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PubMed1954

Studies on variants of poliomyelitis virus. I. Experimental segregation and properties of avirulent variants of three immunologic types.

Attempts were made to "convert" highly virulent strains of the 3 immunologic types of poliomyelitis virus (Mahoney, Y-SK, and Leon) into avirulent variants. Tests involving intracerebral, intramuscular, or oral administration of virus to cynomolgus monkeys indicated that mere propagation in cultures of kidney tissue of cynomolgus monkeys had no effect on virulence when single or small numbers of virus particles were used as seed, and harvests were delayed for 24 hours or more after the appearance of cytopathogenic change. On the other hand, passages at 24 hour intervals with large inocula (10(5) to 10(6) TCD(60)) produced culture fluids with diminished virulence and unusual patterns of response in cynomolgus monkeys. Purification of such culture fluids by the terminal dilution technique yielded modified strains which proved to be avirulent after administration by the intracerebral, intramuscular, or oral routes in cynomolgus monkeys. Neither paralysis nor CNS lesions were found in any of more than 80 monkeys inoculated intracerebrally with various amounts of virus. However, focal neuronal lesions were found in the spinal cord of 3 of 48 monkeys inoculated intramuscularly with various amounts of the Mahoney variant, in 2 of 20 receiving the Y-SK variant, though in none of 40 inoculated with various amounts of the Leon variant. Virus recovered from the spinal cord of one of the monkeys in the Mahoney group produced no paralysis on intracerebral passage in monkeys. It is assumed that all 3 modified viruses possess a limited capacity to affect lower motor neurones of cynomolgus monkeys when these are directly exposed to them by accidental intraneural or traumatic intracerebral injection. On propagation in cynomolgus kidney cultures the modified viruses reached titers of approximately 10(7) TCD(50) per ml., as measured by cytopathogenic activity on renal epithelial cells in vitro, yet produced no perceptible pathologic changes in the muscles, kidneys, testes, ovaries, heart, pancreas, adrenals, liver, or spleen of cynomolgus monkeys inoculated intramuscularly. The modified viruses were immunogenic after intramuscular injection, but a large proportion of cynomolgus monkeys failed to develop antibody after small doses, indicating that in this host the experimentally produced variants multiplied less readily in non-nervous tissue than the virulent parent strains. Tests with the Type 1 virus showed that the orally administered avirulent variant can induce the formation of antibody and bring about resistance to the occurrence of paralysis such as results from ingestion of the virulent, parent strain. The Types 1 and 2 modified viruses are paralytogenic in mice after direct spinal inoculation whereas the Type 3 virus is not. The Type 1 virus became paralytogenic for mice when it lost its virulence for cynomolgus monkeys by the indicated routes. The Type 2 virus lost its virulence for mice by the intracerebral but not intraspinal routes when it was still fully virulent for cynomolgus monkeys, and retained its paralytogenic activity in intraspinally inoculated mice after it had lost its virulence for cynomolgus monkeys by the indicated routes. The parent Type 3 virus was paralytogenic in intraspinally inoculated mice when it was still fully virulent for cynomolgus monkeys, but this property disappeared in the modified virus when it became avirulent for monkeys.

Animals↗

PubMed2001

Histone H2A variants and the inactive X chromosome: identification of a second macroH2A variant.

MacroH2A1 is an unusual variant of the core histone H2A which is enriched in chromatin on the inactive X chromosome of female mammals. The N-terminal third of the protein shares 65% amino acid identity with core histone H2A, while the remaining two-thirds of the protein are novel, with a small stretch of basic amino acids and a putative leucine zipper motif. We have now cloned a second macroH2A gene, encoding macroH2A2 which shares 80% amino acid identity with macroH2A1. Despite mapping to different chromosomes, the genomic organization of the macroH2A2 and macroH2A1 genes are nearly identical. The leucine zipper motif of macroH2A1 is not conserved in macroH2A2. Like macroH2A1, macroH2A2 forms a Macro Chromatin Body in the nuclei of female cells which is coincident with an X chromosome and co-localizes with macroH2A1. To address the distribution of other histone H2A variants in relation to macroH2A and the inactive X chromosome, we constructed a series of epitope-tagged versions of other histone H2A variants. Like the recently described H2A-Bbd (Barr body-deficient) variant, the histone variant H2A.Z was found to be deficient in chromatin on the inactive X chromosome in a significant proportion of female nuclei. This study provides further information about the nucleosomal composition of chromatin on the inactive X chromosome and indicates that a number of H2A variants are non-randomly distributed on the active and inactive X chromosomes.

Amino Acid Sequence↗

PubMed1979

Thymidine kinase enzyme variants in Physarum polycephalum. In vitro interconversion of the enzyme variants.

Isoelectric focusing of plasmodial extracts of Physarum polycephalum demonstrated the presence of several multiple enzyme variants of thymidine kinase, which appear sequentially during the nuclear division cycle. Variants (A) + (A1) are the only enzyme variants found in the late G2-phase, whereas the variants (C) + (C1) are only present at the time of mitosis and S-phase (1, 2). Evidence is presented that multiple forms of thymidine kinase (A) + (A1) with high pI arise by dephosphorylation of a primary translation product with low pI (C and/or C1). The thymidine kinase fractions (A) + (A1) and (C) + (C1) + (c1) were separated and partially purified by DEAE-cellulose chromatography. The enzyme variants (C) + (C1) are converted in vitro by an endogenous enzymatic factor as well as by bacterial alkaline phosphatase into the variants (A) + (A1).

4-Nitrophenylphosphatase↗

PubMed2005

Understanding the role of Leu22 variants in methotrexate resistance: comparison of wild-type and Leu22Arg variant mouse and human dihydrofolate reductase ternary crystal complexes with methotrexate and NADPH.

Structural data are reported to 2.5 A resolution for the first full analysis of the methotrexate-resistant Leu22Arg (L22R) variant of mouse dihydrofolate reductase (mDHFR) crystallized as a ternary complex with methotrexate (MTX) and the cofactor NADPH. These results are compared with the MTX and NADPH ternary complexes of L22R human DHFR (hDHFR) and those of mouse and human wild-type DHFR enzymes. The conformation of mDHFR Arg22 is such that it makes hydrogen-bonding contacts with Asp21, Trp24 and a structural water molecule, observations which were not made in the L22R hDHFR ternary complex. These data show that there is little difference between the structures of the wild type and L22R variant for either mouse or human DHFR; however, there are significant differences between the species. Comparison of these structures reveals that the active site of mDHFR is larger than that in the hDHFR structure. In mDHFR, the position of MTX is shifted 0.6 A toward helix C (residues 59-65), which in turn is shifted 1.2 A away from the active site relative to that observed in the hDHFR ternary complexes. In the L22R variant mDHFR structure, MTX makes shorter contacts to the conserved residues Ile7, Val115 and Tyr121 than in the L22R variant human DHFR structure. These contacts are comparable in both wild-type enzymes. The unexpected results from this comparison of the mouse and human DHFR complexes bound with the same ligand and cofactor illustrate the importance of detailed study of several species of enzyme, even when there is a high sequence homology between them. These data suggest that the differences in binding interactions of the L22R variant are in agreement with the weaker binding affinity for MTX in the variant enzymes; the larger size of the binding site in mDHFR supports the observation that the binding affinity of MTX for L22R mDHFR is significantly weaker than that of the L22R hDHFR enzyme.

Amino Acid Sequence↗

PubMed2005

Histiocytoid breast carcinoma: solid variant of invasive lobular carcinoma with decreased expression of both E-cadherin and CD44 epithelial variant.

Histiocytoid breast carcinoma (HBC) is a rare type of breast carcinoma with morphologic characteristics resembling those of histiocytes. Described herein are cytological and histological findings in a case of HBC. Fine-needle aspiration cytology revealed numerous loosely cohesive tumor cells with abundant foamy to granular cytoplasm and bland-appearing nuclei. The resected tumor exhibited a solid growth pattern instead of classic invasive lobular patterns observed in most reported cases of HBC. However, distinct intracytoplasmic lumina and Pagetoid extension to ducts suggested that this tumor was a variant of invasive lobular carcinoma. To determine the cause of the loose cellular cohesiveness of this HBC, its expression of the epithelium-related cell adhesion molecules E-cadherin and CD44v8-10 (CD44 epithelial variant) was examined. Immunohistochemically, E-cadherin was not detected, similar to most lobular carcinomas. Furthermore, competitive reverse transcription-polymerase chain reaction (RT-PCR) analyses among alternatively spliced variants of CD44 revealed that the ratio of expression of CD44v8-10 to that of CD44v10 (dominant variant in leukocytes) was lower than that for the reference breast carcinoma samples. It is concluded that the present case of HBC was a solid variant of invasive lobular carcinoma exhibiting foamy to granular cytoplasmic change. Decreased expression of both E-cadherin and CD44 epithelial variant may be responsible for the loose cellular cohesiveness observed in HBC.

Aged↗

PubMed2003

The new variant of the Creutzfeldt-Jakob disease accounts for no relative increase of the Creutzfeldt-Jakob disease mortality rate in the United Kingdom; this fits ill with the new variant being the consequence of consumption of food infected with the agent of Bovine Spongiform Encephalopathy.

BACKGROUND: A new variant of Creutzfeldt-Jakob disease was described in the United Kingdom. It is often claimed that it is caused by consumption of food infected with the agent of bovine spongiform encephalopathy. However, this remains open to question because the number of cases of the variant is, at the present time, less than would be expected from a major food-borne source. DISCUSSION: The EUROCJD cooperative study presents currently available epidemiological data of Creutzfeldt-Jakob disease and its new variant, for nine European countries plus Australia and Canada. Unexpectedly, for the United Kingdom where all but a few cases of the new variant have been reported, these cases have to be included in the incidence curve of the sporadic forms of the disease in order to obtain the best fit with the median curve from all the countries. This variant could be merely a rare clinical phenotype within the sporadic disease. The published clinical and experimental data which suggest that it is linked with bovine spongiform encephalopathy, lead us to propose that this link could be a common etiological origin other than consumption of bovine infected food. In any case, public health recommendations hold and further investigation is required. SUMMARY: The lack of a relative increase of the Creutzfeldt-Jakob-disease mortality rate in the United Kingdom, does not fit well with the new variant being the consequence of consumption of food infected with the agent of bovine spongiform encephalopthy.

Animals↗

PubMed1996

Thyroxine binding to transthyretin (TTR) variants--two variants (TTR Pro 55 and TTR Met 111) with a particularly low binding affinity.

Thyroxine (T4) binding is a well-characterized function of transthyretin (TTR) and has been used to assess structural alterations of TTR variants. Most TTR variants deposit as amyloid fibrils originating different forms of hereditary amyloidosis. It has been hypothesized that amino acid substitutions in the TTR variants induce structural alterations that may be responsible for the amyloidogenicity of the mutant proteins. To test for structural alterations in TTR, we studied T4 binding to TTR variants both in whole serum and in isolated form obtained from heterozygotic carriers of amyloidogenic and non-amyloidogenic variants and compared the binding with the corresponding homozygotic recombinant variants. The results obtained indicated a normal T4 binding affinity for heterozygotic TTR Ala 49, TTR Leu 68, TTR Ala 71 and TTR Arg 102. Concerning TTR Pro 55 and TTR Met 111, we found a consistent decrease in binding affinity. These results were more pronounced for the equivalent recombinant proteins. Recombinant TTR Pro 55 did not show specific binding to T4 and recombinant TTR Met 111 presented very low binding affinity. Neither TTR Pro 55 nor TTR Met 111 are localized in the T4 binding channel, thus structural alterations induced by these mutations should be transmitted to the binding channel interfering with T4 binding. The results now reported, together with ongoing structural data by X-ray analyses on mutants Pro 55 and Met 111 and future binding studies with other ligands, will contribute to the elucidation of the structure and function of TTR, particularly in thyroid hormone metabolism.

Amino Acid Sequence↗

PubMed2026

Preimplantation genetic testing for concurrent Meckel Syndrome and hereditary breast cancer in a Chinese family harboring a novel NPHP3 pathogenic variant and a canonical BRCA2 frameshift variant.

Meckel syndrome (MKS) is a lethal autosomal recessive disease with high phenotypic and genetic heterogeneity. Defects in NPHP3 cause MKS type 7. Herein, we report a case of a Chinese family with a newborn male proband presenting with occipital encephalocele and polycystic kidneys. Whole-exome sequencing was performed on genomic DNA extracted from peripheral blood. Potential variants were assessed for pathogenicity. Two compound heterozygous variants of NPHP3 (c. 950T>C, p. Phe317Ser, and c.2694-2_2694-1delAG) were identified, which were inherited from both parents, with c.950T>C representing a novel variant. Two BRCA2 variants (c.5576_5579delTTAA, p. Ile1859Lysfs*3, and c.9357A>C,p. Leu 3119 Phe) were identified, which were inherited from the father. After the proband was diagnosed with MKS7, the couple chose preimplantation genetic testing for monogenic disorders (PGT-M) to simultaneously prevent the transmission of NPHP3 and BRCA2 pathogenic variants, leading to a successful pregnancy. Our study expands the NPHP3 variant spectrum and contributes to the molecular diagnosis and genetic counseling of MKS. This case indicates that PGT-M is a viable option for NPHP3-related MKS and BRCA-positive patients to avoid transmission while maintaining their families. Successful application of PGT-M provides a potential approach for treating other monogenic diseases.

Journal Article↗

PubMed1989

A genetic electrophoretic variant of high-sulfur hair proteins for forensic hair comparisons. I. Characterization of variant high-sulfur proteins of human hair.

In a survey of the proteins from human hair, a genetic electrophoretic variant has been observed in the high-sulfur protein region. S-carboxymethylated proteins were examined by 15% polyacrylamide gel electrophoresis at pH 8.9. Out of 150 unrelated samples of Japanese head hairs analyzed, 107 showed 6 major high-sulfur protein bands (normal) and the remaining 43 samples showed an additional high-sulfur protein band (variant). Of 21 Caucasian samples analyzed only one variant sample was found. Characterization of the proteins by two-dimensional electrophoresis evidenced a variant protein spot which showed an apparent molecular weight of 30 k Da. Isoelectric points of the high-sulfur proteins ranged from 3.25-3.55 and that of variant protein band from 3.3-3.4. Family studies of 21 matings resulting in 49 children indicated that this variant was inherited in an autosomal fashion.

Electrophoresis, Polyacrylamide Gel↗

PubMed1980

Glucose-6-phosphate dehydrogenase variants: reexamination of G6PD Chicago and Cornell and a new variant (G6PD Pea Ridge) resembling G6PD Chicago.

Two large and unrelated families were investigated for hereditary nonspherocytic hemolytic anemia associated with deficiency of erythrocyte glucose-6-phosphate dehydrogenase (G6PD). In both families, the kinetic and electrophoretic features of the G6PD variants resembled those of G6PD Chicago. Further investigation revealed that members of one of these families previously had been characterized as having the G6PD variants Chicago and Cornell. However, it is clear that each of these terms has been applied to the same variant in this single large kindred. In the second family, we describe a newly identified variant with unique characteristics, which we have designated G6PD Pea Ridge. G6PD Pea Ridge resembles G6PD Chicago but differs in electrophoretic mobility and in a few kinetic parameters. It exhibits an unusually high Ki for NADPH and thus appears to be insensitive to product inhibition. As other cases previously considered to be the Chicago variant become more fully characterized, this probably will be shown to be a heterogeneous group of variants.

Adult↗

PubMed1996

Increased basal tone and hyperresponsiveness to acetylcholine and ergonovine in spasm related coronary arteries in patients with variant angina--basal coronary artery tone in patients with variant angina.

In patients with variant angina, previous data have been inconclusive as to whether basal coronary artery tone is elevated at the spastic and non-spastic sites. Thus, the purpose of this study was to assess the basal coronary artery tone and the responsiveness to acetylcholine (Ach) and ergonovine (Erg) in patients with variant angina. We compared the basal coronary artery tone and the constrictive responses to Ach and Erg between 31 patients (Group 1) with variant angina in whom spasm was provoked by the low doses of Ach (intracoronary 20 micrograms) or Erg(intravenous 50 micrograms) and 35 patients (Group 2) provoked by higher doses of Ach (intracoronary 100 micrograms) or Erg (intravenous cumulative dose of 350 micrograms), and 26 control subjects. Patients with variant angina in whom spasm was provoked by low doses of Ach or Erg, had a higher incidence of mixed disease, multi-vessel spasm and higher disease activity. The basal coronary artery tone at the spastic and nonspastic sites of spasm related artery was significantly more elevated in Group 1 than that in Group 2 (44 +/- 17 vs 14 +/- 11% and 26 +/- 14 vs 16 +/- 10% respectively, P < 0.05), but not in the nonspasm related artery, The magnitudes of vasoconstrictive responses to Ach and Erg at the nonspastic sites were also greater in Group 1 than those in Group 2 and the control groups (Ach; 40 +/- 20 vs 26 +/- 11, 27 +/- 12%: Erg; 37 +/- 18 vs 12 +/- 8, 13 +/- 10% respectively, P < 0.05). However, the basal coronary artery tone was not elevated at the spastic and nonspastic sites in Group 2 compared to the in control subjects. These findings suggest that the basal coronary artery tone is increased in patients with variant angina with higher disease activity at the spastic sites and nonspastic sites of the spasm-related artery, and this may be related to the occurrence of coronary artery spasm.

Acetylcholine↗

PubMed2006

Selective assembly of fibulin-1 splice variants reveals distinct extracellular matrix networks and novel functions for perlecan/UNC-52 splice variants.

Fibulin-1C and fibulin-1D splice variants have been conserved throughout metazoan evolution and have distinct functions in Caenorhabditis elegans development. Both splice variants are required for the assembly of hemidesmosome-mediated mechanosensory neuron and uterine attachments, although the molecular associations that underlie their distinct functions at these locations are not known. Here, we show that the assembly of fibulin-1C and fibulin-1D splice variants at these anchorages is dependent upon distinct components of the extracellular matrix (ECM): Fibulin-1D assembly at uterine and mechanosensory neurons attachments is dependent upon a perlecan/ UNC-52 splice variant that includes alternately spliced IG8-IG10, whereas the assembly of fibulin-1C at mechanosensory neuron attachments is dependent upon laminin/ EPI-1. These data not only indicate that fibulin-1C and fibulin-1D are components of distinct networks of ECM but also demonstrates a novel function for a major class of perlecan splice variants found in C. elegans and mouse. In addition, we demonstrate that overexpression of another ECM protein, collagen XVIII, can suppress gonad morphogenesis defects associated with loss of fibulin-1C, suggesting that some genetic defects that result in a weakened basement membrane can be compensated by overexpression of genes for ECM components that stabilize basement membranes.

Alternative Splicing↗

PubMed1977

Genetic variants of cytoplasmic malate dehydrogenase (MDH:EC:1.1.1.37) in populations in England and the Indian subcontinent. A new S-MDH variant.

A new variant malate dehydrogenase is described, designated S-MDHInd to indicate its discovery in the Indian subcontinent pending full comparison with all other variants. It occurred during a survey of the incidence of variant S-MDH phenotypes in 4149 subjects in north-east England and 1494 subjects from several populations in the Indian region. The variants previously thought to be restricted to the New Guinea region and to African populations occurred in three English subjects in northeast England. The incidence of variant S-MDH phenotypes in other populations is summarised.

Bangladesh↗

PubMed1982

A polymorphic variant of human erythrocyte carbonic anhydrase I with a widespread distribution in Australian aborigines, CAI Australia-9 (8 Asp leads to Gly): purification, properties, amino acid substitution, and possible physiological significance of the variant enzyme.

Carbonic anhydrase I (EC 4.2.1.1) purified from the pooled packed red blood cells of 100 individuals typed as heterozygous for the common Australian Aboriginal carbonic anhydrase I variant CAI Australia-9 had a slightly higher specific CO2 hydratase or esterase (toward p-nitrophenyl acetate) activity than the normal component and a higher Km and Vmax using the esterase substrate. The variant enzyme was slightly more resistant to heat inactivation. The extent of inhibition of both enzymes by the specific inhibitor acetazolamide was identical, as was their immunological behavior and the lability of the active-site zinc ion. The variant enzyme was more resistant to chloride inhibition. The physiological importance of this observation is discussed in the context of a proposed adaptive advantage of the variant gene in the arid western and central regions of Australia. The amino acid substitution in the Aboriginal variant of a glycine for an aspartic acid residue has been located at residue 8 from the N terminus (i.e., 8 Asp leads to Gly), by proteolytic and partial acid hydrolyses. The possible effects of this substitution on the structure and function of the molecule are discussed.

Amino Acid Sequence↗

PubMed1989

Characterization of variant and parental-cross-protective immunity to immunogenic variants of a murine fibrosarcoma using the local adoptive transfer assay.

The purpose of this study was to characterize the lymphocyte populations responsible for rejection of immunogenic (Imm+) tumor variants, and the cross-protective immunity engendered by Imm+ variants against the weakly immunogenic parental tumor. Immunogenic clones of the weakly immunogenic methylcholanthrene-induced fibrosarcoma MCA-F have been generated using 1-methyl-3-nitro-1-nitrosoguanidine, 5-aza-2'-deoxycytidine, or ultraviolet radiation (UV-B; 280-320 nm). These clones grow progressively in immunosuppressed adult-thymectomized irradiated mice, but are rejected by immunocompetent syngeneic hosts. The parental MCA-F tumor grows progressively in both groups. Mice that have rejected a challenge of 1 x 10(5) Imm+ cells show an anamnestic immune response against both the Imm+ clone and the parental MCA-F tumor. Using the local adoptive transfer assay and depletion of T-cell subsets with antibody plus complement, we show that immunity induced by the Imm+ variants against the parent MCA-F was mediated by the Thy1.2+, L3T4a+ population without an apparent contribution by Lyt2.1+ cells. Although antivariant immunity was also dependent upon Thy1.2+ cells, depletion of either the L3T4a+ or the Lyt2.1+ cells failed to abolish immunity against the variant. A role for Lyt2.1+ T lymphocytes in antivariant immunity, but not antiparent immunity, was supported by the results of cytotoxic T lymphocyte (CTL) assays. Following immunization with high numbers (1 x 10(5) to 5 x 10(5) of viable Imm+ cells, antivariant, but not antiparent CTL activity was detected in mixed lymphocyte tumor cell cultures. Immunization with lower numbers (3 x 10(4] of viable Imm+ or with high numbers of mitomycin-C-treated Imm+ engenders only antivariant immunity without parental cross-protection. Under these conditions lymphocytes mediating immunity against the variant in the local adoptive transfer assay were exclusively of the Thy1.2+, L3T4a+ phenotype, with no contribution from the Lyt2.1+ cells. Identical results were obtained for Imm+ clones of MCA-F induced by methylnitronitrosoguanidine, 5-azadeoxycytidine, and UV-B, suggesting that the nature of the antitumor immunity engendered by Imm+ is not significantly affected by the agent used. Furthermore, these results demonstrate that the cross-reactivity and cellular effectors of antitumor immunity in this system are influenced by the immunizing dose of Imm+ cells: the predominant effectors of both antivariant and parental-cross-reactive immunity were of the CD4+ T cell subclass, with a CD8+ cytotoxic population contributing to antivariant immunity only after high-dose immunization.

Animals↗

PubMed1991

Recombinant gp135 envelope glycoproteins of caprine arthritis-encephalitis lentivirus variants inhibit homologous and heterologous variant-specific neutralizing antibodies.

The envelope (env) genes of two antigenic variants of caprine arthritis-encephalitis virus (CAEV), defined by serum neutralization, were expressed in vaccinia virus. Recombinant gp135 envelope glycoprotein competitively inhibited neutralizing activity of serum from CAEV-infected goats, indicating gp135 is a dominant target antigen of CAEV neutralizing antibody. In addition, type-specific neutralizing activity of goat serum directed against one variant was inhibited by both homologous and heterologous variant recombinant gp135. Hence, a CAEV variant env gene encodes type-specific neutralization epitopes of both variants. The results indicate that antigenic variation of CAEV involves env gene mutations encoding amino acid differences outside conserved neutralization epitopes affecting epitope exposure to the immune system.

Animals↗

PubMed2003

Interaction effect of Serine447Stop variant of the lipoprotein lipase gene and C-514T variant of the hepatic lipase gene on serum triglyceride levels in young adults: the Bogalusa Heart Study.

The opposing effects of lipoprotein lipase (LPL) Serin447Stop (S447X) polymorphism and hepatic lipase (HL) C-514T polymorphism on serum triglyceride (TG) levels have been known. However, little is known about the interaction effect of these 2 functional gene variants on serum triglyceride levels. This aspect was examined in a community-based sample of 902 whites and 389 blacks aged 18 to 41 years, using a repeated measures analysis in a mixed model. The frequency of the LPL X447 allele was higher in whites than blacks (16% v 11%, P <.05); whereas the frequency of HL T-514 allele was higher in blacks than whites (77% v 40%, P <.001). The combined genotype distribution was also different between whites and blacks (P <.001). Although the frequency of carriers of both variants was similar in whites and blacks (7% v 8%), more whites carried the LPL X447 allele only (9% v 3%), and more blacks carried the HL T-514 allele only (70% v 33%). Mean levels of TG adjusted for age, sex, and body mass index (BMI) in carriers versus noncarriers of the LPL X447 allele were lower by 13.5% (P <.0001) in whites, 15.8% (P <.01) in blacks and 16.0% (P <.0001) in the total sample. No such phenotypic effect was noted with respect to HL T-514 allele either in blacks or whites, although the mean level in carriers was marginally (P =.08) higher in the total sample. The interaction effect of LPL and HL variants on TG levels was significant in the total sample (P =.016) and marginal in whites (P =.079). In the total sample, the decrease of TG in carriers versus noncarriers of the LPL X447 was 1.8-fold greater in carriers versus noncarriers of the HL T-514 allele (13.6 mg/dL v 7.4 mg/dL, P =.016). Whites tended to show a similar trend (16.8 mg/dL v 6.1 mg/dL, P =.079). Blacks also showed a similar, but nonsignificant, trend (10.4 mg/dL v 8.6 mg/dL, P =.45). These results by showing modulation of association between S447X variant of the LPL gene and serum TG by C-514T variant of the HL gene underscore the importance of gene-gene interactions in the assessment of genetic effects on complex traits.

Adult↗

PubMedDate not supplied

SHP-1 variant proteins are absent in motheaten mice despite presence of splice variant transcripts with open reading frames.

Motheaten mice have a mutation that causes abnormal splicing of the SHP-1 gene producing transcripts that are out of frame. Thus, motheaten mice cannot produce normal SHP-1 protein. However, we have found that the SHP-1 locus in normal mice is expressed as multiple in-frame splice variant transcripts. We report here that the motheaten SHP-1 gene is likewise expressed in multiple spliced forms, two of which are in frame. One of these two variants, which is also present in normal mice, lacks the exon containing the motheaten mutation and is therefore expected to encode an active phosphatase with only one of the two SH2 domains of SHP-1. We showed that both of these variants produce phosphatases with a higher specific activity than SHP-1, suggesting that motheatein mice are not SHP-1 null. The possibility that motheaten mice produce disregulated phosphatases offered a simple explanation for the puzzling observation that substrates of SHP-1 are hypo-phosphorylated in motheaten mice. We tested this by measuring for SHP-1 protein and activity in motheaten macrophages. However, we did not detect specific activity, and found that one of these variant proteins was unstable. These findings likewise suggest that little or no SHP-1 variant proteins exist in normal cells.

Alternative Splicing↗