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At least 271 records · Page 15Linked to original sources
PubMed2006

Identification of novel functional variants of the melanocortin 1 receptor gene originated from Asians.

Human melanocortin 1 receptor (MC1R) is a seven transmembrane G-coupled protein receptor that upregulates the cAMP pathway. Several functional variants of MC1R that show an impaired ability to activate the cAMP pathway are strongly associated with fair skin and red hair in Europeans and European descendants. The sequence variations of the MC1R gene were repeatedly investigated against worldwide populations; however, there was no evidence that functional variant of MC1R exists in non-European descendants. We report the presence of novel functional variants of MC1R with Asian origins. Three novel variants of MC1R, Phe147Delta, Thr157Ile, and Pro159Thr, were identified in our screening for the sequence variations of the MC1R gene against 995 individuals from 30 Asian and Oceanian populations; there was a single case for the Pro159Thr variant allele and two instances of Phe147Delta and Thr157Ile variant alleles. Our pharmacological assay revealed that Phe147Delta, Thr157Ile, and Pro159Thr variant showed similar or more dramatically impaired activities in comparison with Arg151Cys, which is a major functional variant of MC1R in Europeans. These functional variant alleles were geographically localized in relatively high latitudes, which suggest that the adaptation to ambient UV light intensity may play an important role in shaping the geographical distribution of MC1R alleles in Asia and Oceania.

Animals↗
PubMed1988

Apolipoprotein C-II deficiency: identification of a structural variant ApoC-II Padova.

Apolipoprotein(apo) C-II DNA, RNA and protein from a patient with a familial deficiency of apoC-II were evaluated and compared to normal individuals. No major defect of the apoC-II gene could be detected by Southern blot hybridization. Northern and slot blot analyses of total liver RNA documented normal levels of a normal sized apoC-II mRNA. Immunohistochemical studies of the liver of the apoC-II deficient patient revealed a normal to slightly elevated intracellular content of the C-II apolipoprotein. Plasma apoC-II was 3 to 5% of normal apoC-II levels and exhibited abnormal electrophoretic mobility on two dimensional gel electrophoresis and immunoblotting. We postulate that at the molecular level, the deficiency of apoC-II in the plasma of this patient results from a structural defect in the coding portion of the apoC-II gene leading to either defective secretion of cellular apoC-II or increased catabolism of a structurally defective apoC-II in plasma.

Apolipoprotein C-II↗
PubMed1989

Analysis of transketolase and identification of an enzyme variant in human leukocytes.

Human leukocyte transketolase of fresh cell extracts has been analyzed by isoelectrofocusing on agarose gels (pH 3-10). The enzyme was then transblotted on nitrocellulose and detected with specific anti-transketolase IgG coupled to an avidin/biotin-immunoperoxidase system. Each sample yielded multiple enzyme forms, within a pI range of about 7.4-8.4. Transketolase profile, however, was not identical in all extracts. There are two mainly distinct patterns, showing qualitative and quantitative differences: a standard profile, which is predominant, and a variant, found in three unrelated subjects out of the two hundred and twenty. Standard and variant enzyme have similar Km values for ribose 5-P and xylulose 5-P and the same mobility on SDS-PAGE.

Cytosol↗
PubMed1983

Identification and characterization of variant forms of the gastrin-releasing peptide (GRP).

Porcine intestinal gastrin-releasing peptide (GRP) has been demonstrated to be structurally identical to the previously characterized gastric GRP. Ion-exchange and high-performance liquid chromatography of porcine intestinal extracts have identified two variant GRP forms. Studies on one of these variant forms suggest that a beta-aspartyl shift has occurred in the Asn-His structure of GRP; such a modification in an Asn-His structure occurring in a natural peptide or protein has not been previously reported. This variant GRP, although retaining bioactivity, appears to have reduced potency in elevating canine plasma gastrin levels.

Amino Acid Sequence↗
PubMed1993

Identification of masked and variant Ph (complex type) translocations in CML and classic Ph in AML and ALL by fluorescence in situ hybridization with the use of bcr/abl cosmid probes.

In the present study, three chronic myelogenous leukemia (CML) patients with variant Philadelphia (Ph) chromosomes (complex types), two CML patients with a masked Ph, one case with Ph positive acute lymphocytic leukemia (ALL), and one with Ph positive acute myelocytic leukemia (AML) were analyzed by standard cytogenetic techniques (G-banding), Southern blot studies, and fluorescence in situ hybridization (FISH) procedures using probes from portions of the bcr and abl genes. It has been previously shown that this FISH approach could detect the bcr/abl fusion event in CML patients with classic or variant (simple type) Ph. Our results demonstrate that this FISH assay can also detect the bcr/abl fusion status in CML patients with masked or variant (complex type) Ph chromosomes and in some patients with Ph positive ALL or AML.

Adult↗
PubMed1987

Identification of gastrin molecular variants in gastrinoma syndrome.

The molecular species of gastrin in the circulation and in tumor extracts were studied in two groups of patients: (1) with benign gastrinoma and (2) with gastrinoma with liver metastases. Radioimmunoassays (RIAs) and immunoaffinity chromatography for the amino (NH2)- and amidated COOH-terminus of gastrin-17 (antiserum G17) and the NH2-terminus of gastrin-34 (antiserum G34) were employed. In both benign and metastatic tumors the molecular forms of gastrin in boiling water extracts measured by the gastrin-17 NH2- and COOH-terminal assays were similar. In addition to a molecular component resembling the amidated gastrin-17, there were also significant amounts of larger molecular weight (mol. wt.) forms. The larger mol. wt. forms absorbed by the NH2-terminus of G17 antiserum corresponded to the COOH-terminus-extended forms of gastrin-17. Furthermore, larger mol. wt. gastrins immunopurified by antiserum to the NH2-terminus of gastrin-34 corresponded to gastrin-34 extended molecules. Sera of patients with liver metastases had higher concentrations of the NH2-terminal of gastrin-17 whereas sera of patients with benign gastrinoma contained predominantly gastrins detected by the COOH-terminal assay. These results suggest that: (a) there are differences in the molecular pattern of gastrin in the circulation of patients with benign and metastatic gastrinomas; (b) gastrins which are fully processed with carboxy-terminal amidation predominate in the circulation of patients with benign gastrinoma; and (c) gastrins containing the gastrin-17 and COOH-terminally extended gastrin-17 and gastrin-34 precursor molecules occur in high concentration in the circulation of gastrinoma patients with metastases to the liver.

Chromatography, Gel↗
PubMed1991

Complete nucleotide sequence of a genomic clone encoding HLA-B35 isolated from a Caucasian individual of Hispanic origin. Identification of a new variant of HLA-B35.

The primary structure of an HLA class I genomic clone isolated from a homozygous HLA-B35 Caucasian individual of hispanic origin was determined. The nucleotide sequence of exons 1, 2, 4, 5, 6, and 7 is identical to that of the HLA-B35 allele of Oriental origin reported previously. Exon 3 differs in only three nucleotides present in a stretch of 23 bp. These changes introduce three amino acid substitutions in residues 109 (Leu----Phe), 114 (Asp----Asn), and 116 (Ser----Tyr), two of which (114 and 116) are located in one of the beta sheets at the bottom of the peptide binding site. The nature of these replacements in this HLA-B35 variant is likely to affect peptide binding and recognition by T lymphocytes. Introns 1, 2, 3, 4, 5, and 6 from this genomic clone are identical to those present in HLA-Bw58, further confirming the evolutionary origin of HLA-B35.

Amino Acid Sequence↗
PubMed1982

Purification and identification of two structural variants of porcine tissue plasminogen activator by affinity adsorption on fibrin.

Porcine tissue plasminogen activator has been purified from delipidized heart tissue by affinity adsorption to fibrin. A crude fraction is prepared from an acid tissue extract by precipitation with ammonium sulphate. The tissue activator of this fraction is isolated by adsorption on fibrin and elution with KSCN. The procedure also includes chromatography on arginine-Sepharose and two gel-filtration steps. The final product has a specific activity of 250 000 IU/mg (+/- 16 000) as compared to an international urokinase reference preparation. The yield calculated from the active ammonium sulphate precipitate is about 28%. An approx. 7 000-fold increase of specific activity is obtained, most of which is achieved in the fibrin step. The native tissue plasminogen activator consists of a single chain molecule with a molecular weight of 64 000 as measured by SDS-polyacrylamide gel electrophoresis. In a previous report, it was claimed that the activator is composed of two disulphide-connected polypeptide chains. These results were due to a preparation artefact, caused by proteolytic activity present in the tissue extracts. The introduction of the protease inhibitor aprotinin and 6-amino-hexanoic acid in the purification procedure has abolished the effect of the protease contaminant, leading to the production of a one-chain activator. Treatment with plasmin transforms the native, one-chain tissue activator into a variant composed of two chains of about equal size (Mr 32 000) connected by disulphide bonding. This modified activator is indistinguishable from the one obtained at insufficient protection against proteolytic enzymes. The cleavage by plasmin causes about an 8-fold increase of amidolytic activity as measured on H-D-Val-Gly-Arg-p-nitroanilide. The fibrinolytic activity as measured by clot lysis in only slightly increased. The physiological significance of the cleavage is discussed.

Amino Acids↗
PubMed1995

Identification of a splice variant of the rat and human mineralocorticoid receptor genes.

The sequence of a splice variant of the rat mineralocorticoid receptor (MR) gene is presented. A cDNA clone corresponding to rat MR was isolated from a rat brain cDNA library. Sequence analysis of the region corresponding to the DNA binding domain revealed the presence of a 12 base pair (bp) insertion. Analysis of mRNA from several rat tissues suggests that the variant is less abundant than the wild type in most tissues. The insertion variant is also a product of the human MR gene, the identical splice variant was also observed in human white blood cell mRNA. Unlike other splice variants reported for the MR, this variant alters the encoded protein by the addition of four amino acid residues in the DNA binding domain. The altered protein may influence the affinity of the MR for mineralocorticoid or glucocorticoid response elements.

Alternative Splicing↗
PubMed2006

Identification of novel splice variants of the human CD44 gene.

The CD44 gene contains 10 variable exons (v1-v10) that can be alternatively spliced to generate hundreds of different CD44 protein isoforms, several of which have been implicated in the metastatic spread of tumour cells. Here, we describe a cryptic splice site, in intron 6 of the human CD44 gene, used during mRNA processing. This cryptic splice site is used in conjunction with variable exon 3, or independently from it in the form of a pseudo-exon of 49 bp, which generates a stop codon by frame shift in the contiguous variable exon downstream. This pseudo-exon has been found inserted immediately 3' to any other variable exon from v4 to v10, in the final CD44 mRNA. The implication of this cryptic splice site in haltering CD44 protein translation is questioned in the context of Nonsense Mediated Decay and the overall regulation of CD44 expression.

Alternative Splicing↗
PubMed2006

Porcine Parkin: molecular cloning of PARK2 cDNA, expression analysis, and identification of a splicing variant.

Parkin, encoded by the PARK2 gene, is an E3 ligase which functions as an integral component of the cytoplasmic ubiquitin/proteasomal protein degradation pathway. Mutations in the PARK2 gene, resulting in the loss of parkin function, leads to autosomal recessive juvenile Parkinsonism (AR-JP). This work reports the cloning and characterization of the porcine (Sus scrofa) PARK2 cDNA (SsPARK2) and splicing variants hereof. The PARK2 cDNA was amplified by the reverse transcriptase polymerase chain reaction (RT-PCR) using oligonucleotide primers derived from in silico sequences. The porcine PARK2 cDNA codes for a protein of 461 amino acids which shows a high similarity to orangutan (91%), human (86%), and to rat (82%) parkin. A splicing variant of the porcine PARK2 with a complete deletion of exon 9 was also identified. Expression analysis by quantitative real-time RT-PCR revealed presence of PARK2 transcript in all examined organs and tissues. Differential expression was observed, with very high levels of PARK2 mRNA in cerebellum, heart, and kidney. In addition, expression analysis showed that porcine PARK2 transcripts could be detected early in embryo development in different brain regions. The porcine PARK2 orthologue was mapped to chromosome 1p24-25. Single nucleotide polymorphism (SNP) analysis revealed seven SNPs in the porcine PARK2 gene, one missense and one silent mutation in exon 7 and five SNPs in intron 7.

Alleles↗
PubMed2004

Identification of PIK3C3 promoter variant associated with bipolar disorder and schizophrenia.

BACKGROUND: Genes involved in phosphoinositide (PI) lipid metabolism are excellent candidates to consider in the pathogenesis of bipolar disorder (BD) and schizophrenia (SZ). One is PIK3C3, a member of the phosphatidylinositide 3-kinase family that maps closely to markers on 18q linked to both BD and SZ in a few studies. METHODS: The promoter region of PIK3C3 was analyzed for mutations by single-strand conformation polymorphism analysis and sequencing. A case-control association study was conducted to determine the distribution of variant alleles in unrelated patients from three cohorts. Electromobility gel shift assays (EMSA) were performed to assess the functional significance of variants. RESULTS: Two polymorphisms in complete linked disequilibrium with each other were identified, -432C- > T and a "C" insert at position -86. The -432T allele occurs within an octamer containing an ATTT motif resembling members of the POU family of transcription factors. In each population analyzed, an increase in -432T was found in patients. EMSAs showed that a -432T containing oligonucleotide binds to brain proteins that do not recognize -432C. CONCLUSIONS: A promoter mutation in a PI regulator affecting the binding of a POU-type transcription factor may be involved in BD and SZ in a subset of patients.

Alleles↗
PubMed2006

BRCA1-2 mutations in breast cancer: identification of nine new variants of BRCA1-2 genes in a population from central Western Spain.

We carried out a mutational analysis of BRCA1 and BRCA2 genes in 103 individuals from a population in Western Central Spain and we identified nine new variants: two truncating mutations in BRCA2 [2604C>A (Y792X), 8873del4], three missense mutations in BRCA2 [677A>G (H150R), 958G>A (D224N) and 3398A>G (K1057R], and four silent mutations, two in BRCA1 [1115T>G (R332R) and IVS24+36 C>G], and two in BRCA2 [2583T>A (I785I) and 7854G>A (T2542T)]. In two unrelated families of our population, we identified the BRCA1 1806C>T (Q563X) mutation, which is considered to be a Swedish founder mutation. BRCA1 1806C>T (Q563X) and BRCA2 3036del4 gene mutations were the most frequent in our series.

Breast Neoplasms↗
PubMed2026

Identification of novel HUWE1 variants in Turner-type X-linked intellectual disability.

OBJECTIVE: To characterize the clinical phenotypes and identify the genetic etiology in four unrelated families affected by Turner-type X-linked intellectual disability (XLID). METHODS: Peripheral blood samples were collected from four probands and their parents. Genomic DNA was extracted, and a comprehensive genetic analysis was performed using trio-based Whole Exome Sequencing (WES) combined with low-pass Copy Number Variation sequencing (CNV-seq). Candidate variants were subsequently validated via Sanger sequencing. RESULTS: Genetic analysis identified distinct variants in the HUWE1 across the four families. Specifically, four distinct HUWE1 variants were identified across the families: a hemizygous c.10034 > T (p.Lys3345Met) in Family 1; a heterozygous c.9209G > A (p.Arg3070His) in Family 2; a heterozygous c.12688T > C (p.Phe4230Leu) in Family 3; and a hemizygous c.9070G > A (p.Ala3024Thr) in Family 4. In accordance with ACMG guidelines, the novel variants in Families 1, 3, and 4 were classified as "Likely Pathogenic" (PS2 + PM2_Supporting + PP2 + PP3). In contrast, the previously reported variant in Family 2 was categorized as "Pathogenic" based on the criteria PS2 + PM2_Supporting + PM5 + PP2 + PP3_Moderate. All probands were clinically diagnosed with Turner-type XLID. CONCLUSIONS: This study expands the pathogenic variant spectrum of HUWE1 and provides novel molecular evidence for the clinical diagnosis of Turner-type XLID. These findings are of significant value for genetic counseling, carrier screening, and prenatal diagnosis for the affected families.

Humans↗
PubMed2005

Identification of functional genetic variants in cyclooxygenase-2 and their association with risk of esophageal cancer.

BACKGROUND & AIMS: Overexpression of cyclooxygenase-2 (COX-2) is implicated in many steps of cancer development. Single nucleotide polymorphisms (SNPs) in the COX-2 promoter might contribute to differential COX-2 expression and subsequent interindividual variability in susceptibility to cancer. This study sought to identify functional SNPs in the COX-2 promoter and evaluated their effects on the risk of developing esophageal squamous cell carcinoma (ESCC). METHODS: Thirty individual DNA samples were sequenced to search for SNPs, and the function of the SNPs was examined by a set of biochemical assays. Genotypes and haplotypes were analyzed in 1026 patients and 1270 controls, and odds ratios and 95% confidence intervals (CIs) were estimated by logistic regression. RESULTS: Three SNPs, -1290A-->G, -1195G-->A, and -765G-->C, were identified; the frequencies of variant alleles were 0.04, 0.51, and 0.02, respectively. The -1195G-->A change creates a c-MYB binding site and displays a higher promoter activity. The -1195A-containing haplotypes had significantly increased luciferase expression and COX-2 messenger RNA levels in esophageal tissues compared with the -1195G-containing counterparts. A case-control analysis showed a 1.72-fold (95% CI, 1.35-2.20) and 2.24-fold (95% CI, 1.59-3.16) excess risk of developing ESCC for the -1195AA or -765CC genotype carriers compared with noncarriers. A greater risk of developing ESCC was observed for A(-1195)-C(-765)-containing haplotypes compared with G(-1195)-G(-765)-containing haplotypes, suggesting an interaction between the -1195G-->A and -765G-->C polymorphisms in the context of haplotype. CONCLUSIONS: These findings indicate that genetic variants in COX-2 may play a role in mediating susceptibility to esophageal cancer.

Adult↗
PubMed2006

Identification of novel splice variants of Adhesion G protein-coupled receptors.

Alternative splicing is an important mechanism to generate proteome diversity in higher eukaryotic organisms. We searched for splice variants of the human Adhesion family of G protein-coupled receptors (GPCRs) using mRNA sequences and expressed sequence tags. The results presented here describe 53 human splice variants among the 33 Adhesion GPCRs. Many of these variants appear to be coding for "functional" proteins (29) while the others are seemingly "non-functional" (24). Novel functional splice variants were found for: CD97, CELR3, EMR2, EMR3, GPR56, GPR110, GPR112-GPR114, GPR116, GPR123-GPR126, GPR133, HE6, and LEC1-LEC3. Splice variants for GPR116, GPR125, GPR126, and HE6 were found conserved in other species. Several of the functional splice variants lack one or more of the functional domains that are found in the N-termini of these receptors. These functional domains are likely to affect ligand binding or interaction with other proteins and these novel splice variants may have important roles for the specificity of interactions between these receptors and extracellular molecules. Another type of splice variants found here lacks a GPCR proteolytic site (GPS). The GPS domain has been shown to be essential for the proteolytic cleavage of the receptors N-termini and for cellular surface expression. We suggest that these alternative splice variants may be crucial for the function of the receptors while the seemingly non-functional splice variants may be a part of a regulative mechanism.

Alternative Splicing↗
PubMed2006

Identification of a novel variant of human hepatitis E virus in Hungary.

First human case of hepatitis E infection detected in Hungary is reported. This hepatitis E virus (HEV), Hungary1, belongs to genotype 3 and had 95% and 90% nucleotide identity within the capsid region of the European swine and human (Greece2) strains, respectively. Hungary1 represents a potential novel human variant of HEV in genus Hepevirus.

Female↗