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PubMed2001

Human delta Np73 regulates a dominant negative feedback loop for TAp73 and p53.

Inactivation of the tumour suppressor p53 is the most common defect in cancer cells. p53 is a sequence specific transcription factor that is activated in response to various forms of genotoxic stress to induce cell cycle arrest and apoptosis. Induction of p53 is subjected to complex and strict control through several pathways, as it will often determine cellular fate. The p73 protein shares strong structural and functional similarities with p53 such as the potential to activate p53 responsive genes and the ability to induce apoptosis. In addition to alternative splicing at the carboxyl terminus which yields several p73 isoforms, a p73 variant lacking the N-terminal transactivation domain (Delta Np73) was described in mice. In this study, we report the cloning and characterisation of the human Delta Np73 isoforms, their regulation by p53 and their possible role in carcinogenesis. As in mice, human Delta Np73 lacks the transactivation domain and starts with an alternative exon (exon 3'). Its expression is driven by a second promoter located in a genomic region upstream of this exon, supporting the idea of two independently regulated proteins, derived from the same gene. As anticipated, Delta Np73 is capable of regulating TAp73 and p53 function since it is able to block their transactivation activity and their ability to induce apoptosis. Interestingly, expression of the Delta Np73 is strongly up-regulated by the TA isoforms and by p53, thus creating a feedback loop that tightly regulates the function of TAp73 and more importantly of p53. The regulation of Delta Np73 is exerted through a p53 responsive element located on the Delta N promoter. Expression of Delta Np73 not only regulates the function of p53 and TAp73 but also shuts off its own expression, once again finely regulating the whole system. Our data also suggest that increased expression of Delta Np73, functionally inactivating p53, could be involved in tumorogenesis. An extensive analysis of the expression pattern of Delta Np73 in primary tumours would clarify this issue.

Amino Acid Sequence↗
PubMed1993

A high proportion of the V delta 1+ synovial fluid gamma delta T cells in juvenile rheumatoid arthritis patients express the very early activation marker CD69, but carry the high molecular weight isoform of the leucocyte common antigen (CD45RA).

We have previously shown that gamma delta T cells in the synovial compartment of patients with juvenile rheumatoid arthritis (JRA) express activation antigens (CD69 and HLA-DR) and that they are predominantly of the V delta 1 subset. In this study we have analysed the expression of activation antigens (CD69 and HLA-DR) and different isoforms of the leucocyte common antigen (CD45RO and CD45RA) on the V delta 1 and the V delta 2 subsets of gamma delta T cells in paired samples of synovial fluid and peripheral blood of nine patients with JRA, and in the peripheral blood of five children with idiopathic scoliosis. In the synovial fluid of children with JRA, there were significantly more V delta 1+CD69+ and V delta 2+CD69+ cells compared with the peripheral blood of the same patients. In contrast, however, in the synovial fluid the V delta 1 and the V delta 2 subsets differed with respect to the expression of the two isoforms of the leucocyte common antigen. The majority of the V delta 1+ cells expressed the high molecular weight isoform (CD45RA+) while most of the V delta 2+ cells carried the low molecular weight variant (CD45RO+) of this molecule.

Adolescent↗
PubMed2004

Properties of antigenomic hepatitis delta virus ribozyme cis- and trans- analogs.

A series of permuted variants of antigenomic HDV ribozyme and trans-acting variants were constructed. The catalytic activity study of the ribozymes has shown that all the variants were capable of self-cleaving with equally biphasic kinetics. Ribonuclease and Fe(II)-EDTA cleavage have provided evidence that all designed ribozymes fold according to the pseudoknot model and the conformations of the initial and cleaved ribozyme are different. A scheme of HDV ribozyme self-cleavage reaction was suggested. The role of hydrogen bonds in the reaction was evaluated by substitution of ribose in the ribozyme for deoxyribose. It was found that the 2'-OH group of U23 and C27 is critical for the reaction to occur; the 2'-OH group of U32 and U39 is important, while 2'-OH groups of other nucleotides of loop 3, stem 4 and stem 1 are unimportant for the cleavage activity.

Base Sequence↗
PubMed1995

Gamma-chain heterogeneity in Greek (delta beta)zero-thalassemia.

A molecular and biochemical population study of (delta beta)zero thalassemia in central Greece is described. The molecular study was focused on the type of the deletion and the status of G gamma-XmnI polymorphism, whereas the biochemical approach was centered on the G gamma/A gamma ratio as well as the frequency of the A gamma T chain in the fetal hemoglobin of 19 delta beta-thalassemia heterozygotes and 3 homozygotes. This study includes individuals from the mountainous district of Epirus (northwestern Greece) where the trait was found to be concentrated along the river Arachthos. The Sicilian (delta beta)zero thalassemia deletion was found in all subjects tested by direct PCR. The levels for the G gamma-chain presented values ranging from 29 to 83% of the total gamma-chain content. Thirteen heterozygotes had the adult G gamma/A gamma ratio (mean G gamma: 35% +/- 10) of whom 10 were XmnI-negative (- / -), 6 had the newborn ratio (mean G gamma: 70% +/- 9) and were XmnI-positive, while homozygotes had equal amounts of G gamma and A gamma. Five of the 19 heterozygotes were A gamma T-positive with low levels of this A gamma-chain variant, suggesting an in-trans to the delta beta-thalassemia determinant production.

Adolescent↗
PubMed1991

Requirements for cell surface expression of the human TCR/CD3 complex in non-T cells.

The T-cell antigen receptor (TCR) consists of a glycoprotein heterodimer (alpha/beta or gamma/delta) which is non-covalently associated with at least four or five invariant polypeptides (CD3 gamma, delta, epsilon, zeta and eta). In T-cell variants lacking TCR alpha, beta or zeta, it has been shown that incomplete TCR/CD3 complexes are retained within the cell. To examine requirements for cell surface expression of TCR/CD3, we transfected COS monkey kidney cells with cDNAs encoding TCR alpha, beta and CD3 gamma, delta, epsilon and zeta. We report that cell surface appearance of TCR/CD3 on COS cells requires coordinate expression of all six proteins. In the absence of the zeta chain, subcomplexes comprising from two to five chains were readily demonstrable in COS cells, but they failed to reach the cell surface or to acquire N-linked oligosaccharide side chains indicating failure to reach the medial Golgi. Pulse-chase metabolic labelling of transfected COS cells showed that three chains (CD3 gamma, CD3 epsilon, and zeta) were stable while three (TCR alpha, TCR beta and CD3 delta) were rapidly degraded. In two- and three-chain co-transfections specific intracellular subcomplexes were formed between TCR alpha and CD3 gamma, TCR alpha and CD3 delta, or TCR beta and CD3 epsilon. Binary subcomplexes having at least one stable chain (CD3 epsilon - TCR beta) were stable while one formed by two unstable chains (TCR alpha - CD3 delta) was still degraded. Assembly of the TCR/CD3 complex in COS cells thus appears centered around the metabolically stable CD3 gamma and CD3 epsilon proteins. Site-specific mutations of the negatively-charged transmembrane amino acid of residues of the CD3 chains to alanines served to either abolish (for TCR alpha - CD3 delta and TCR beta - CD3 epsilon) or diminish (for TCR alpha -CD3 gamma) these TCR-CD3 interactions. These mutations had no effect, however, on CD3-CD3 interactions or upon synthesis, metabolism, or intracellular distributions of the CD3 proteins. The transmembrane domains of CD3 gamma, delta, and epsilon thus appear to play a major role in associations of CD3 with TCR chains.

Animals↗
PubMed1989

Molecular genetic analysis of a hybrid gene encoding Sta glycophorin of the human erythrocyte membrane.

Sta is an antigen of the human MNSs blood group system carried by a variant glycophorin residing in the erythrocyte membrane. We examined the structure, organization, and inheritance of Sta gene identified in genomic DNA from an Oriental family. Southern blotting detected a useful genetic marker tightly linked to the Sta gene. Differential hybridization and secondary restriction analyses showed that Sta gene is a fusion hybrid of delta and alpha glycophorin genes. Genomic mapping by extensive use of synthetic oligonucleotides, with overlapping sequence specificity, allowed us to define the delta-alpha junction site and disclose the organization of the variant gene. The junction point of Sta hybrid gene is encompassed by an unexpressed exonlike sequence of the delta gene at the 5' site, and an expressed sequence of the alpha gene spanning codons 59 through 71, at the 3' site. Dosage quantification demonstrated the occurrence of Sta gene as a single copy in the genome. Blood group inheritance, evaluated by DNA typing, established the tight linkage of Sta to the alpha M and delta S genes. The data support a single unequal crossing-over event between misaligned delta and alpha genes on the homologous chromosomes as the mechanism for the origin of Sta gene. The Sta gene is similar in overall structure to another delta-alpha hybrid gene, Dantu, but differs from it in junction structure, copy number, gene linkage, and antigen specificity.

Amino Acid Sequence↗
PubMed1995

Modulation of cell adhesion by changes in alpha L beta 2 (LFA-1, CD11a/CD18) cytoplasmic domain/cytoskeleton interaction.

The integrin alpha L beta 2 (leukocyte function-associated molecule 1, CD11a/CD18) mediates activation-dependent adhesion of leukocytes. The cytoplasmic domains of alpha L beta 2 have been demonstrated to modulate adhesiveness of alpha L beta 2. Affinity changes of alpha L beta 2 for its ligand or postreceptor events can be responsible for this modulation of adhesiveness. To investigate the possible role of the alpha L beta 2 cytoplasmic domains in postreceptor events we constructed cDNA encoding chimeric proteins with intracellular alpha L beta 2 domains, which are responsible for alpha L beta 2 specific intracellular interactions, and extracellular alpha IIIb beta 3 (GP IIb/IIIa) domains, which allow the assessment of the receptor affinity state. The cDNA was stably transfected in Chinese hamster ovary cells and chimeric heterodimer formation proven by immunoprecipitations and flow cytometry. The chimeric receptors mediate adhesion to immobilized fibrinogen, and this adhesion is increased by phorbol myristate acetate and abolished by cytochalasin D. However, neither treatment affects the affinity state of the chimeric receptor, suggesting involvement of the cytoskeleton in the regulation of alpha L beta 2 mediated cell adhesion. To exclude the possibility of postoccupancy affinity changes of the chimeric receptors, we locked the receptors into a high affinity state by creating a deletion variant. The region deleted (VGFFK) is highly conserved in integrin alpha subunit cytoplasmic domains. Cotransfection of this deletion variant with a beta subunit truncation (beta 3 delta 724) and a triple mutation at 758-760 (TTT to AAA) of beta 2 abolishes adhesion without changing the affinity state. A single mutation (TTT to TAT) reduces adhesion by half without affinity change. Scanning electron microscopy reveals impaired spreading of these truncated/mutated chimeras. Immunofluorescence microscopy demonstrates a correlation between impaired adhesion and a decrease in the ability to form focal adhesions and to organize the cytoskeleton into stress fibers. These results describe the integrin/cytoskeleton interaction, the organization of the cytoskeleton, and cell spreading as postreceptor events modulating alpha L beta 2 cytoplasmic domain mediated cell adhesion. Furthermore, we demonstrate that the cytoplasmic domain of the beta 2 subunit, and within it the TTT region, are required for these postreceptor events. Additionally, we present a new approach, using deletion variants to lock integrins in a high affinity state without interfering with the investigated integrin/cytoskeleton interaction. This approach may be generally useful to investigate the role of postreceptor events in integrin-mediated cell adhesion and migration.

Amino Acid Sequence↗
PubMed2000

Differential expression of p73 splice variants and protein in benign and malignant ovarian tumours.

The p73 gene encodes a protein with substantial structural and functional similarities to the tumour-suppressor p53. Alternative splicing of p73 mRNA leads to expression of 6 known RNA species and proteins (alpha, beta, gamma, delta, epsilon, zeta). We analysed the expression of these splice variants in ovarian adenocarcinoma by RT-PCR followed by detection of amplicons with the Southern technique and by immunoblot in 32 malignant and benign epithelial ovarian tumour specimens and 3 ovarian adenocarcinoma cell lines (A2780, 2008, OVCAR-3). p73alpha mRNA was expressed in all 17 ovarian cancer specimens, and 14 of 17 expressed at least 3 splice variants. In contrast, a different expression pattern was present in the ovarian adenomas: p73alpha was detected in 6 of 12 benign tumours, and only 1 adenoma expressed 3 splice variants. p73 protein was expressed in 9 of 16 ovarian cancer specimens, in all cell lines and in 1 of 3 borderline tumours. In contrast, none of 9 ovarian adenomas expressed detectable amounts of p73 protein. Expression of p73 mRNA and protein was not correlated with FIGO stage and histological grade, but we observed a significant correlation with over-expression of p53 protein. In summary, epithelial ovarian cancers express a more complex p73 isoform pattern and higher levels of p73 mRNA and protein than ovarian adenomas.

Adenocarcinoma↗
PubMed2003

Organization and evolution of multifunctional Ca(2+)/CaM-dependent protein kinase genes.

The "multi-functional" Ca(2+) and calmodulin-dependent protein kinase, type II (CaMK-II) is an evolutionarily conserved protein. It has been found as a single gene in the horseshoe crab, marine sponge, sea urchin, nematode, and fruit fly, whereas most vertebrates possess four genes (alpha, beta, gamma, and delta). Species from fruit flies to humans encode alternative splice variants which are differentially targeted to phosphorylate diverse downstream targets of Ca(2+) signaling. By comparing known CaMK-II protein and nucleotide sequences, we have now provided evidence for the evolutionary relatedness of CaMK-IIs. Parsimony analyses unambiguously indicate that the four vertebrate CaMK-II genes arose via repeated duplications. Nucleotide phylogenies show consistent but moderate support for the placement of the vertebrate delta CaMK-II as the earliest diverging vertebrate gene. delta CaMK-II is the only gene with both central and C-terminal variable domains and has three to four times more intronic sequence than the other three genes. beta and gamma CaMK-II genes show strong sequence similarity and have comparable exon and intron organization and utilization. alpha CaMK-II is absent from amphibians (Xenopus laevis) and has the most restricted tissue specificity in mammals, whereas beta, gamma, and delta CaMK-IIs are expressed in most tissues. All 38 known mammalian CaMK-II splice variants were compiled with their tissue specificity and exon usage. Some of these variants use alternative 5' and 3' donors within a single exon as well as alternative promoters. These findings serve as an important benchmark for future phylogenetic, developmental, or biochemical studies on this important, conserved, and highly regulated gene family.

Amino Acid Sequence↗
PubMed1991

[A screening survey of variant glycophorins on the erythrocyte membranes among healthy chinese young people].

A screening survey of variant glycophorins (GP) on the erythrocyte membranes was conducted among 114 healthy Chinese young people who belong to several different ethnic groups by immunoblotting techniques. The majority (70) were of the Han ethnic group; 24 out of 41 Hainanese belonged to the Li ethnic group. Ten subjects showed variant GP profiles, with an incidence of 8.8%. The frequency of variants was significantly higher in the Li ethnic group (25%) than in the Han ethnic group (5.7%); none was seen among the other ethnic minorities. Probing with four antibodies specific to different regions of GP molecules revealed three distinct types of GP among the variant individuals. Type I observed in four individuals was reminiscent of that exhibited by Sta glycophorin. Among them, in one subject the Sta blood group phenotype was confirmed by serological typing. The absence of delta GP was noted in another subject carrying type II variant GP. Patterns in the remaining five individuals (type III) could not be correlated with known GP profiles of variants of MNSs blood system. This study suggests that there may be a high incidence of GP variants among certain ethnic groups in China. The sialic acid contents of erythrocyte membranes in seven GP propositi were significantly higher than those of the control.

Adolescent↗
PubMed1995

Sequence and diversity of rabbit T-cell receptor gamma chain genes.

The nucleotide sequences of one constant (C), six variable (V), and two joining (J) gene segments coding for the rabbit T-cell receptor gamma chain (Tcrg) were determined by directly sequencing fragments amplified by the cassette-ligation mediated polymerase chain reaction. The Tcrg-C gene segment did not encode a cysteine residue for connection to the Tcr delta chain in the connecting region, and two variant forms of the Tcrg-C gene segment were generated by alternative splicing, like the human Tcrg-C2 gene. Five of six rabbit Tcrg-V gene segments belonged to the same family and displayed similarity to five productive human Tcrg-V1 family genes as well as the mouse Tcrg-V5 gene. The remaining rabbit Tcrg-V gene segment displayed similarity to the human Tcrg-V3 gene. Both rabbit Tcrg-J gene segments displayed similarity to the human Tcrg-J2.1 and 2.3, respectively. These findings suggested that the genomic organization of rabbit Tcrg genes is more similar to that of human than of mouse Tcrg genes.

Amino Acid Sequence↗
PubMed2003

A comparison of the properties of a Bcl-xL variant to the wild-type anti-apoptosis inhibitor in mammalian cell cultures.

The overexpression of bcl-2 and its homologues is a widely used strategy to inhibit apoptosis in mammalian cell culture systems. In this study, we have evaluated the Bcl-2 homologue, Bcl-x(L) and compared its effectiveness to a Bcl-x(L) mutant lacking most of the non-conserved unstructured loop domain, Bcl-x(L)Delta (deletion of amino acids 26 through 83). The cell line, Chinese hamster ovary (CHO), was genetically modified to express constitutively Bcl-x(L) or the Bcl-x(L) variant and subjected to model apoptotic insults including Sindbis virus (SV) infection, gradual serum withdrawal, and serum deprivation. When cells were engineered to overexpress Bcl-x(L)Delta, cell death due to the SV was inhibited, and Bcl-x(L)Delta provided comparable protection to the wild-type Bcl-x(L) even though expression levels were much lower for the mutant. Furthermore, the cells expressing Bcl-x(L)Delta continued to proliferate following infection while CHO-bcl-x(L) ceased proliferation immediately following infection. As a result, total production of a heterologous protein encoded on the SV was highest in cell lines expressing Bcl-x(L)Delta. Cells expressing the variant Bcl-x(L) also continued to proliferate and showed increased viable cell numbers following gradual serum withdrawal. In contrast, wild-type Bcl-x(L) expressing CHO cells were found to arrest growth but maintain viability following serum withdrawal. Interestingly, CHO cells expressing Bcl-x(L)Delta were also able to recover and return to rapid growth rates much faster than either the wild-type CHO-bcl-x(L) or CHO following the replenishment of fresh complete medium containing 10% FBS. Confocal imaging of yellow fluorescent protein (YFP) fused to the N terminus of Bcl-x(L) and Bcl-x(L)Delta indicated dense aggregates of the Bcl-x(L)Delta while the wild-type protein was distributed throughout the cell in a manner resembling transmembrane localization. As an alternative to complete removal of the loop domain, Bcl-x(L) variants were created in which aspartate residues containing potential caspase recognition sites within the loop domain of Bcl-x(L) were removed. Cell populations expressing various Bcl-x(L)-Asp mutants were exposed to an apoptotic spent medium stimulus, and the cells expressing these Bcl-x(L) variants provided increased viabilities as compared to cells containing wild-type Bcl-x(L) protein. These studies indicate that modification of anti-apoptotic genes can affect multiple cellular properties including response to apoptotic stimuli and cell growth. This knowledge can be valuable in the design of improved apoptosis inhibitors for biotechnology applications.

Alphavirus Infections↗
PubMed1986

Occurrence of normal circulating proalbumin in a hemophilic A patient after acute hepatitis related to the delta virus.

Circulating proalbumin in humans has been described in two distinct events: genetic variants of proalbumin related to mutations at the cleavage site, and normal proalbumin related to an abnormal cleaving enzyme system. We report a case of acquired proalbuminemia that appeared after an acute episode of hepatitis related to the delta agent, in a chronic carrier of hepatitis B virus. This component, not present in normal plasma, was identified as proalbumin by immunological methods. It was indistinguishable from the molecule normally present in hepatocytes as judged by electrophoretic mobility, limited susceptibility to tryptic digestion, and its inability to bind labeled Ni. We suggest that this release of proalbumin is related to the concurrent presence of both hepatitis B and delta virus in some of the infected hepatocytes.

Adult↗
PubMed1991

A deletion mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) locus: Delta I507.

During the development of an amplification refractory mutation system (ARMS) assay for the detection of the Delta F508 mutation and corresponding normal locus in cystic fibrosis we discovered a family in which a further variant of the sequence exists. PCR amplification and direct sequencing of a region of exon 10 of the CFTR locus indicated the deletion of the three base pairs encoding isoleucine or isoleucine, or possibly the presence of a single base substitution in conjunction with the Delta F508 mutation. The resulting protein has a deletion of an isoleucine residue at position 507 as opposed to the previously described deletion of phenylalanine at position 508. We conclude that the loss of an isoleucine residue at position 507 (Delta I507) is another defective variant of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene product.

Amino Acid Sequence↗
PubMed1980

Genetic linkage between Bf S0.7 (Bf S1) and HLA-Bw50.

Two hundred and one unrelated French Basque individuals were studied for HLA-A, B, C, DR and Bf polymorphisms. The results show that the Bf S0.7 (Bf S1) variant, which is known to be associated with HLA-Bw21, presents a highly significant linkage disequilibrium with a subtypic specificity, i.e., Bw50 (delta = 0.0123, delta S=100%, P less than 10(-8)). As neither Bf S0.7 variant nor Bw50 antigen is found in Mongoloid populations, it is suggested that in evolutionary terms, the Bf S0.7 mutation is a more recent event than the HLA-Bw21 split.

Alleles↗
PubMed2007

A novel beta-delta globin gene fusion, anti-Lepore Hong Kong, leads to overexpression of delta globin chain and a mild thalassaemia intermedia phenotype when co-inherited with beta(0)-thalassaemia.

Anti-Lepore haemoglobins (Hb) are rare betadelta fusion variants that arise from non-homologous crossover during meiosis, resulting in a delta-betadelta-beta configuration. A novel anti-Lepore mutation (anti-Lepore Hong Kong) was found in two Chinese families with raised Hb A(2). Direct sequencing revealed a crossover within a 54-bp region spanning the junction of cap site (CAP) and exon 1, which predicted the production of normal delta-globin. Determination of alpha/beta-mRNA ratios by quantitative real-time polymerase chain reaction demonstrated downregulation of the beta gene in cis due to the interposed betadelta fusion gene. Although heterozygotes have normal red cell indices and are clinically silent, compound heterozygotes with beta(0) mutation in trans produce a mild thalassaemia intermedia phenotype with a markedly raised Hb A(2) level that may mimic clinically mild Hb E-beta(+)-thalassaemia. Awareness of the presence of anti-Lepore Hong Kong will help to resolve diagnostic problems in regions with significant prevalence of globin disorders.

Adult↗
PubMed2000

The role of dynamic palmitoylation in Ca2+ channel inactivation.

N- and P/Q-type Ca(2+) channels regulate a number of critical physiological processes including synaptic transmission and hormone secretion. These Ca(2+) channels are multisubunit proteins, consisting of a pore-forming alpha(1), and accessory beta and alpha(2)delta subunits each encoded by multiple genes and splice variants. beta subunits alter current amplitude and kinetics. The beta(2a) subunit is associated with slowed inactivation, an effect that requires the palmitoylation of two N-terminal cysteine residues in beta(2a). In the current manuscript, we studied steady state inactivation properties of native N- and P/Q-type Ca(2+) channels and recombinant N-type Ca(2+) channels. When bovine alpha(1B) and beta(2a) and human alpha(2)delta were coexpressed in tsA 201 cells, we observed significant variations in inactivation; some cells exhibited virtually no inactivation as the holding potential was altered whereas others exhibited significant inactivation. A similar variability in inactivation was observed in native channels from bovine chromaffin cells. In individual chromaffin cells, the amount of inactivation exhibited by N-type channels was correlated with the inactivation of P/Q-type channels, suggesting a shared mechanism. Our results with recombinant channels with known beta subunit composition indicated that inactivation could be dynamically regulated, possibly by alterations in beta subunit palmitoylation. Tunicamycin, which inhibits palmitoylation, increased steady-state inactivation of Ca(2+) channels in chromaffin cells. Cerulenin, another drug that inhibits palmitoylation, also increased inactivation. Tunicamycin produced a similar effect on recombinant N-type Ca(2+) channels containing beta(2a) but not beta(2b) or beta(2a) subunits mutated to be palmitoylation deficient. Our results suggest that Ca(2+) channels containing beta(2a) subunits may be regulated by dynamic palmitoylation.

Animals↗
PubMed1995

Identification of two novel amino acid polymorphisms in beta-cell/liver (GLUT2) glucose transporter in Japanese subjects.

The beta-cell/liver glucose transporter (GLUT2) gene was screened for mutations using single-strand conformation polymorphism analysis (SSCP) in 30 Japanese subjects with non-insulin dependent diabetes mellitus (NIDDM). Analysis of all exons and adjacent intron regions identified six SSCP polymorphisms, three of which resulted in amino acid substitutions: V101I, T110I and G519E. The V101I and G519E, substitutions represent new polymorphisms in this gene. The six polymorphisms were observed in both NIDDM and control groups and there were no significant differences in allele frequencies between groups. A portion of the insulin receptor substrate 1 gene in 30 NIDDM subjects and in normal control subjects was also screened for mutations. Two SSCP variants that change the sequence of the protein, delta S686/687 (deletion of the codons for serine-686 and 687) and G972R, were identified in two different NIDDM subjects, both whom were also heterozygous for the V101I polymorphisms in GLUT2. The GLUT2 and IRS1 amino acid polymorphisms did not show a simple pattern of co-inheritance with NIDDM in the families of these subjects suggesting that neither polymorphism is sufficient to cause NIDDM but may increase diabetes-susceptibility through their interaction with other loci and environmental factors.

Amino Acid Sequence↗