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PubMed2002

A multigeneration analysis of cytochrome b(562) redox variants: evolutionary strategies for modulating redox potential revealed using a library approach.

The redox potential of cytochromes sets the energy yield possible in metabolism and is also a key determinant of the rate at which redox reactions proceed. Here, the heme protein, cytochrome b(562), is used to study the in vitro evolution of redox potential within a library of variants containing the same structural archetype, the four-helix bundle. Multisite variations in the active site of cytochrome b(562) were introduced. A library of variants containing random mutations in place of R98 and R106 was created, and the redox potentials of a statistical sampling of this library were measured. This procedure was carried out for both the low- and high-potential variants of a previously studied F61X/F65X, first-generation library [Springs, S. L., Bass, S. E., and McLendon, G. L. (2000) Biochemistry 39, 6075]. The second-generation library reported here has a range of redox potentials which is greater than 40% (160 mV) of the known accessible potential among cytochromes with identical axial ligands (but different folds) and exceeds the range exhibited phylogenetically by the cytochrome c' family which internally maintains the same axial ligation and fold. A statistical analysis of the libraries examined reveals that the redox potential of WT cyt b(562) is found at the high-potential extremum of the distribution, indicating that this protein apparently evolved to differentially stabilize the reduced protein. The 2.7 A crystal structure of F61I/F65Y/R106L (low-potential variant of the second-generation library) was solved and is compared to the wild-type structure and the 2.2 A resolution structure of the F61I/F65Y variant (low-potential variant of the first-generation library). The structures indicate that charge-dipole effects are responsible for shifting the redox equilibrium toward the oxidized state in both the F61I/F65Y and F61I/F65Y/R106L variants. Specifically, a new protein dipole is introduced into the heme microenvironment as a result of the F65Y mutation, two new internal water molecules (one in hydrogen-bonding distance of Y65) are found, and in the case of F61I/F65Y/R106L (DeltaE(m) = 158 mV vs NHE), increased solvent exposure of the heme as a result of the R106L substitution is identified.

Binding Sites↗

PubMed2002

Differences in the efficiency of reductive activation of methionine synthase and exogenous electron acceptors between the common polymorphic variants of human methionine synthase reductase.

Methionine synthase reductase (MSR) catalyzes the conversion of the inactive form of human methionine synthase to the active state of the enzyme. This reaction is of paramount physiological importance since methionine synthase is an essential enzyme that plays a key role in the methionine and folate cycles. A common polymorphism in human MSR has been identified (66A --> G) that leads to replacement of isoleucine with methionine at residue 22 and has an allele frequency of 0.5. Another polymorphism is 524C --> T, which leads to the substitution of serine 175 with leucine, but its allele frequency is not known. The I22M polymorphism is a genetic determinant for mild hyperhomocysteinemia, a risk factor for cardiovascular disease. In this study, we have examined the kinetic properties of the M22/S175 and I22/S175 and the I22/L175 and I22/S175 pairs of variants. EPR spectra of the semiquinone forms of variants I22/S175 and M22/S175 are indistinguishable and exhibit an isotropic signal at g = 2.00. In addition, the electronic absorption and reduction stoichiometries with NADPH are identical in these variants. Significantly, the variants activate methionine synthase with the same V(max); however, a 3-4-fold higher ratio of MSR to methionine synthase is required to elicit maximal activity with the M22/S175 and I22/L175 variant versus the I22/S175 enzyme. Differences are also observed between the variants in the efficacies of reduction of the artificial electron acceptors: ferricyanide, 2,6-dichloroindophenol, 3-acetylpyridine adenine dinucleotide phosphate, menadione, and the anticancer drug doxorubicin. These results reveal differences in the interactions between the natural and artificial electron acceptors and MSR variants in vitro, which are predicted to result in less efficient reductive repair of methionine synthase in vivo.

2,6-Dichloroindophenol↗

PubMed2004

Kinetic and thermodynamic characterization of the common polymorphic variants of human methionine synthase reductase.

Human methionine synthase reductase (MSR) is a protein containing both FAD and FMN, and it reactivates methionine synthase that has lost activity due to oxidation of cob(I)alamin to cob(II)alamin. In this study, anaerobic redox titrations were employed to determine the midpoint reduction potentials for the flavin cofactors in two highly prevalent polymorphic variants of MSR, I22/L175 and M22/S175. The latter is a genetic determinant of plasma homocysteine levels and has been linked to premature coronary artery disease, Down's syndrome, and neural tube defects. The I22/L175 polymorphism has been described in a homocystinuric patient. Interestingly, this polymorphism is in the extended linker region between the two flavin domains, which may mediate or facilitate interaction with methionine synthase. In MSR I22/L175, the FMN potentials are -103 mV (oxidized/semiquinone) and -175 mV (semiquinone/hydroquinone) at pH 7.0 and 25 degrees C, and the corresponding FAD potentials are -252 and -285 mV, respectively. For the M22/S175 variants, the values of the four midpoint potentials are -114 mV (FMN oxidized/semiquinone), -212 mV (FMN semiquinone/hydroquinone), -236 mV (FAD oxidized/semiquinone), and -264 mV (FAD semiquinone/hydroquinone). The midpoint potential values in the two variants are generally comparable to those originally determined for the MSR I22/S175 variant [Wolthers, K. R. (2003) Biochemistry 42, 3911-3920], with relatively minor variations in the different redox couples. In each case, blue neutral flavin semiquinone species are stabilized on both flavins, and are characterized by a broad absorption band in the long wavelength region. In addition, stopped-flow absorption and fluorescence spectroscopy were used to study the pre-steady state reduction kinetics by NADPH of the two polymorphic variants. The reversible kinetic model proposed for wild-type MSR was validated for the I22/L175 and M22/S175 variants. Thus, the biochemical penalties associated with these polymorphisms, which result in less effective methionine synthase activation, do not appear to result from differences in their reduction kinetics. It is likely that differences in their relative affinities for the redox partner, methionine synthase, underlie the differences in the relative efficiencies of reductive activation exhibited by the variants.

Amino Acid Substitution↗

PubMed1996

Subtilisin BPN' variants: increased hydrolytic activity on surface-bound substrates via decreased surface activity.

Site-directed mutagenesis and random mutagenesis were used to produce variants of subtilisin BPN' (Bacillus amyloliquefaciens) protease with variable surface adsorption properties. Protease adsorption and peptide hydrolysis rate were measured for these variants using a model substrate consisting of a peptide covalently bound to a surface. While most variants adsorb at a level very similar to that of native BPN', several variants were identified which adsorb either more or less. For surface-bound substrates we report a linear dependence between the concentration of adsorbed protease enzyme and substrate hydrolysis, similar to the linear dependence between enzyme solution concentration and hydrolysis of soluble substrates. On the basis of this knowledge we hypothesized that variants designed to adsorb at a higher level on a surface-bound peptide substrate would hydrolyze that surface-bound substrate faster. Contrary to our original expectations, the variants that adsorb more on the covalently bound peptide surface hydrolyze this substrate slower. In addition, variants of BPN' which adsorb at a lower level than native BPN' hydrolyze the surface-bound substrate faster. Enzyme adsorption and the subsequent peptide hydrolysis are altered by substituting amino acids that modify the surface charge or hydrophobicity of the native enzyme. This effect is most dramatic when the changes were made at surface-exposed sites around the binding pocket/active site of the enzyme. One mechanism that is consistent with the data is based on the relationship between the level of adsorption and the enzyme's affinity for the surface. In this mechanism weakly adsorbed enzymes are postulated to move more rapidly from site to site on the surface, thereby increasing substrate hydrolysis.

Adsorption↗

PubMed2003

Rheological properties of concentrated skim milk: influence of heat treatment and genetic variants on the changes in viscosity during storage.

Heat treatment during manufacturing of milk powder is one of the most important tools for manipulation of its functional properties, and it is the basis of the classification of these proteins into low-, medium-, and high-heat types. Slight differences in the sequences of the major proteins in milk (genetic variants) seem to have also a significant effect in milk powder processing (U.S. patent). Therefore, the effects of high-temperature storage and heat treatment on skim milk of defined genetic variants of beta-lactoglobulin (beta-LG) were measured. The samples had 45% total solids, the temperature of aging was 50 degrees C, and the heat treatment was 90 degrees C for 10 min prior to evaporation. Measurements on shear rate and on apparent viscosity were determined for each sample. During storage of the concentrated milk, the apparent viscosity and yield values increased markedly, and the age-dependent increase in viscosity in heat-treated concentrated skim milks was much more pronounced than in those prepared from unheated skim milks. The increase in apparent viscosity and yield value with storage time was notably different for milks containing different genetic variants. Unheated concentrated milks containing the B variant of beta-LG showed the most rapid increase in apparent viscosity with storage time, whereas the viscosity increase was slowest in the concentrate containing the A variant. In contrast, heat-treated concentrated milks containing the A variant of beta-LG showed the most rapid increase in viscosity with storage time, whereas the viscosity increase was slowest in the concentrate containing the AB variant. The changes in apparent viscosity of concentrated milk were largely reversible under high shear during the early stages of storage, but samples stored for a long time showed irreversible changes in apparent viscosity. Particle size analysis confirmed irreversible aggregation and fusion of casein particles during storage.

Animals↗

PubMed2000

Identification of insertion and deletion genes in Autographa californica nucleopolyhedrovirus variants isolated from Galleria mellonella, Spodoptera exigua, Spodoptera litura and Xestia c-nigrum.

The genomic DNA of four Autographa californica multinucleocapsid nucleopolyhedrovirus (AcMNPV) variants isolated from Galleria mellonella, Spodoptera exigua, Spodoptera litura and Xestia c-nigrum was analyzed in comparison with the AcMNPV E2 strain. Restriction endonuclease analysis revealed a deletion and an insertion in collinear regions of the four variants. Polymerase chain reaction analysis indicated that, in the four variants, the deletion occurred in the region corresponding to AcMNPV C6 ORF86 (pnk/pnl). Also the insertion, with a length of approximately 1.1 kb, was commonly identified in the fragments corresponding to the PstI-J fragment (18.5 m.u.-21.2 m.u.) of AcMNPV E2. Sequencing analysis of the variant from S. litura showed that the insertion contains an additional open reading frame encoding 322 amino acids between homologues of AcMNPV ORF30 and ORF31 (the superoxide dismutase gene). This ORF has 82.8% amino acid identity to Bombyx mori NPV T3 ORF 22 (bro-a, one of the baculovirus repeated ORFs) and thus, it was named Splt-bro-a. Southern blot hybridization study indicated that the other three variants also contain Splt-bro-a homologue. In addition, the labeled Splt-bro-a gene weakly hybridized to the PstI-D fragment (99.0 m.u.-8.0 m.u.) of AcMNPV E2. This fragment contains AcMNPV ORF2, a member of bro family. The signal was also observed on the corresponding fragment of the four variants. This result suggested that two bro genes are present in the four variants, although AcMNPV E2 and C6 are known to contain a single bro gene.

Amino Acid Sequence↗

PubMed2001

Role of biantennary glycans and genetic variants of human alpha1-acid glycoprotein in enantioselective binding of basic drugs as studied by high performance frontal analysis/capillary electrophoresis.

PURPOSE: To establish a clear understanding of the role of biantennary branching glycans and genetic variants of alpha1-acid glycoprotein (AGP) in enantioselective bindings of basic drug. METHODS: Human native AGP was separated using concanavalin A affinity chromatography into two subfractions, the unretained fraction (UR-AGP, defect of biantennary glycan) and the retained fraction (R-AGP, possessing biantennary glycan(s)). Imminodiacetate-copper (II) affinity chromatography was used to separate human native AGP into A variant and a mixture of F1 and S variants (F1*S variants). The mixed solutions of the (R)- or (S)-isomer of the model drugs (15 microM disopyramide (DP) or 30 microM verapamil (VER)) and 40 microM of respective AGP species were subjected to high-performance frontal analysis/capillary electrophoresis (HPFA/CE) to determine the unbound drug concentrations. RESULTS: The unbound concentrations (Cu) of DP in UR-AGP solutions were lower than those in R-AGP solutions, whereas there was no significant difference in the enantiomeric ratios (Cu(R)/Cu(S)) of DP between UR- and R-AGP solutions. In case of genetic variant, the Cu(R)/Cu(S) values of DP in F1*S and A solutions were 1.07 and 2.37, respectively. On the other hand, the enantiomeric ratio of VER in F1*S and A variant solutions were 0.900 and 0.871, respectively. CONCLUSIONS: The biantennary glycan structures are related to binding affinity of DP to AGP, but not responsible for the enantioselectivity. Genetic variants give significant effect on the enantioselectivity in DP binding, but not in VER binding.

Anti-Arrhythmia Agents↗

PubMed2000

Limited plasticity in the recognition of peptide epitope variants by an alloreactive CTL clone correlates directly with conservation of critical residues and inversely with peptide length.

Although self-restricted T cells are peptide-specific and can distinguish among closely related ligands, they have some flexibility in the recognition of sequence variants of their natural peptide epitopes. Alloreactive cytotoxic T lymphocytes (CTL) can recognize specific peptides bound to the allo-major histocompatibility complex (MHC) molecule, but their plasticity in the recognition of related peptide variants has not been properly defined. The anti-B*2705 alloreactive CTL 27S69 specifically recognizes a natural octamer ligand of HLA-B*2705. In this study, we tested the recognition of a nested set of epitope variants by this CTL clone. Although none of these peptides was recognized equally as the natural epitope, two of the peptide variants were recognized with only slightly decreased efficiency. Peptide sensitization assays showed that CTL recognition of epitope variants correlated directly with conservation of two non-anchor residues that were critical for recognition of the natural epitope, and inversely with peptide length. Molecular modeling of the peptide variants complexed with B*2705 provided a rational explanation for their differential recognition. Location of the two critical peptide residues at the right three-dimensional space favored efficient recognition by CTL 27S69. The negative effect of increasing peptide length on recognition was due to the bigger bulging surface between the two critical residues, which precluded for optimal interaction with the specific T-cell receptors (TCR). Our results demonstrate that an alloreactive CTL has a degree of plasticity in the recognition of peptide epitope variants that is comparable to that of peptide-specific self-restricted CTL, and define the structural features determining crossreaction among related peptides.

Cloning, Molecular↗

PubMed1995

Coexpression of wild-type and variant oestrogen receptor mRNAs in a panel of human breast cancer cell lines.

Wild-type as well as variant oestrogen receptor (ER) mRNAs with exon 5 and 7 deleted were identified in a panel of human breast tumour cell lines by reverse transcriptase-polymerase chain reaction followed by dideoxynucleotide sequence analysis, and then quantitated by ribonuclease protection analysis. All cell lines categorised as ER+ by ligand-binding analysis expressed both wild-type and variant ER transcripts. Most cell lines classified as ER- did not express any ER transcript. However, three ER- cell lines (BT-20, MDA-MB-330 and T47Dco) expressed both wild-type and variant transcripts. A differential pattern of expression of wild type to variant was seen in both ER+ and ER- cell lines, however this pattern was not paralleled by differences in ligand-binding activity. Breast tumour cell lines previously classified as ER- expressed significantly lower levels of ER transcripts than did their ER+ counterparts. In view of these findings, as well as earlier reports that the exon 5 deletion ER variant encodes a dominant-positive receptor, it seems clear that some cell lines are misclassified as ER-, and express both wild-type and variant ER mRNAs, and that the overexpression of this variant may account, in part, for their oestrogen-independent phenotype.

Base Sequence↗

PubMed2026

PubMind: literature-based genetic variant extraction and functional annotation using large language models.

Biomedical literature contains extensive functional knowledge on genetic variants, but much remains inaccessible in unstructured text. Existing resources such as ClinVar and HGMD remain limited by coverage, submission bias, update frequency, and sparse annotation. We develop PubMind, an artificial intelligence (AI) framework that uses large language models (LLMs) to triage and extract variant-function-disease associations and supporting evidence from biomedical text. PubMind captures single-nucleotide, copy-number, structural, and gene-fusion variants, and normalizes records to genomic and transcriptomic coordinates. Benchmarking shows >90% accuracy for variant recognition and 99% precision for disease extraction. Applied to >41 million PubMed abstracts and >5 million full-text articles, PubMind generates PubMind-DB, a database of ~1.3 million unique variants with contextual annotations, accessible via web interface and API. Only ~10% of PubMind variants overlap with ClinVar, and >80% of them show concordant pathogenicity labels. PubMind transforms unstructured biomedical text into structured genomic knowledge, advancing variant interpretation for precision medicine.

Large Language Models↗

PubMed2023

Bi-allelic ATG4D variants are associated with a neurodevelopmental disorder characterized by speech and motor impairment.

Autophagy regulates the degradation of damaged organelles and protein aggregates, and is critical for neuronal development, homeostasis, and maintenance, yet few neurodevelopmental disorders have been associated with pathogenic variants in genes encoding autophagy-related proteins. We report three individuals from two unrelated families with a neurodevelopmental disorder characterized by speech and motor impairment, and similar facial characteristics. Rare, conserved, bi-allelic variants were identified in ATG4D, encoding one of four ATG4 cysteine proteases important for autophagosome biogenesis, a hallmark of autophagy. Autophagosome biogenesis and induction of autophagy were intact in cells from affected individuals. However, studies evaluating the predominant substrate of ATG4D, GABARAPL1, demonstrated that three of the four ATG4D patient variants functionally impair ATG4D activity. GABARAPL1 is cleaved or "primed" by ATG4D and an in vitro GABARAPL1 priming assay revealed decreased priming activity for three of the four ATG4D variants. Furthermore, a rescue experiment performed in an ATG4 tetra knockout cell line, in which all four ATG4 isoforms were knocked out by gene editing, showed decreased GABARAPL1 priming activity for the two ATG4D missense variants located in the cysteine protease domain required for priming, suggesting that these variants impair the function of ATG4D. The clinical, bioinformatic, and functional data suggest that bi-allelic loss-of-function variants in ATG4D contribute to the pathogenesis of this syndromic neurodevelopmental disorder.

Journal Article↗

PubMed2002

CHEK2 variants in susceptibility to breast cancer and evidence of retention of the wild type allele in tumours.

We have recently shown that the CHEK2*1100delC mutation acts as a low penetrance breast cancer susceptibility allele. To investigate if other CHEK2 variants confer an increased risk of breast cancer, we have screened an affected individual with breast cancer from 68 breast cancer families. Five of these individuals were found to harbour germline variants in CHEK2. Three carried the 1100delC variant (4%). One of these three individuals also carried the missense variant, Arg180His. In the other two individuals, missense variants, Arg117Gly and Arg137Gln, were identified. These two missense variants reside within the Forkhead-associated domain of CHEK2, which is important for the function of the expressed protein. None of these missense variants were present in 300 healthy controls. Microdissected tumours with a germline mutation showed loss of the mutant allele suggesting a mechanism for tumorigenesis other than a loss of the wild type allele. This study provides further evidence that sequence variation in CHEK2 is associated with an increased risk of breast cancer, and implies that tumorigenesis in association with CHEK2 mutations does not involve loss of the wild type allele.

Adult↗

PubMed2002

The human 5-HT7 serotonin receptor splice variants: constitutive activity and inverse agonist effects.

1. Using membranes from stably or transiently transfected HEK293 cells cultured in 5-HT-free medium and expressing the recombinant human 5-HT(7) receptor splice variants (h5-HT(7(a)), h5-HT(7(b)) and h5-HT(7(d))), we compared their abilities to constitutively activate adenylyl cyclase (AC). 2. All h5-HT(7) splice variants elevated basal and forskolin-stimulated AC. The basal AC activity was reduced by the 5-HT(7) antagonist methiothepin and this effect was blocked by mesulergine (neutral 5-HT(7) antagonist) indicating that the inhibitory effect of methiothepin is inverse agonism at the 5-HT(7) receptor. 3. Receptor density correlated poorly with constitutive AC activity in stable clonal cell lines and transiently transfected cells. Mean constitutive AC activity as a percentage of forskolin-stimulated AC was significantly higher for the h5-HT(7(b)) splice variant compared to the h5-HT(7(a)) and h5-HT(7(d)) splice variants but only in stable cell lines. 4. All eight 5-HT antagonists tested inhibited constitutive AC activity of all splice variants in a concentration-dependent manner. No differences in inverse agonist potencies (pIC(50)) were observed between the splice variants. The rank order of potencies was in agreement and highly correlated with antagonist potencies (pK(b)) determined by antagonism of 5-HT-stimulated AC activity (methiothepin >metergoline> mesulergine > or = clozapine > or = spiperone > or = ritanserin > methysergide > ketanserin). 5. The efficacy of inverse agonism was not receptor level dependent and varied for several 5-HT antagonists between membrane preparations of transiently and stably transfected cells. 6. It is concluded that the h5-HT(7) splice variants display similar constitutive activity and inverse agonist properties.

Adenylyl Cyclase Inhibitors↗

PubMed2003

Genetic differentiation and habitat preference of flowering-time variants within Gymnadenia conopsea.

Using fast-evolving microsatellites, more slowly evolving ITS markers and performing habitat analyses, we demonstrated a drastic genetic divergence and significant habitat differentiation between early- and late-flowering variants of plants morphologically belonging to Gymnadenia conopsea ssp conopsea. The two phenological variants can either be found in separate or in mixed populations. Information from microsatellite markers and ITS sequences indicated the occurrence of an early historical split between the two flowering-time variants, a split that has been maintained until the present time even within sympatric populations. Early-flowering variants were also far more genetically diverse, had more alleles per microsatellite locus and a wider habitat amplitude than late-flowering variants. As a comparison, we included G. odoratissima in the sequencing study. We found G. odoratissima to be most closely related to the early-flowering type. This indicates a more ancient divergence event between the two flowering-time variants within G. conopsea ssp conopsea than between the two different species G. odoratissima and the early-flowering variant of G. conopsea. Possible explanations to the results arrived at and possible mechanisms maintaining the genetic separation are discussed.

DNA, Plant↗

PubMedDate not supplied

An alternate splicing variant of the human telomerase catalytic subunit inhibits telomerase activity.

Telomerase, a cellular reverse transcriptase, adds telomeric repeats to chromosome ends. In normal human somatic cells, telomerase is repressed and telomeres progressively shorten, leading to proliferative senescence. Introduction of the telomerase (hTERT) cDNA is sufficient to produce telomerase activity and immortalize normal human cells, suggesting that the repression of telomerase activity is transcriptional. The telomerase transcript has been shown to have at least six alternate splicing sites (four insertion sites and two deletion sites), and variants containing both or either of the deletion sites are present during development and in a panel of cancer cell lines we surveyed. One deletion (beta site) and all four insertions cause premature translation terminations, whereas the other deletion (alpha site) is 36 bp and lies within reverse transcriptase (RT) motif A, suggesting that this deletion variant may be a candidate as a dominant-negative inhibitor of telomerase. We have cloned three alternately spliced hTERT variants that contain the alpha, beta or both alpha and beta deletion sites. These alternate splicing variants along with empty vector and wild-type hTERT were introduced into normal human fibroblasts and several telomerase-positive immortal and tumor cell lines. Expression of the alpha site deletion variant (hTERT alpha-) construct was confirmed by Western blotting. We found that none of the three alternate splicing variants reconstitutes telomerase activity in fibroblasts. However, hTERT alpha- inhibits telomerase activities in telomerase-positive cells, causes telomere shortening and eventually cell death. This alternately spliced dominant-negative variant may be important in understanding telomerase regulation during development, differentiation and in cancer progression.

Alternative Splicing↗

PubMed2001

Over-representation of a germline variant in the gene encoding RET co-receptor GFRalpha-1 but not GFRalpha-2 or GFRalpha-3 in cases with sporadic medullary thyroid carcinoma.

In contrast to the hereditary form of medullary thyroid carcinoma (MTC), little is known about the etiology of sporadic MTC. Somatic gain-of-function mutations in the RET proto-oncogene, encoding a receptor tyrosine kinase, are found in an average of 40% of sporadic MTC. We analysed 31 sporadic MTC for somatic and germline variants in GFRA1, GFRA2 and GFRA3 which encode the co-receptors of RET. Although there were no somatic mutations in any of the three genes, a sequence variant (-193C>G) in the 5'-UTR of GFRA1 was found in 15% of cases. Three patients were heterozygous (het); another three patients homozygous (hom) for the G variant. The G allele was not observed in 31 race-matched normal controls. Hence, the relative frequency of this variant in sporadic MTC cases and controls differed significantly (P<0.05). Since this variant lies in the 5' UTR, likely at the transcriptional start site, we analysed for differential expression of GFRalpha-1 at the transcript and protein levels. At the mRNA level, GFRA1 was over-expressed in tumors harboring the rare variant (P=0.06). The presence of the G polymorphic allele seemed to be associated with increased expression by immunostaining for GFRalpha-1. Interestingly, cytoplasmic staining was stronger in intensity for het patients and nuclear staining predominant in hom cases. In conclusion, mutation analysis of GFRA1, GFRA2 and GFRA3 revealed over-representation of a rare variant in GFRA1 (-193C>G) in the germline of sporadic MTC cases. Our data suggest that the mechanism is related to over-expression of GFRalpha-1 and differential subcellular compartmentalization but the precise mechanism as to how it acts as a low penetrance susceptibility allele for the development of sporadic MTC remains to be elucidated.

Carcinoma, Medullary↗

PubMed2005

Elevated expression of survivin-splice variants predicts a poor outcome for soft-tissue sarcomas patients.

The aim of this study was to investigate the level and the prognostic value of the expression of different survivin transcript variants--survivin, survivin-DeltaEx3 and survivin-2B--in tumours of 76 soft tissue sarcoma (STS) patients. The expression of survivin transcript variants in STS tissue samples and in 12 nonmalignant control tissues was analysed by quantitative RT-PCRs. Expression levels of all survivin transcript variants were strongly elevated in STS compared to normal tissues. A positive correlation between expression of splice variants and tumour stage was found (P=0.02; chi2 test). The multivariate Cox's proportional hazards regression model revealed a 7.3-fold increased risk of tumour-related death for patients with survivin-DeltaEx3 overexpressing tumours (P=0.007). The effect of surivivin (wildtype variant) and survivin-2B was less pronounced but still significant (2.2- and 1.9-fold, resp., P<0.05 each). Our results show for the first time that mRNA expression of survivin-variants is significantly correlated to a poor prognosis for STS patients, and we suggest expression of survivin splice variants together with tumour stage as independent predictor of survival.

Biomarkers, Tumor↗

PubMed2001

Physiological effects of variants in human uncoupling proteins: UCP2 influences body-mass index.

The purpose of this review is to summarize the evidence from more than 40 studies that naturally occurring variants of uncoupling proteins 1-3 (UCP1-3) have detectable physiological effects in humans. Although UCP1 is known to influence mitochondrial proton leak in vitro and core body temperature in mice, genetic studies in humans have produced only weak evidence for association of naturally occurring variants with body-mass index (BMI); the best-reported P value is 0.01. In contrast, current evidence is consistent with the hypothesis that UCP2 and 3 influence BMI, since the best reported P values are better: four studies report associations of 0.001 (2 studies) to 0.002 (1 study) and 0.005 (1 study) for a UCP2 insertion/deletion variant, while the best P values for association of UCP3 with BMI are 0.003 (1 study) and 0.0037 (1 study). UCP2 and 3 are adjacent to each other on chromosome 11 and variants in each are in linkage disequilibrium. Thus, variants in UCP2 or 3 may influence results from association studies of variants in the other. Since UCP2 has a greater influence on BMI in humans than UCP3, then the two most likely hypotheses are that only UCP2 affects BMI, and positive results for UCP3 result from linkage disequilibrium to UCP2, or both UCP2 and 3 affect BMI. It is unlikely that only UCP3 influences BMI. UCP2 associations have been observed in a variety of ethnic groups, including Caucasians, African Americans, South Indians and Chinese. Consistent results from diverse ethnic groups are concordant with the hypothesis that the UCP2 insertion/deletion variant itself underlies the association with BMI.

Body Mass Index↗