat polymorphism located near the gene. The TNFA locus showed evidence for linkage to osteoporosis, with mean allele sharing of 0.478 (P = 0.30) in discordant pairs and 0.637 (P = 0.001) in concordant affected pairs. Linkage with osteopenia was also significant in concordant affected pairs (P = 0.017). Analyses limited to the post-menopausal women in our cohort showed similar or even stronger linkage for both phenotypes. The results provide evidence that genetic variations within the TNFA locus or adjacent genes affect regulation of mineral metabolism in bone and some of them confer risk for osteoporosis in adult women.

Adult↗

PubMed2000

Fine localization of a major disease-susceptibility locus for diffuse panbronchiolitis.

Diffuse panbronchiolitis affecting East Asians is strongly associated with the class I human leukocyte antigen (HLA) alleles. Recent observations suggest that a major disease-susceptibility gene may be located between the HLA-B and HLA-A loci in the class I region of the major histocompatibility complex on chromosome 6. To test this possibility, we analyzed 14 polymorphic markers in 92 Japanese patients and 93 healthy controls. Of these, seven marker alleles, including HLA-B54 and HLA-A11, were significantly associated with the disease. Maximum-likelihood haplotype analysis and subsequent direct determination of individual haplotypes identified a group of disease-associated haplotypes, one of which contained all seven disease-associated marker alleles. Another haplotype, containing HLA-B*5504, was also associated with the disease. All these haplotypes seem to have diverged from a common ancestral haplotype in East Asians and share a specific segment containing three consecutive markers between the S and TFIIH loci in the class I region. Furthermore, one of the markers within the candidate region showed the highest delta value, indicating the strongest association. Of 20 Korean patients with diffuse panbronchiolitis, 17 also shared the combination of the disease-associated marker alleles within the candidate region. These results indicate that an HLA-associated major susceptibility gene for diffuse panbronchiolitis is probably located within the 200 kb in the class I region 300 kb telomeric of the HLA-B locus on the chromosome 6p21.3.

Alleles↗