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PubMed1995

Complement component C3: molecular basis of the C3*S025 variant and evidence for molecular heterogeneity of other variants.

Complement component 3 (C3) is the central molecule of the complement system. It displays a number of polymorphic variants with, as yet, unclear functional consequences. We have investigated a number of rare C3 variants by PCR-SSCP (polymerase chain reaction-single strand conformation polymorphism) analysis and could identify the molecular basis of a C3*S025 variant. The decreased electrophoretic mobility of this protein is caused by the exchange of a neutral serine residue to an arginine residue (positively charged). This exchange is unlikely to have functional consequences as it maps to the C-terminus of the alpha-chain. C3 variants appear to have originated from various independent mutations as we could not detect this mutation in different allotypes.

Base Sequence↗

PubMed1977

LBA technique in the detection of chromosome variants. II. Chromosomes except for those with Q variants.

In Part I of this communication, a technique (LBA) was described which used DNA replication in the evaluation of chromosome variants in man. It was shown that the method was very useful in the detection of variants in D- and G-group chromosomes. Results on pars 3 and 4 were also presented. In Part II, the rest of chromosomes were examined. In the evaluation of qh variants in 1, 9 and 16, the LBA technique proved itself to be a very effective implement. It was practically free of technical variables coherent with C-band technique and, therefore, it was possible to use the size of an euchromatic segment of a chromosome as a reference standard. LBA variants were observed in about 50% of the members of the remaining 12 pairs of chromosomes, i.e., 2, 5, 6, 7, 8, 10, 11, 12, 17, 18, 19, and 20.

Chromosomes, Human↗

PubMed1986

Fourteen genetically variant proteins of mouse brain: discovery of two new variants and chromosomal mapping of four loci.

With the description here of variant proteins A13 (pI 5.9, MW 62 kd) and A14 (pI 5.3, MW 26 kd), 14 polypeptides of mouse brain visualized by two-dimensional electrophoresis (2DE) exhibit genetic variation in isoelectric point. Using 22 B X D recombinant inbred strains, we map four of these loci and show that a fifth is independent of known loci. A pI 5.6, 81-kd protein of mouse brain mitochondria designated A1 is demonstrated to be an independent locus closely linked to LY-2 and LVP-1 on mouse chromosome 6. A pI 5.6, 28-kd genetically variant brain polypeptide designated A12 maps to chromosome 1 and shows identity with the known mouse locus LTW-4. The locus for A8 is not closely linked to any previously mapped locus. However, the locus for the newly described variant A13 shows 3 of 18 recombinants with the DNA polymorphism RN7S-2 and 2 of 18 recombinants with HC (hemolytic complement) and is thus probably located proximally to HC near the centromere of chromosome 2. Genetic and biochemical evidence is presented for the identification of A14 as ALP-1 (apolipoprotein 1), mapping to chromosome 9. In addition to these 13 genetically variant polypeptides, the positions of 12 other polypeptides which have been identified on 2DE gels of mouse brain are given.

Animals↗

PubMed2000

Natural variants of human p85 alpha phosphoinositide 3-kinase in severe insulin resistance: a novel variant with impaired insulin-stimulated lipid kinase activity.

AIMS/HYPOTHESIS: Phosphoinositide 3-kinase (PI 3K) plays a central part in the mediation of insulin-stimulated glucose disposal. No genetic studies of this enzyme in human syndromes of severe insulin resistance have been previously reported. METHODS: Phosphoinositide 3-kinase p85 alpha regulatory subunit cDNA was examined in 20 subjects with syndromes of severe insulin resistance by single strand conformational polymorphism and restriction fragment length polymorphism analyses. Insulin-stimulated phosphoinositide 3-kinase activity and recruitment into phosphotyrosine complexes of variants of p85 alpha were studied in transiently transfected HEK293 cells. Phosphopeptide binding characteristics of wild-type and mutant p85 alpha-GST fusion proteins were examined by surface plasmon resonance. RESULTS: The common p85 alpha variant, Met326I1e, was identified in 9 of the 20 subjects. Functional studies of the Met326Ile variant showed it to have equivalent insulin-stimulated lipid kinase activity and phosphotyrosine recruitment as wild-type p85 alpha. A novel heterozygous mutation, Arg409Gln, was detected in one subject. Within the proband's family, carriers of the mutation had a higher median fasting plasma insulin (218 pmol/l) compared with wild-type relatives (72 mol/l) (n = 8 subjects, p = 0.06). The Arg409Gln p85 alpha subunit was associated with lower insulin-stimulated phosphoinositide 3-kinase activity compared with wild-type (mean reduction 15%, p < 0.05, n = 5). The recruitment of Arg409Gln p85 alpha into phosphotyrosine complexes was not significantly impaired. GST fusion proteins of wild-type and mutant p85 alpha showed identical binding to phosphopeptides in surface plasmon resonance studies. CONCLUSION/INTERPRETATION: Mutations in p85 alpha are uncommon in subjects with syndromes of severe insulin resistance. The Met326Ile p85 alpha variant appears to have no functional effect on the insulin-stimulated phosphoinositide 3-kinase activity. The impaired phosphoinositide 3-kinase activity of the Arg409Gln mutant suggests that it could contribute to the insulin resistance seen in this family.

Adult↗

PubMed1991

Infantile neuronal ceroid lipofuscinosis (CLN1): linkage disequilibrium in the Finnish population and evidence that variant late infantile form (variant CLN2) represents a nonallelic locus.

Two forms of neuronal ceroid lipofuscinosis (CLN) are enriched in the Finnish population: the infantile form (CLN1), which is the most common progressive encephalopathy of small children, and the variant late infantile form (variant CLN2), which is a rare, atypical form of neuronal ceroid lipofuscinosis. We recently established the linkage of the infantile form (CLN1) to the short arm of chromosome 1 close to the anchor marker D1S7. Here we demonstrate a linkage disequilibrium of CLN1 chromosomes using the two closest markers, DIS62 and L-MYC at the short arm of chromosome 1 (P less than 0.0025). The results of linkage analyses in Finnish variant CLN2 families using the markers linked to CLN1 revealed an exclusion; i.e., this form of CLN is caused by a locus different from that of CLN1. This finding was confirmed with the result of the M-test for heterogeneity. The genealogical data collected further support the molecular genetic findings and provide evidence that the mutation causing CLN1 in Finland is very old, whereas the mutation causing the variant CLN2 could be a result of a younger, i.e., more recent founder effect.

Alleles↗

PubMed2001

Transcriptional activities of p73 splicing variants are regulated by inter-variant association.

p73 has been identified as a gene that encodes a protein with significant identity with the tumour suppressor p53. The main structural difference between p73 and p53 is the additional C-terminal region of p73. Six isoforms of p73 with differing C-terminal structures, alpha, beta, gamma, delta, epsilon and xi, have been reported. These variants differ in transcriptional activity on p53-responsive promoters. Here we report a possible mechanism of transcriptional activation by p73 splicing variants. C-terminal deletion mutants of p73 alpha showed a significantly higher level of transcriptional activity than wild-type p73 alpha, suggesting that the C-terminal structure of p73 alpha functions to repress the transcriptional activity of p73 alpha. The results of immunoprecipitation assays and two-hybrid assays in mammalian cells showed that the p73 variants interacted with each other, but not with p53. The transcriptional activity of p73 beta was reduced by co-expression with either p73 alpha or p73 epsilon, which bears an identical C-terminal structure to p73 alpha. Co-expression of the C-terminal portion of p73 alpha or p73 epsilon with p73 beta also resulted in reduced transcriptional activity. Moreover, we observed that the level of endogenous p21 protein induced by p73 beta was decreased by co-expression of full-length p73 epsilon or the C-terminal region of p73 alpha or p73 epsilon. These observations suggest that p73-mediated gene expression is regulated by the interactions of p73 splicing variants in the cell.

Animals↗

PubMed1980

An electrophoretically cryptic alcohol dehydrogenase variant in Drosophila melanogaster. I. Activity ratios, thermostability, genetic localization and comparison with two other thermostable variants.

The alcohol dehydrogenase (ADH) variant ADH-FCh.D. has a secondary alcohol/primary alcohol activity ratio characteristic of ADH-S although it has an electrophoretic mobility inseparable from ADH-F. ADH-FCh.D. is distinguished from these two common ADH variants by being much more thermostable. Genetic analysis suggests tht ADH-FCh.D. is specified by an allele at the Adh locus. Biochemical comparisons show that ADH-FCh.D. has the same electrophoretic mobility, activity ratio and thermostability as the two other heat-resistant variants which have been reported, ADH-F71K in Europe and ADH-Fr in North America. The geographically widespread distribution of a thermostable ADH variant within the ADH-F electrophoretic class indicates that it should be considered in attempts to explain the Adh polymorphism in natural populations.

Alcohol Oxidoreductases↗

PubMed1998

Ratio of CD44 epithelial variant to CD44 hematopoietic variant is a useful prognostic indicator in gastric and colorectal carcinoma.

BACKGROUND: The CD44 is a cell adhesion molecule that is present as numerous isoforms created by mRNA alternative splicing. Expression of variant isoforms of CD44 is associated with tumor growth and metastasis. The aim of this study was to evaluate whether CD44 isoform expression is a prognostic factor in gastric and colorectal cancer. METHODS: We performed a polymerase chain reaction analysis following reverse transcriptase treatment for CD44 expression in fresh surgical specimens obtained from 25 colon carcinomas and 30 gastric carcinomas and matched adjacent normal mucosa. We determined the epithelial variant/hematopoietic variant (E/H) ratio (the amount of the CD44 epithelial variant transcript relative to the CD44 hematopoietic variant transcript) in cancer tissues and examined it for correlations with clinicopathological parameters and survival rate. RESULTS: The E/H ratio in tumor tissue was significantly higher than that in adjacent non-cancerous mucosa. In gastric and colorectal cancer tissues, there was no significant relationship between E/H ratio and clinicopathological parameters. However, patients who died due to tumor recurrence had a higher E/H ratio than surviving patients with colorectal cancer. In gastric cancer, patients with high E/H tumors had a shorter survival time than those with low E/H tumors. CONCLUSIONS: Our results suggest that the E/H ratio is a useful indicator of prognosis in gastric and colorectal carcinoma.

Adult↗

PubMedDate not supplied

Mitochondrial genetic variants and Alzheimer disease: a case-control study of the T4336C and G5460A variants.

The T4336C mitochondrial genetic variant was associated with Alzheimer disease in several previous studies. Recent investigations, however, failed to confirm this association. We tested this association in newly diagnosed Alzheimer disease cases and controls of similar age and gender recruited from an established HMO serving Seattle, Washington and surrounding areas. In this, the largest case-control study reported to date, the T4336C variant was not associated with Alzheimer disease overall (present in 6 of 236 cases and 7 of 328 controls; odds ratio = 1.20, 95% CI 0.33 to 4.22). There was evidence of effect modification by Apolipoprotein E (APOE) status--among subjects with an APOE epsilon 4 allele, the T4336C variant was associated with disease (present in 5 of 139 cases and none of 82 controls; odds ratio = infinity, 95% CI 0.73 to infinity). APOE may be an important modifier of the T4336C effect, potentially explaining variable findings across previous studies. Alternatively, the positive findings reported to date may simply reflect the problem of "type I" error inherent in genetic association studies. Substantially larger samples than are currently available would be required to resolve this question. G5460(A/T) variants were also investigated and found not to be associated with Alzheimer disease.

Aged↗

PubMed1998

Analysis of human immunodeficiency virus type 1 env and gag sequence variants derived from a mother and two vertically infected children provides evidence for the transmission of multiple sequence variants.

In order to investigate the transmission of human immunodeficiency virus type 1 (HIV-1) from mother-to-child we have examined serial plasma RNA samples obtained from a mother over an eight year period spanning four pregnancies. Child 1 and 2 (born January 1987 and June 1990) were uninfected whilst child 3 and 4 (born July 1992 and February 1994) were HIV positive. Genetic variation was examined within the viral population of the mother and her two infected children for both the V3 loop and flanking regions of the env gene and the p17 region of the gag gene. In one child (child 4) a highly homogeneous virus population was observed within both env and gag in contrast to the more heterogeneous virus population observed within the mother. Viral sequences of child 4 clustered within a single branch within the reconstructed phylogenetic tree. This is consistent with the transmission of a single maternal variant to the child in this case, which may indicate a selective process. By contrast, child 3 showed substantial genetic heterogeneity even within the first samples obtained shortly after birth. Sequences of child 3 clustered in two distinct groups within the phylogenetic tree and were separated by sequences of the mother. These results are not consistent with the selective transmission of a single maternal variant to the child in this case and we therefore propose that the infection within child 3 is the result of the transmission of multiple sequence variants to the child. All transmitted sequence variants were predicted to be of the macrophage-tropic, nonsyncytium-inducing (NSI) phenotype.

Amino Acid Sequence↗

PubMed1981

Immunochemical studies of human placental-type variants of alkaline phosphatase. Structural differences between the "Nagao isoenzyme" and the placental "D-variant".

Hyperimmune antisera raised against the rare FD and SD phenotypes of human placental alkaline phosphatase and the related cancer-associated Nagao isoenzyme were exhaustively absorbed with the common SS and FF phenotype enzymes conjugated to Sepharose. The antibodies so obtained had one of three specificities, determined by testing all the common phenotypes of placental alkaline phosphatase, the rare FD, SD and S-17 phenotypes, and five samples of purified cancer patient enzymes: (I) antibodies reactive with the S, D and I variant enzymes, but not with the F, 17 or Nagao enzymes; (II) antibodies reactive with the F, 17 and Nagao enzymes, but not with the S, D, and I variant enzymes; and (III) antibodies reactive with the D, 17 and Nagao enzymes and not with the S, F or I variant enzymes. Based on these data, and on the information obtained from biochemical characterization, it is argued that the Nagao isoenzyme and the D-variant are closely related but distinct enzymes. We propose a hypothetical scheme for the divergence of these two enzymes from a common ancestral gene product. In this scheme, an ancestral gene duplication resulted in two isoenzymes, one of which is completely specific to the placenta, and one of which (the "Nagao isoenzyme") has an unknown normal tissue localization, but is found in some cases of cancer. We use the term "syn-placental" to describe this latter isoenzyme, reflecting its close structural relationship to the placental isoenzyme.

Alkaline Phosphatase↗

PubMed2005

Evaluation of the Bio-Rad VARIANT II HbA2/HbA1C Dual Program for measurement of hemoglobin concentrations and detection of variants.

In this work data obtained on the VARIANT II hemoglobin analyzer using the Dual Kit elution system were compared to those obtained with the beta-Thalassemia Short Program. Since many laboratories still use an earlier model of the hemoglobin analyzer, the Variant 1, these data were also compared to those obtained with the latter instrument. Our study is divided into two parts. The first is an evaluation of the precision of the VARIANT II for determining the levels of hemoglobin (Hb)A2 and Hb F. This was carried out for normal subjects, thalassemic patients and patients with HbS. The second part concerns the potential of this instrument in the presumptive identification of Hb variants.

Fetal Hemoglobin↗

PubMed1975

Variants of the group-specific component system as demonstrated by immunofixation electrophoresis. Report of a new variant, Gc Boston (Ge B).

Immunofixation electrophoresis is a relatively simple and reliable method for the genetic phenotyping of the group-specific component (Gc) of serum. This method permits direct comparison of electrophoretic mobilities and band concentrations, with no interference by other proteins. The variants Gc Ab and Gc Y appear identical by this technique; the Eskimo variant appears to be similar to Gc D but not to Gc Ab as previously reported. Gc Norway, also designated Gc 1C, is electrophoretically cathodal to the slower band of Gc 1 and therefore appears to be a distinct variant. A new variant, Gc Boston, is single banded with mobility between the two bands of Gc 1.

Amniotic Fluid↗

PubMed1991

Cuttlefish spermatid-specific protein T. Molecular characterization of two variants T1 and T2, putative precursors of sperm protamine variants Sp1 and Sp2.

In cuttlefish, as in selachians and mammals, spermiogenesis is characterized by the double nuclear protein transition histones----intermediate protein (protein T)----protamine (protein Sp). The cuttlefish protein T, which consists of two structural variants phosphorylated at different degrees, is the first invertebrate spermatid-specific protein to be fully characterized and sequenced. The primary structures of these two variants were established from sequence analysis and mass spectrometric data of the proteins and their fragments. T1 and T2 are two highly related proteins of 78 and 77 residues, respectively, which differ only by four conservative substitutions, two inversions Ser in equilibrium with Arg, and the deletion of 1 residue of arginine in variant T2. The asymmetrical distribution of the hydrophobic and basic residues determines two well defined domains: an amino-terminal domain (residues 1-21) devoid of arginine and aromatic residues and containing all the aliphatic hydrophobic residues and a highly basic carboxyl-terminal domain (residues 22-77 or 78) that contains 77% of arginine, all the tyrosine residues, and most of the phosphorylated serine residues present in the protein. The complete structural identity of the basic carboxyl-terminal domain of spermatidal proteins T1 and T2 with the protamine variants Sp1 and Sp2 isolated from cuttlefish spermatozoa strongly suggests that T1 and T2 could be precursors of Sp1 and Sp2, respectively.

Amino Acid Sequence↗

PubMed1988

A new transferrin variant from Iran (Tf B-Iran): review of 36 variant alleles.

A total of 2581 serum samples collected from five population groups of Iran was studied for electrophoretic variations of the transferrin (Tf). Besides the common phenotype Tf C the authors could observe 41 individuals with rare Tf types: CB1, CB2, CD1, CDChi, CD2. In addition to these Tf types two individuals with a new Tf B variant were observed. This new variant was found in the Dezfooli sample and was designated as Tf B-Iran. The electrophoretic position of this variant is described, and all the hitherto known Tf variants are reviewed.

Alleles↗

PubMed1980

Structure of a newly isolated variant of Simian virus 40 DNA containing monkey DNA and its similarity to previously isolated variants.

The structure of a newly and independently isolated defective variant of simian virus 40 that contains covalently linked monkey and SV40 DNA sequences is described. This variant, termed 290, has a structure essentially identical with a previously isolated and characterized variant named CVP8/1/P2 (Eco RI res). The structural similarities include the monkey (host) DNA segment that is combined with viral DNA sequences, the particular viral DNA segment that is present, and the arrangement of these within the defective genome. The monkey DNA segment contains sequences derived from both low and high reiteration frequency monkey DNA. The viral sequences include the origin of replication. The separate isolation of essentially identical variants suggests a high level of specificity in the events leading to the formation and amplification of this type of defective genome.

Animals↗

PubMed1988

Variant specific transcripts from the co-transposed segments of variant surface glycoprotein genes in Trypanosoma brucei.

We examined steady-state transcripts from the sequences immediately upstream of the 1 and 11 variant surface glycoprotein (VSG) genes in Trypanosoma brucei of the IsTaR 1 serodeme. These sequences, the co-transposed segment, differ in size and sequence, and produce a variety of variant-specific polyadenylated transcripts. Most, if not all, of these transcripts, some of which may be precursors, contain the spliced leader (SL). Variant specific transcription extends from 5' of the co-transposed segment to 100-400 nucleotides downstream of the major VSG mRNA polyadenylation site. The 1 VSG mRNA has at least 2, and possibly 3, SL addition sites; the major site is 120 nucleotides downstream of the polyadenylation site identified by sequencing a cDNA from the co-transposed segment. Two general models for the production of the co-transposed segment transcripts are discussed.

Animals↗

PubMed1982

Immunoglobulin V region variants in hybridoma cells. I. Isolation of a variant with altered idiotypic and antigen binding specificity.

The hybridoma cell line B1-8.delta 1 expresses an IgD antibody with specificity for the hapten 4-hydroxy-3-nitro-phenylacetyl (NP). Two monoclonal antibodies, each recognizing an idiotypic determinant (idiotope) in the variable region of antibody B1-8, and fluorescence-activated cell sorting were used for the isolation of spontaneous somatic cell variants whose antibody product lacks the expression of one of the two idiotopes. The variant cells carry a mutation which is expressed in the variable region of the antibody heavy chains and which reduces the affinity of the antibody for hapten greater than 100-fold. Idiotope loss variants of the selected phenotype are present in the B1-8.delta 1 cell population at low frequency.

Animals↗