Emi M

References (13)

Title : Association of an intronic haplotype of the LIPC gene with hyperalphalipoproteinemia in two independent populations - Iijima_2008_J.Hum.Genet_53_193
Author(s) : Iijima H , Emi M , Wada M , Daimon M , Toriyama S , Koyano S , Sato H , Hopkins PN , Hunt SC , Kubota I , Kawata S , Kato T
Ref : J Hum Genet , 53 :193 , 2008
Abstract : Hepatic lipase (HL) plays a major role in the regulation of plasma lipids. Several groups seeking to find association between the gene encoding HL (LIPC) and plasma concentrations of high-density lipoprotein cholesterol (HDLc) using various methods and populations have reported conflicting results. We have approached the problem of demonstrating a relationship between the LIPC locus and HDLc by means of haplotype association using four single nucleotide polymorphisms (SNPs) (rs12594375G/A, rs8023503C/T, rs4775047C/T, and rs11634134T/A) located in intron 1 of the LIPC gene in two independent Japanese populations consisting of 2,970 and 1,638 individuals, respectively. Significant association between hyperalphalipoproteinemia and a specific haplotype in this intron was detected in both populations. When HDLc levels among the three haplotypic categories were analyzed [haplotype rs8023503C/rs12594375G (haplotype-1; H1) homozygotes (H1H1), haplotype rs8023503T/rs12594375A (haplotype-2; H2) homozygotes (H2H2), and heterozygotes (H1H2)], HDLc levels were lowest among H1H1 [mean +/- standard error (SE) = 58.4 +/- 0.4 mg/dl], highest among H2H2 (62.5 +/- 0.8 mg/dl), and intermediate among H1H2 (59.2 +/- 0.4 mg/dl) (P = 0.00011), indicating that H2 haplotype elevates plasma HDLc levels. This association was validated in the second population (n = 1,638) (P = 0.00070). The results provide convincing evidence that the LIPC locus influences HDL metabolism.
ESTHER : Iijima_2008_J.Hum.Genet_53_193
PubMedSearch : Iijima_2008_J.Hum.Genet_53_193
PubMedID: 18160998

Title : Common null variant, Arg192Stop, in a G-protein coupled receptor, olfactory receptor 1B1, associated with decreased serum cholinesterase activity - Koyano_2008_Hepatol.Res_38_696
Author(s) : Koyano S , Emi M , Saito T , Makino N , Toriyama S , Ishii M , Kubota I , Kato T , Kawata S
Ref : Hepatol Res , 38 :696 , 2008
Abstract : AIM: Non-functioning single nucleotide polymorphisms (nSNPs) that result in premature termination codons, that is null-alleles of the respective genes, may have phenotypic effects on clinical parameters. We conducted association studies involving several G-protein coupled receptors (GPCRs) that harbor nSNPs, using clinical parameters of liver function in a general population consisting of 2969 Japanese adults. METHODS: SNP typings were performed with TaqMan and Invader assays. Quantitative associations between genotypes and clinical parameters were analyzed by analysis of variance. Linkage disequilibrium (LD) was tested by Haploview Version 3.3. Haplotype-based association was performed using the haplo.stats program. RESULTS: A significant correlation (P = 0.0057) was identified between serum cholinesterase activity (CHE) and an nSNP (Arg192Stop) in the olfactory receptor (OR) 1B1 gene, a member of the GPCR gene family. This nSNP was associated with decreased serum CHE (P = 0.0013). LD analysis based on eight selected SNPs at the locus revealed three LD blocks. The Arg192Stop nSNP was located on the second LD block, which covered one-third of the 3'-portion of the gene. CONCLUSION: These results suggested that the null-allele of OR1B1 might affect metabolism of serum cholinesterase in carriers of this nSNP.
ESTHER : Koyano_2008_Hepatol.Res_38_696
PubMedSearch : Koyano_2008_Hepatol.Res_38_696
PubMedID: 18328065

Title : Functional impairment of two novel mutations detected in lipoprotein-associated phospholipase A2 (Lp-PLA2) deficiency patients - Ishihara_2004_J.Hum.Genet_49_302
Author(s) : Ishihara M , Iwasaki T , Nagano M , Ishii J , Takano M , Kujiraoka T , Tsuji M , Hattori H , Emi M
Ref : J Hum Genet , 49 :302 , 2004
Abstract : Plasma lipoprotein-associated phospholipase A2 (Lp-PLA2), also known as platelet-activating factor (PAF) acetylhydrolase (PAF-AH), is a member of the serine-dependent class of A2 phospholipases that hydrolyze sn2-ester bonds of fragmented or oxidized phospholipids at sites where atherosclerotic plaques are forming. Most circulating Lp-PLA2 is bound to low-density lipoprotein (LDL) particles in plasma and the rest to high-density lipoprotein (HDL). Deficiency of Lp-PLA2 is a predisposing factor for cardiovascular diseases in the Japanese population. We describe here two novel mutations of the gene encoding Lp-PLA2, InsA191 and I317N in Japanese subjects. The first patient, with partial Lp-PLA2 deficiency, was heterozygous for the InsA191 mutation; macrophages from this patient secreted only half the normal amount of Lp-PLA2 in vitro. The other patient, who showed complete Lp-PLA2 deficiency, was a compound heterozygote for the novel I317N mutation and a common V279F mutation; macrophages from that patient failed to secrete any Lp-PLA2. Measurement of Lp-PLA2 mass, activity and Western blotting verified impaired production and secretion of the enzyme after transfection of mutant construct into COS-7 cells. These results indicated that both novel mutants, InsA191 and I317N, impair function of the Lp-PLA2 gene.
ESTHER : Ishihara_2004_J.Hum.Genet_49_302
PubMedSearch : Ishihara_2004_J.Hum.Genet_49_302
PubMedID: 15148590
Gene_locus related to this paper: human-PLA2G7

Title : Soluble epoxide hydrolase variant (Glu287Arg) modifies plasma total cholesterol and triglyceride phenotype in familial hypercholesterolemia: intrafamilial association study in an eight-generation hyperlipidemic kindred - Sato_2004_J.Hum.Genet_49_29
Author(s) : Sato K , Emi M , Ezura Y , Fujita Y , Takada D , Ishigami T , Umemura S , Xin Y , Wu LL , Larrinaga-Shum S , Stephenson SH , Hunt SC , Hopkins PN
Ref : J Hum Genet , 49 :29 , 2004
Abstract : Plasma lipid and lipoprotein in general reflect the complex influences of multiple genetic loci, for instance, even familial hypercholesterolemia (FH), a representative example of monogenic hyperlipidemia, often presents with phenotypic heterogeneity. In the course of investigating familial coronary artery disease in Utah, we studied 160 members of an eight-generation extended family of FH in which 69 members were affected with type IIa hyperlipoproteinemia (HLPIIa; high plasma cholesterol) and ten with type IIb hyperlipoproteinemia (HLPIIb; high plasma cholesterol as well as plasma triglyceride). Soluble epoxide hydrolase ( EPHX2, sEH) plays a role in disposition of epoxides in plasma lipoprotein particles. Intrafamilial correlation analysis of the modifier effect of Glu287Arg substitution in the EPHX2 gene was carried out among 79 LDLR mutation carriers and 81 noncarriers. In the carriers, plasma cholesterol levels were elevated among carriers of the 287Arg allele (mean +/- SD=358 +/- 72 mg/dl) in comparison with 287Glu homozygotes (mean +/- SD=302 +/- 72 mg/dl) (p=0.0087). Similarly, in the LDLR mutation carriers, the plasma triglyceride levels were elevated among carriers of the 287Arg allele (mean +/- SD=260 +/- 100 mg/dl) in comparison with 287Glu homozygotes (mean +/- SD=169 +/- 83 mg/dl) (p=0.020). No such gene-interactive effect was observed among noncarriers of the LDLR mutation. Half of the patients who presented with HLPIIb had inherited a defective LDLR allele as well as an EPHX2-287Arg allele, whereas the majority who presented with HLPIIa had a defective LDLR allele but not an EPHX2-287Arg allele. These results indicate a significant modification of the phenotype of FH with defective LDLR allele by EPHX2-287Arg variation in our studied kindred.
ESTHER : Sato_2004_J.Hum.Genet_49_29
PubMedSearch : Sato_2004_J.Hum.Genet_49_29
PubMedID: 14673705
Gene_locus related to this paper: human-EPHX2

Title : Overestimated frequency of a possible emphysema-susceptibility allele when microsomal epoxide hydrolase is genotyped by the conventional polymerase chain reaction-based method - Keicho_2001_J.Hum.Genet_46_96
Author(s) : Keicho N , Emi M , Kajita M , Matsushita I , Nakata K , Azuma A , Ohishi N , Kudoh S
Ref : J Hum Genet , 46 :96 , 2001
Abstract : A recent association study suggested that the His113 variant of microsomal epoxide hydrolase (mEPHX) may confer a risk for development of emphysema, presumably by increasing susceptibility to smoking injury. Before considering a possible role of this enzyme in pulmonary disease, we attempted to characterize the genetic polymorphism further. The Tyr/His113 polymorphism within exon 3 of mEPHX was initially examined in 62 healthy individuals by conventional methods involving polymerase chain reaction (PCR)-based determination of a restriction fragment length polymorphism (RFLP). Genomic nucleotide sequences, including the polymorphic site and the downstream primer sequence, were further analyzed in 95 unrelated, healthy Japanese volunteers by single-stranded conformation polymorphism (SSCP) analysis and direct sequencing. Genotyping by the first method (PCR-RFLP) revealed that the allelic distribution in our test population apparently deviated from Hardy-Weinberg equilibrium. Sequence analysis showed that a synonymous nucleotide substitution, AAG to AAA (Lys119), was located just within the published primer site. The AAA at codon 119 was present only in alleles with Tyr113, and its frequency reached 0.31 in our panel of 190 Japanese alleles. This substitution potentially hampered PCR amplification because of the nucleotide mismatch, with the result that the frequency of the Tyr113 variation was underestimated. The frequency of His113, a possible emphysema susceptibility allele of the mEPHX gene, was thus overestimated when human DNA samples were genotyped in the conventional way. Depending on the population(s) tested, this anomaly could represent a pitfall for PCR-based association studies.
ESTHER : Keicho_2001_J.Hum.Genet_46_96
PubMedSearch : Keicho_2001_J.Hum.Genet_46_96
PubMedID: 11281420

Title : Structure, organization, and chromosomal mapping of the human macrophage scavenger receptor gene - Emi_1993_J.Biol.Chem_268_2120
Author(s) : Emi M , Asaoka H , Matsumoto A , Itakura H , Kurihara Y , Wada Y , Kanamori H , Yazaki Y , Takahashi E , Lepert M , Jean-Marc Lalouel JM , Kodama T , Mukai T
Ref : Journal of Biological Chemistry , 268 :2120 , 1993
Abstract : Macrophage scavenger receptors (MSR) mediate the binding, internalization, and processing of a wide range of negatively charged macromolecules. Functional MSR are trimers of two C-terminally different subunits that contain six functional domains. We have cloned an 80-kilobase human MSR gene and localized it to band p22 on chromosome 8 by fluorescent in situ hybridization and by genetic linkage using three common restriction fragment length polymorphisms. The human MSR gene consists of 11 exons, and two types of mRNAs are generated by alternative splicing from exon 8 to either exon 9 (type II) or to exons 10 and 11 (type I). The promoter has a 23-base pair inverted repeat with homology to the T cell element. Exon 1 encodes the 5'-untranslated region followed by a 12-kilobase intron which separates the transcription initiation and the translation initiation sites. Exon 2 encodes a cytoplasmic domain, exon 3, a transmembrane domain, exons 4 and 5, an alpha-helical coiled-coil, and exons 6-8, a collagen-like domain. The position of the gap in the coiled coil structure corresponds to the junction of exons 4 and 5. These results show that the human MSR gene consists of a mosaic of exons that encodes the functional domains. Furthermore, the specific arrangement of exons played a role in determining the structural characteristics of functional domains.
ESTHER : Emi_1993_J.Biol.Chem_268_2120
PubMedSearch : Emi_1993_J.Biol.Chem_268_2120
PubMedID: 8093617
Gene_locus related to this paper: human-LPL

Title : Binding of lipoprotein lipase to heparin. Identification of five critical residues in two distinct segments of the amino-terminal domain - Hata_1993_J.Biol.Chem_268_8447
Author(s) : Hata A , Ridinger DN , Sutherland S , Emi M , Shuhua Z , Myers RL , Ren K , Cheng T , Inoue I , Wilson DE , et al.
Ref : Journal of Biological Chemistry , 268 :8447 , 1993
Abstract : Binding to heparan sulfate governs many aspects of the physiological action and regulation of the lipolytic enzyme, lipoprotein lipase (LPL). In an attempt to identify the structural determinants which mediate this interaction, basic residues in three segments of the primary sequence of human LPL (residues 147-151, 279-282, and 292-304) were replaced with alanine, either singly or in various combinations, and variant proteins were subjected to affinity chromatography on heparin-Superose. Five basic residues in two distinct segments of the primary sequence were critical determinants of the high affinity for heparin manifested by the active enzyme (R279, K280, R282, K296, R297). By contrast, no such evidence could be detected for basic residues in the first cluster (K147, K148) or for other basic residues in the third cluster (K292, R294, K304), while the evidence for K300 was unresolved. The conformation of this heparin-binding domain can be inferred by reference to the three-dimensional structure of the homologous enzyme, pancreatic lipase (Winkler, F. K., D'Arcy, A., and Hunziker, W. (1990) Nature 343, 771-774). Affinity of the active enzyme for heparin could not be reduced below a threshold, suggesting that other heparin-binding determinants exist elsewhere in the molecule, as supported by recently published evidence (Davis, R. C., Wong, H., Nikazy, J., Wang, K., Han, Q., and Schotz, M. C. (1992) J. Biol. Chem. 267, 21499-21504).
ESTHER : Hata_1993_J.Biol.Chem_268_8447
PubMedSearch : Hata_1993_J.Biol.Chem_268_8447
PubMedID: 8473288

Title : Missense mutations in exon 5 of the human lipoprotein lipase gene. Inactivation correlates with loss of dimerization - Hata_1992_J.Biol.Chem_267_20132
Author(s) : Hata A , Ridinger DN , Sutherland SD , Emi M , Kwong LK , Shuhua J , Lubbers A , Guy-Grand B , Basdevant A , Iverius PH , et al.
Ref : Journal of Biological Chemistry , 267 :20132 , 1992
Abstract : Most missense mutations of the lipoprotein lipase (LPL) gene identified among LPL-deficient subjects cluster in a segment of the sequence that encodes the catalytic triad as well as functional elements involved in the activation of the lipase at lipid-water interfaces. Consequently, loss of activity may result either from direct alterations of such functional elements or from less specific effects on protein folding and stability. This issue was addressed by examining biochemical properties of four such variants (A176T, G188E, G195E, and S244T) in a heterologous expression system (COS-1 cells). Variant G195E (GGA----GAA) was previously unreported. In all instances, inactive enzyme was recovered in medium, albeit at reduced levels. Cellular synthesis and extracellular degradation were similar to those for wild type, suggesting that reduced secretion resulted from increased intracellular degradation. When cell extracts were subjected to heparin-Superose affinity chromatography followed by elution on a linear salt gradient, all variants exhibited a single, inactive, low affinity immunoreactive peak. By contrast, wild-type enzyme presented an additional, high affinity, active species, which we interpret as homodimeric enzyme. Substitution of the active-site serine (S132A) led to loss of activity but maintenance of the high affinity species. When large amounts of the G188E variant were applied to the column, small but significant amounts of high affinity, active enzyme were recovered. Systematic substitutions at residue 188 showed that only glycine could accommodate structural constraints at this position. We conclude that the mutations examined did not impart lipase deficiency by affecting specific functional elements of the enzyme. Rather, they appear to affect protein folding and stability, and thereby formation and maintenance of subunit assembly.
ESTHER : Hata_1992_J.Biol.Chem_267_20132
PubMedSearch : Hata_1992_J.Biol.Chem_267_20132
PubMedID: 1400331
Gene_locus related to this paper: human-LPL

Title : Missense mutation (Gly----Glu188) of human lipoprotein lipase imparting functional deficiency - Emi_1990_J.Biol.Chem_265_5910
Author(s) : Emi M , Wilson DE , Iverius PH , Wu L , Hata A , Hegele R , Williams RR , Lalouel JM
Ref : Journal of Biological Chemistry , 265 :5910 , 1990
Abstract : Cloning and sequencing of lipoprotein lipase (LPL) cDNA prepared from the adipose tissue of a patient with classical LPL deficiency revealed a G to A transition at nucleotide 818 in all sequenced clones, leading to the substitution of glutamic acid for glycine at residue 188 of the mature protein. Hybridization of genomic DNA with allele-specific oligonucleotides confirmed that the patient was homozygous for this mutation and revealed that carrier status for this mutation among relatives of the patient was significantly associated with hypertriglyceridemia. Assay of the patient's plasma for immunoreactive enzyme and activity demonstrated the presence of a circulating inactive enzyme protein, the concentration of which was further increased by injection of heparin. The mutant sequence was produced by oligonucleotide-directed mutagenesis, and both normal and mutant sequences were cloned into the expression vector pSVL and transfected into COS-1 cells. The normal sequence led to the in vitro expression of an enzyme that bound to heparin-Sepharose and had a specific catalytic activity similar to that of normal postheparin plasma enzyme. By contrast, the mutant enzyme expressed in vitro was catalytically inactive and displayed a lower affinity for heparin than the normal enzyme. We conclude that this single amino acid substitution leads to the in vivo expression of an inactive enzyme accounting for the manifestations of LPL deficiency noted in the patient.
ESTHER : Emi_1990_J.Biol.Chem_265_5910
PubMedSearch : Emi_1990_J.Biol.Chem_265_5910
PubMedID: 1969408
Gene_locus related to this paper: human-LPL

Title : Lipoprotein lipase deficiency resulting from a nonsense mutation in exon 3 of the lipoprotein lipase gene - Emi_1990_Am.J.Hum.Genet_47_107
Author(s) : Emi M , Hata A , Robertson M , Iverius PH , Hegele R , Lalouel JM
Ref : American Journal of Human Genetics , 47 :107 , 1990
Abstract : In DNA from a male patient of German and Polish ancestry who has lipoprotein lipase deficiency, sequencing of all nine exons and intron-exon boundaries corresponding to the coding region of the lipoprotein lipase gene detected a C----T transition leading to the substitution of a stop signal for the codon that normally determines a glutamine at position 106 of the mature enzyme. Hybridization with allele-specific oligonucleotides at this position established that the patient was homozygous for this mutation. This mutation must lead to the synthesis of a sharply truncated protein, accounting for the enzymatic deficiency noted in the patient.
ESTHER : Emi_1990_Am.J.Hum.Genet_47_107
PubMedSearch : Emi_1990_Am.J.Hum.Genet_47_107
PubMedID: 2349938
Gene_locus related to this paper: human-LPL

Title : Direct detection and automated sequencing of individual alleles after electrophoretic strand separation: identification of a common nonsense mutation in exon 9 of the human lipoprotein lipase gene - Hata_1990_Nucleic.Acids.Res_18_5407
Author(s) : Hata A , Robertson M , Emi M , Lalouel JM
Ref : Nucleic Acids Research , 18 :5407 , 1990
Abstract : Large-scale screening by direct sequencing of DNA to detect molecular variants remains a laborious endeavor whose difficulty is compounded by heterozygosity. We show that mobility shifts of single-stranded DNA electrophoresed under nondenaturing conditions can be used not only to detect variants (Orita,M. et al., 1989, Genomics, 5, 874-879), but also to separate and sequence directly individual alleles. In this manner, we have identified a common variant of human lipoprotein lipase resulting from a nonsense mutation in exon 9 of the gene. Whether this variant is of functional significance remains to be determined.
ESTHER : Hata_1990_Nucleic.Acids.Res_18_5407
PubMedSearch : Hata_1990_Nucleic.Acids.Res_18_5407
PubMedID: 2216713

Title : Compound heterozygote for lipoprotein lipase deficiency: Ser----Thr244 and transition in 3' splice site of intron 2 (AG----AA) in the lipoprotein lipase gene - Hata_1990_Am.J.Hum.Genet_47_721
Author(s) : Hata A , Emi M , Luc G , Basdevant A , Gambert P , Iverius PH , Lalouel JM
Ref : American Journal of Human Genetics , 47 :721 , 1990
Abstract : Cloning and sequencing of translated exons and intron-exon boundaries of the lipoprotein lipase gene in a patient of French descent who has the chylomicronemia syndrome revealed that he was a compound heterozygote for two nucleotide substitutions. One (TCC----ACC) leads to an amino acid substitution (Ser----Thr244), while the other alters the 3' splice site of intron 2 (AG----AA). The functional significance of the Thr244 amino acid substitution was established by in vitro expression in cultured mammalian cells.
ESTHER : Hata_1990_Am.J.Hum.Genet_47_721
PubMedSearch : Hata_1990_Am.J.Hum.Genet_47_721
PubMedID: 2121025
Gene_locus related to this paper: human-LPL

Title : Phenotypic expression of heterozygous lipoprotein lipase deficiency in the extended pedigree of a proband homozygous for a missense mutation - Wilson_1990_J.Clin.Invest_86_735
Author(s) : Wilson DE , Emi M , Iverius PH , Hata A , Wu LL , Hillas E , Williams RR , Lalouel JM
Ref : J Clinical Investigation , 86 :735 , 1990
Abstract : Familial lipoprotein lipase (LPL) deficiency is a rare genetic disorder accompanied by well-characterized manifestations. The phenotypic expression of heterozygous LPL deficiency has not been so clearly defined. We studied the pedigree of a proband known to be homozygous for a mutation resulting in nonfunctional LPL. Hybridization of DNA from 126 members with allele-specific probes detected 29 carriers of the mutant allele. Adipose tissue LPL activity, measured previously, was reduced by 50% in carriers, but did not reliably distinguish them from noncarriers. Carriers were prone to the expression of a form of familial hypertriglyceridemia characterized by increased plasma triglyceride, VLDL cholesterol and apolipoprotein B, and decreased LDL and HDL cholesterol concentrations. These manifestations were age modulated, with conspicuous differences between carriers and noncarriers observed only after age 40. Several noncarriers exhibited similar lipid abnormalities, but without the inverse relationship between VLDL cholesterol and LDL cholesterol noted among carriers. In addition to age and carrier status, the potentially reversible conditions, obesity, hyperinsulinemia and lipid-raising drug use were contributory. Thus heterozygous lipoprotein lipase deficiency, together with age-related influences, may account for a form of familial hypertriglyceridemia.
ESTHER : Wilson_1990_J.Clin.Invest_86_735
PubMedSearch : Wilson_1990_J.Clin.Invest_86_735
PubMedID: 2394828