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PubMed2005

Identification and characterization of variant alleles at CODIS STR loci.

Short tandem repeat (STR) profiles from 32,671 individuals generated by the ABI Profiler Plus and Cofiler systems were screened for variant alleles not represented within manufacturer-provided allelic ladders. A total of 85 distinct variants were identified at 12 of the 13 CODIS loci, most of which involve a truncated tetranucleotide repeat unit. Twelve novel alleles, identified at D3S1358, FGA, D18S51, D5S818, D7S820 and TPOX, were confirmed by nucleotide sequence analysis and include both insertions and deletions involving the repeat units themselves as well as DNA flanking the repeat regions. Population genetic data were collected for all variants and frequencies range from 0.0003 (many single observations) to 0.0042 (D7S820 '10.3' in North American Hispanics). In total, the variant alleles identified in this study are carried by 1.6% of the estimated 1 million individuals tested annually in the U.S. for the purposes of parentage resolution. A paternity case involving a recombination event of paternal origin is presented and demonstrates how variant alleles can significantly strengthen the genetic evidence in troublesome cases. In such instances, increased costs and turnaround time associated with additional testing may be eliminated.

Adult↗
PubMed2006

[Analysis of variant and modified structures of proteins by mass spectrometry--application for clinical laboratory test].

We have successfully applied soft ionization MS for the analysis of proteins in blood and tissues. This article is a summary of a lecture presented on March 8, 2006 in the Hall of Osaka Medical College at the time of the author's retirement from Osaka Medical College. The article addresses the detection and characterization of hemoglobin (Hb) variants, an improved reference method for HbAlc measurement, identification of variants of transthyretin (TTR) and Cu/Zn-superoxide dismutase (SOD-1) and the diagnostic application of the signals of modified forms of TTR. During the process of TTR analysis, we found unique isoforms of TTR, which showed changes of the cysteine (10th from amino terminal) residue to glycine, dehydroalanine, and S-sulfocysteine residues. Without the addition of sulfuric acid, the S-sulfonated adduct was generated, namely, sulfur was generated from the peptide or protein itself via dimer formation. These experiments suggest that transformation starts from beta-elimination of disulfide linkage to dehydroalanine and S-thiocysteine. Dehydroalanine reacts easily with H2O, generating serine, which changes to glycine. S-thiocysteine is oxidized easily to S-sulfocysteine. Such modified structures were never seen in SOD-1 and Hb in our extensive analyses by MS, although these molecules have free cysteine residue. Susceptibility to beta-elimination may depend on adjacent amino acids in the stereochemical structure of the protein. Basic amino acids located near cysteine 10, lysine residues at 9 and/or 15, may promote the reaction. As dehydroalanine in protein reacts strongly with other amino acids either in the molecule or between molecules, the reaction may generate cross-linking covalently or noncovalently, causing amyloidosis. Dehydroalanine reacts with cysteine, forming a thiazolidine ring, followed by cleavage of the peptide-bond at the N-terminal side of dehydroalanine. This type of non-enzymatic cleavage may occur in amyloidogenic precursor protein before fiber formation or in amyloid fibers.

Blood Proteins↗
PubMed1990

Identification of a Ets1 variant protein unaffected in its chromatin and in vitro DNA binding capacities by T cell antigen receptor triggering and intracellular calcium rises.

We previously showed that thymocytes express high levels of c-ets-1 protein (Ets1) that can be rapidly phosphorylated following mitogenic stimulation using lectins. We demonstrate here that T cell receptor (TCR) specific stimulation with monoclonal antibodies of mature CD8+ or CD4+ T cells also results in the rapid phosphorylation of Ets1, reinforcing the hypothesis of a possible role for Ets1 in T cell activation. In addition to the major Ets1 product (mu-p63c-ets-1), we identify in mouse thymocytes and mature T cells a distinct 52 Kd Ets1 related protein (mu-p52c-ets-1). In contrast to the major Ets1 protein, mu-p52c-ets-1 is poorly phosphorylated in unstimulated cells. Furthermore, mitogenic stimulation of thymocytes and T cells failed to induce in mu-p52c-ets-1 the Ca2(+)-dependent phosphorylation events which are known to drastically affect the migration of the major Ets1 protein in SDS polyacrylamide gels. Mu-p52c-ets-1, like mu-p63c-ets-1, is a nuclear-chromatin associated protein which exhibits DNA binding activity in vitro. However, in contrast to the major Ets1 protein, the association of mu-p53c-ets-1 with chromatin and its ability to bind to DNA in vitro are unaffected by activation stimuli resulting in an increase in [Ca2+]i. Finally, we present indications suggesting that mu-p52c-ets-1 might be the murine equivalent of the translation product of an alternatively c-ets-1 spliced mRNA described in human cells by others.

Amino Acid Sequence↗
PubMed1988

Population polymorphism of the GLO1 enzyme. Identification of two new variants.

A new electrophoretic technique for the determination of the glyoxalase I (GLO1) polymorphism on mixed agarose and starch gel is applied to the genetic study of "Provinces Françaises" and some other human populations. Four rare electrophoretic variants are revealed; two of them (GLO1*4, GLO1*5), both new, are discussed. In the "Provinces Françaises" the mating GLO1 2-1 x GLO1 2-1 shows an irregular segregation of the GLO1 alloenzymes.

Africa, Western↗
PubMed1983

Molecular heterogeneity of hereditary pyropoikilocytosis: identification of a second variant of the spectrin alpha-subunit.

In hereditary pyropoikilocytosis (HPP), the red cell membrane skeletons exhibit a mechanical instability that can be correlated to defective self-association of spectrin heterodimers. To determine the underlying molecular defect, we have subjected HPP spectrin to limited tryptic digestion, followed by one- and two-dimensional separations of the peptides. Two of the HPP kindreds exhibited a marked decrease in 80,000-dalton peptide (previously identified as the spectrin dimer-dimer contact domain of the alpha-subunit) and a concomitant increase of the 74,000-dalton polypeptide (presumably derived from the 80,000-dalton domain) and a decrease in a 22,000-dalton polypeptide. We now report tryptic digests of two other HPP kindred that are characterized by a decrease or complete absence of the 80,000-dalton tryptic fragment, with a concomitant increase in fragments at 46,000 and 17,000 daltons. The 46,000-dalton fragment separated into multiple spots on isoelectric focusing, ranging in isoelectric point from 5.25 to 5.35, and the 17,000-dalton fragment focused to a single spot at 5.4. Minor fragments at 56,000 and 22,000 daltons were also decreased, while a 38,000-dalton fragment increased. Limited tryptic digestion of the separated alpha- and beta-subunits revealed that the 74,000-dalton fragment in the first group of patients and the 46,000-dalton fragment in the second group of patients were derived from the alpha-subunit. Both subtypes exhibited a similar defect of spectrin self-association, with 30%-38% of spectrin dimers in O degrees C extracts. The results indicate that at least two distinct forms of structurally defective spectrin may give rise to the clinical presentation of HPP.

Adolescent↗
PubMed1980

[Identification of pyruvate kinase variants from red blood cells using trypsinization and electrophoresis].

Enzymopathies of pyruvate kinase (PK) are characterized by polymorphism. Nine distinct variants of the L-type from 10 patients suffering from nonspherocytic haemolytic anaemia have been identified by electrophoretic and kinetic methods. Typical changes of the electrophoretic mobility and kinetic properties of the L-type and K-type of PK can be produced by incubation of cytolysates and tissue homogenates in the presence of trypsin. After trypsinization the three distinct forms of the L-type from liver and erythrocytes show identical mobility. Trypsinization of haemolysates has proved to be a diagnostic tool for the differentiation of PK variants. The results also allow to distinguish whether the mutation is located in the region of the peptide chain which is split off by trypsin or not. In three cases the occurrence of two instead of one enzyme form after trypsinization indicates a double heterozygote heredity of PK-deficiency. The appearance of the K-type isoenzyme of PK in red blood cells may be considered as a physiological event during a limited period of erythropoiesis. The K-isoenzyme was found only in samples of red blood cells containing erythroblasts. One of the patients has shown a still unknown form of PK. The properties of this form resembled those of the major part of PK from human placenta.

Anemia, Hemolytic, Congenital Nonspherocytic↗
PubMed1997

HLA class I typing by one-dimensional isoelectric focusing and identification of the new variants in Thai population.

One-dimensional isoelectric focusing (1D-IEF) is the technique to define HLA class I antigens based on difference in isoelectric point of HLA molecules. Different IEF subtypes are shown in different populations. In this study, 1D-IEF was employed to study HLA-A and -B subtypes in Thai population. A panel of 117 samples including all serologically defined HLA-A and -B antigens in Thai population were typed by 1D-IEF. Serological specificities and subtypes correlated well with IEF results and some antigens with unclear serological specificities could be confirmed by IEF. In addition, more subtypes could be obtained by IEF than by serology. A total of 17 IEF subtypes from HLA-A and 31 IEF subtypes from HLA-B could be identified. The subtypes predominantly found in Thai population were A2.3, A24.2, A11.1, A33.2, B15.2, B7.1 and B13.1. In addition, new IEF variants were identified in HLA-B35, B5, B56 and B48. The band positions of these variants were different from those previously described. These IEF subtypes are HLA gene products which may be important in transplantation. The combination of IEF and serology for HLA typing can provide a better definition of each allelic product of HLA-A and -B.

Histocompatibility Antigens Class I↗
PubMed1998

[Cytogenetic of nucleolar organizer regions (NOR) of human chromosomes: identification of four morphofunctional variants of NOR, their inter-individual and inter-chromosomal distribution].

Cytogenetic characters of the nucleolus organizer regions (NORs) located on the short arms of five acrocentric chromosomes were studied in chromosome preparations obtained from cultured blood cells of 17 donors. In situ hybridization to a 3H-labeled probe was used to estimate the relative copy number of ribosomal genes (RGs) in all NORs of chromosomes identified by G-banding in each sample. The relative amount of potentially active RGs (0 to 4 arbitrary units) in each NOR was estimated from the size of AgNOR selectively stained with silver nitrate. Linear regression analysis revealed clusters of silent RGs (CSRGs) in 24 out of 170 NORs (14%). Based on the presence or absence of active and inactive RG clusters, NORs of human chromosomes were classified into four morphological functional variants (MFVs): (1) Ag-/CSRG-, (2) Ag-/CSRG+, (3) Ag+/CSRG-, and (4) Ag+/CSRG+. These variants were observed in 7.65%, 2.35%, 11.8%, and 78.2% of 170 analyzed NORs, respectively. NORs with CSRGs (MFV 2 and 3) were absent in 5 out of 17 donors. One, two, and three NORs with CSRGs were observed in four donors each. Analysis of the chromosome distribution of NOR MFVs showed that their frequencies remained almost the same in group-D and group-G acrocentric chromosomes. Although the tested samples were small (34 chromosomes for each pair), two observations were made with regard to individual chromosomes. First, almost half MFV-1 NORs (6 out of 13) were detected on chromosome 15. Second, the frequency of CSRGs was higher in chromosome 21 (29%) than in the other chromosomes (10%).

Adult↗
PubMed1982

Identification of eleven human hemoglobin variants by high-performance liquid chromatography: additional data on functional properties and clinical expression.

Eleven abnormal hemoglobins were detected in the course of cord blood screening or in the evaluation of evident hematological problems in individual cases. Identification of the variant in each case was done by high-performance liquid chromatography (HPLC); HPLC provides a rapid, sensitive means for the examination of abnormal hemoglobins. Some of the 11 variants that were identified have been described repeatedly and are included to provide information on the HPLC behavior of tryptic peptides. Others are much rarer. Additional information is provided about the hematological and clinical expression as well as ethnic and geographical distribution of the abnormal hemoglobin.

Chromatography, High Pressure Liquid↗
PubMed1989

Novel human proalbumin variant with intact dibasic sequence facilitates identification of its converting enzyme.

We describe here the identification of a new genetic variant of human proalbumin with an N-terminal sequence of Arg-Gly-Val-Phe-Arg-Arg-Val-Ala-His-Lys-. Proalbumin Blenheim (10%) and mature albumin Blenheim (38%) with an initial sequence of Val-Ala-His-Lys-make up nearly half the serum albumin in affected individuals. Despite retaining an intact dibasic processing site, proalbumin Blenheim (1 Asp----Val) enters the circulation unprocessed. The observed ratio of proalbumin to albumin can be accounted for by proteolysis in the periphery. Employed as a potential substrate, proalbumin Blenheim provides a unique means of identifying the physiologically relevant proalbumin convertase. In vitro studies showed that the variant is readily cleaved by trypsin. However, it is not cleaved by the proposed proalbumin convertase, a membrane-bound Ca2+-dependent proteinase prepared from rat liver Golgi vesicles, which gives authentic cleavage of normal human proalbumin.

Adult↗