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Mutant Gene (mutant + gene)
Selected AbstractsDegeneration of pontine mossy fibres during cerebellar development in weaver mutant miceEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 4 2002Miwako Ozaki Abstract In weaver mutant mice, substitution of an amino acid residue in the pore region of GIRK2, a subtype of the G-protein-coupled inwardly rectifying K+ channel, changes the properties of the homomeric channel to produce a lethal depolarized state in cerebellar granule cells and dopaminergic neurons in substantia nigra. Degeneration of these types of neurons causes strong ataxia and Parkinsonian phenomena in the mutant mice, respectively. On the other hand, the mutant gene is also expressed in various other brain regions, in which the mutant may have effects on neuronal survival. Among these regions, we focused on the pontine nuclei, the origin of the pontocerebellar mossy fibres, projecting mainly into the central region of the cerebellar cortex. The results of histological analysis showed that by P9 the number of neurons in the nuclei was reduced in the mutant to about one half and by P18 to one third of those in the wild type, whereas until P7 the number were about the same in wild-type and weaver mutant mice. Three-dimensional reconstruction of the nuclei showed a marked reduction in volume and shape of the mutant nuclei, correlating well with the decrease in neuronal number. In addition, DiI (a lipophilic tracer dye) tracing experiments revealed retraction of pontocerebellar mossy fibres from the cerebellar cortex after P5. From these results, we conclude that projecting neurons in the pontine nuclei, as well as cerebellar granule cells and dopaminergic neurons in substantia nigra, strongly degenerate in weaver mutant mice, resulting in elimination of pontocerebellar mossy fibres during cerebellar development. [source] Pleiotropic phenotypes caused by an opal nonsense mutation in an essential gene encoding HMG-CoA reductase in fission yeastGENES TO CELLS, Issue 6 2009Yue Fang Schizosaccharomyces pombe genome contains an essential gene hmg1+ encoding the sterol biosynthetic enzyme, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR). Here, we isolated an allele of the hmg1+ gene, hmg1-1/its12, as a mutant that showed sensitivities to high temperature and to FK506, a calcineurin inhibitor. The hmg1-1 allele contained an opal nonsense mutation in its N-terminal transmembrane domain, yet in spite of the mutation a full-length protein was produced, suggesting a read-through termination codon. Consistently, overexpression of the hmg1-1 mutant gene suppressed the mutant phenotypes. The hmg1-1 mutant showed hypersensitivity to pravastatin, an HMGR inhibitor, suggesting a defective HMGR activity. The mutant treated with FK506 caused dramatic morphological changes and showed defects in cell wall integrity, as well as displayed synthetic growth phenotypes with the mutant alleles of genes involved in cytokinesis and cell wall integrity. The mutant exhibited different phenotypes from those of the disruption mutants of ergosterol biosynthesis genes, and it showed normal filipin staining as well as showed normal subcellular localization of small GTPases. These data suggest that the pleiotropic phenotypes reflect the integrated effects of the reduced availability of ergosterol and various intermediates of the mevalonate pathway. [source] The Differential Susceptibility of Specific Neuronal Populations: Insights from Huntington's DiseaseIUBMB LIFE, Issue 6 2003Ian Mitchell Abstract Recent successes in identifying the genes and associated proteins underlying several familial neurodegenerative conditions have not always resulted in accounts as to why the associated patterns of neuronal damage are so specific and limited. Here, with reference to Huntington's disease, we present a general scheme to show how the mutant protein could interact with associated proteins to form an aggregation product. This could lead to neuronal death by direct actions on caspases, or by raising the levels of intracellular calcium ions and reactive oxygen species above a threshold that cannot be resisted by the protection normally conferred by endogenous factors such as calcium binding proteins, free radical scavengers and trophic factors. The local distributions of vulnerability and protective factors could ultimately dictate the pattern of damage induced by the mutant gene. IUBMB Life, 55: 293-298, 2003 [source] Multiple Endocrine Neoplasia , IntroductionJOURNAL OF INTERNAL MEDICINE, Issue 1 2005S. J. MARX Abstract. Each multiple endocrine neoplasia (MEN) syndrome expresses striking features of hormone oversecretion from its own characteristic group of tissues. Additional expressions include non-hormonal tumours in each MEN syndrome and selected cancers in some syndromes. The complexity of its stereotyped features results in difficult management issues that often justify cooperation across multiple specialties. MEN syndromes, though rare, have long received intense study as models for more common diseases. The syndromal nature often with a large pedigree has promoted recent discovery of the main gene that differs for each of the six MEN syndromes. Each mutant gene has been introduced into clinical decision-making and into further clarification of tumorigenesis. This mini-symposium is related to the 9th International Workshop on Multiple Endocrine Neoplasia in June 2004; it consists of six manuscripts. They report new developments in clinical practices and in basic understandings about this rapidly advancing field. [source] Mutation Causing von Willebrand's Disease in Scottish TerriersJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 1 2000Patrick J. Venta Von Willebrand's Disease (vWD) in the Scottish Terrier breed is a serious, often fatal, hereditary bleeding disorder. Elimination of the mutated gene by selective breeding is an important goal for the health of this breed. Although the standard protein-based tests are accurate for identification of affected Scottish Terriers, they are not reliable for the identification of carriers of the mutant gene unless multiple replicate assays are performed. A simple, highly accurate test for carriers of the disease is needed so that veterinarians can counsel clients on which animals to use in their breeding programs. The complete coding region of von Willebrand factor (vWF) complementary DNA (cDNA) was sequenced from an affected animal, and a single base deletion in the codon for amino acid 85 of the prepro-vWF cDNA that leads to Scottish Terrier vWD was identified. A highly accurate polymerase chain reaction assay was developed that can distinguish homozygous normal animals from those that are homozygous affected or heterozygous. In a voluntary survey of 87 animals provided by Scottish Terrier owners, 15 were carriers and 4 were affected with vWD, 2 of which had previously been shown to have undetectable vWF. The determination of the complete canine vWF cDNA sequence should facilitate the identification of additional vWD alleles in other breeds and other species. [source] Effect of overexpression of transcription factors on the fermentation properties of Saccharomyces cerevisiae industrial strainsLETTERS IN APPLIED MICROBIOLOGY, Issue 1 2009L. Hou Abstract Aims:, To investigate the effect of modulation of transcription factors on the fermentation properties of Saccharomyces cerevisiae industrial strains and to evaluate whether overexpression and co-overexpression of transcription factors would result in higher ethanol yield. Methods and Results:, A mutant gene spt15 (Phe177Ser, Tyr195His, Lys218Arg) was constructed by polymerase chain reaction mediated site-directed mutagenesis. The fermentation properties of the engineered strains in very high gravity fermentations were investigated. It is found that overexpression of SPT3 can enhance the resistance to ethanol and osmotic stress. On the contrary, overexpression of SPT15 or spt15 cannot obviously improve osmotic and ethanol tolerance of industrial strains. Additionally, simultaneous overexpression of SPT15 and SPT3 can not only distinctly enhance the resistance to ethanol and osmotic stress, but also improve fermentation performance. Conclusions:, Simultaneous modulation of the expression level of SPT15 and SPT3 can increase the production of ethanol by improving osmotic tolerance and ethanol tolerance of industrial strains. Significance and Impact of the Study:, Modulation of transcription factors provides a route to fermentation phenotypes of industrial yeast strains that are not readily accessible by traditional methods. [source] Genetic heterogeneity in rheumatoid arthritis mouse models induced by extrinsic and intrinsic factorsPATHOLOGY INTERNATIONAL, Issue 6 2010Shinichi Mizuki A cumulative effect of the susceptibility genes with polymorphic alleles may be responsible for rheumatoid arthritis (RA). The objective of this study was to clarify whether susceptibility to RA is under the control of common allelic loci between two different RA models induced by extrinsic and intrinsic factors, collagen-induced arthritis (CIA) in DBA/1 mice and arthritis in MRL/Mp (MRL) mice associated with the Fas deficient mutant gene, Faslpr, respectively. CIA was examined in mice of parental DBA/1 and MRL, (MRL × DBA/1) F1 and (MRL × DBA/1) F2 progenies. In genome-wide screening of the severity in the F2 using microsatellite markers, significant linkage was observed on chromosomes 5 and 17 at map position of D5Mit259 and H-2, respectively, associated with DBA/1 alleles, while there was no loci associated with arthritis of MRL- Faslpr mice previously identified. In a quantitative trait locus (QTL) analysis, the locus on chromosome 5 showed the highest peak at map position 35 cM (LOD score 6.0). This study may indicate that the arthritis induced by extrinsic and intrinsic factors is under the control of a different combination of susceptibility genes with common and different alleles, possibly simulating the genetic heterogeneity of RA. [source] Genetic and hormonal control of melanization in reddish,brown and albino mutants in the desert locust Schistocerca gregariaPHYSIOLOGICAL ENTOMOLOGY, Issue 1 2010KOUTARO MAENO The genetic and hormonal control of body colouration is investigated using two recessive genetic mutant strains, the reddish,brown (RB) mutant and an albino mutant, as well as a normal (pigmented) strain of the desert locust Schistocerca gregaria. The colour patterns of the RB nymphs are similar to those of a normal strain, although the intensity of the melanization is weaker in the former. Reciprocal crosses between the RB and albino mutants produce only normal phenotypes in the F1 generation. In the F2 generation, the normal, RB and albino phenotypes appear in a ratio of 9 : 3 : 4, indicating that two Mendelian units might determine the appearance of dark body colour and the intensity of melanization, respectively. In other words, at least two steps of regulation might be involved in the expression of body colour. Injections of [His7]-corazonin, a neuropeptide inducing dark colour in this locust, fail to induce dark colour in albino nymphs but show a dose-dependent darkening in RB nymphs in the range, 10 pmol to 1 nmol. Some RB nymphs become indistinguishable from normal individuals after injection of the peptide. Implantation of corpora cardiaca (CC) taken from RB mutants into other RB individuals induces darkening in the latter and CC from RB, albino and normal strains have similar dark colour-inducing activity when implanted into albino Locusta migratoria. These results suggest the possibility that the RB mutant gene regulates the intensity of melanization, possibly through controlling the pathway of pigment biosynthesis associated with [His7]-corazonin. [source] Modulation of F1 hybrid stature without altering parent plants through trans-activated expression of a mutated rice GAI homologuePLANT BIOTECHNOLOGY JOURNAL, Issue 2 2005Ning Su Summary Hybrid breeding, by taking advantage of heterosis, brings about many superior properties to the F1 progeny. However, some properties, such as increased plant height, are not desirable for agronomic purposes. To specifically counter the height increase associated with hybrid progeny, we employed an Arabidopsis model and tested a trans-activation system for specifically expressing a mutated GAI gene only in the F1 hybrid plants to reduce plant stature. A transcriptional activator, the Gal4 DNA-binding domain fused to the acidic activation domain of herpes simplex virus VP16 protein, driven by a maize ubiquitin promoter, was introduced in one parental line. A rice GAI homologue with an N-terminal deletion of the DELLA domain, driven by a promoter that is responsive to the transcriptional activator, was transferred into another parental line. After genetic crossing, trans-activation of the GAI mutant gene resulted in a dwarf phenotype. Over 50 pair-wise crosses between the parental lines were performed, and analyses suggested that the percentage of F1 progeny exhibiting dwarfism ranged from about 25% to 100%. Furthermore, the dwarfism trait introduced in F1 progeny did not seem to affect total seed yield. Our result suggests the feasibility of manipulating F1 hybrid progeny traits without affecting parent plants or the agronomic property of the progeny. [source] The participation of AtXPB1, the XPB/RAD25 homologue gene from Arabidopsis thaliana, in DNA repair and plant developmentTHE PLANT JOURNAL, Issue 4 2001Renata M. A. Costa Summary Nucleotide excision repair in Arabidopsis thaliana differs from other eukaryotes as it contains two paralogous copies of the corresponding XPB/RAD25 gene. In this work, the functional characterization of one copy, AtXPB1, is presented. The plant gene was able to partially complement the UV sensitivity of a yeast rad25 mutant strain, thus confirming its involvement in nucleotide excision repair. The biological role of AtXPB1 protein in A. thaliana was further ascertained by obtaining a homozygous mutant plant containing the AtXPB1 genomic sequence interrupted by a T-DNA insertion. The 3, end of the mutant gene is disrupted, generating the expression of a truncated mRNA molecule. Despite the normal morphology, the mutant plants presented developmental delay, lower seed viability and a loss of germination synchrony. These plants also manifested increased sensitivity to continuous exposure to the alkylating agent MMS, thus suggesting inefficient DNA damage removal. These results indicate that, although the duplication seems to be recent, the features described for the mutant plant imply some functional or timing expression divergence between the paralogous AtXPB genes. The AtXPB1 protein function in nucleotide excision repair is probably required for the removal of lesions during seed storage, germination and early plant development. [source] Diagnostic Performance of Various QTc Interval Formulas in a Large Family with Long QT Syndrome Type 3: Bazett's Formula Not So Bad After All ,ANNALS OF NONINVASIVE ELECTROCARDIOLOGY, Issue 4 2003Jan Brouwer M.D., M.Sc., Ph.D. Background: Recently, we identified a novel mutation of SCN5A (1795insD) in a large family with LQTS3. The aim of this study was to assess whether the various proposed corrections of the QT interval to heart rate help to improve the identification of carriers of the mutant gene. Methods: The study group consisted of 101 adult family members: 57 carriers and 44 noncarriers (mean age 44.6 ± 14.6 and 40.3 ± 12.8 years, respectively). In all individuals a 12-lead ECG, exercise ECG, and 24-hour Holter ECG were obtained. Results: Correction for heart rate significantly improved the diagnostic performance of the QT interval. Diagnostic performance of the Bazett formula was similar to that of the newer formulas (Fridericia, Hodges, Framingham, and a logarithmic formula). At a cut-off value of 440 ms, the Bazett corrected QT interval was associated with a sensitivity and specificity of 90% and 91%, respectively. Using the 24-hour Holter ECG, a prolonged QTc at heart rates less than 60 beats/min was almost pathognomonic for genetic mutation (sensitivity and specificity both 99%), whereas the QTc calculated at the lowest heart rate using Bazett's formula provided full discrimination. Conclusion: In the present family, the resting ECG gave a good indication about the presence or absence of genetic mutation but a 24-hour Holter recording was mandatory to ascertain the diagnosis. In the diagnosis of this form of LQTS3, Bazett's formula was at least as good as other proposed corrections of the QT interval to heart rate. [source] TRANSLATIONAL RESEARCH GOES BOTH WAYS: LESSONS FROM CLINICAL STUDIESCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 4 2008John W Funder SUMMARY 1It is currently assumed that translational research goes from benchtop to bedside; that aldosterone elevates blood pressure via its effects on salt and water homeostasis; that mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) share a common immediate ancestor; and that aldosterone plays a deleterious role in essential hypertension and heart failure. 2Meta-analysis of clinical trials in essential hypertension, in which eplerenone was dose-titrated to attain diastolic blood pressure < 90 mmHg, showed no relationship between blood pressure response and electrolyte effects, as judged by change in plasma (K). 3Reexamination of sequence data, and insights from the S810L MR mutant gene causing juvenile hypertension exacerbated by pregnancy, suggest that MR were the first to branch off the primordial ancestor for MR, GR, androgen receptors (AR) and progesterone receptors (PR). 4In clinical trials of MR blockade in heart failure and essential hypertension baseline aldosterone levels are in the low to normal range and sodium status unremarkable. Under such circumstances cortisol appears to be responsible for MR activation, thus exculpating aldosterone in these conditions. 5On the basis of these clinical studies, there is need to revisit the basic biology of aldosterone and MR as translational research very clearly goes both ways. [source] The transcarboxylase domain of pyruvate carboxylase is essential for assembly of the peroxisomal flavoenzyme alcohol oxidaseFEMS YEAST RESEARCH, Issue 7 2007Paulina Z. Ozimek Abstract Pyruvate carboxylase (Pyc1p) has multiple functions in methylotrophic yeast species. Besides its function as an enzyme, Pyc1p is required for assembly of peroxisomal alcohol oxidase (AO). Hence, Pyc1p-deficient cells share aspartate auxotrophy (Asp,) with a defect in growth on methanol as sole carbon source (Mut,). To identify regions in Hansenula polymorpha Pyc1p that are required for the function of HpPyc1p in AO assembly, a series of random mutations was generated in the HpPYC1 gene by transposon mutagenesis. Upon introduction of 18 mutant genes into the H. polymorpha PYC1 deletion strain (pyc1), four different phenotypes were obtained, namely Asp, Mut,, Asp, Mut+, Asp+ Mut,, and Asp+ Mut+. One mutant showed an Asp+ Mut, phenotype. This mutant produced HpPyc1p containing a pentapeptide insertion in the region that links the conserved N-terminal biotin carboxylation domain (BC) with the central transcarboxylation (TC) domain. Three mutants that were Asp, Mut, contained insertions in the TC domain, suggesting that this domain is important for both functions of Pyc1p. Analysis of a series of constructed C-terminal and N-terminal truncated versions of HpPyc1p showed that the TC domain of Pyc1p, including the region linking this domain to the BC domain, is essential for AO assembly. [source] Chromosomal localization of five mutant genes in rice, Oryza sativa, using primary trisomicsPLANT BREEDING, Issue 1 2000A. C. Sanchez Abstract The chromosomal locations of five mutant genes in rice were determined by crossing the marker stocks with the 12 primary trisomics. Genetic segregation of each gene was studied in the F2 or backcross populations. Out of the 60 possible cross combinations, 43 F2 or BC1 populations were studied. Segregation data indicated that spl11 was located on chromosome 12 while wp2 and eg2(t) were located on chromosome 6. The genes v12(t) and Bc6 were located on chromosomes 8 and 9, respectively, which are sparsely populated with genetic markers. [source] GENES, CALCIUM AND MODIFYING FACTORS IN HYPERTROPHIC CARDIOMYOPATHYCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 1-2 2006Tatiana Tsoutsman SUMMARY 1Familial hypertrophic cardiomyopathy (FHC) is a primary disorder of the myocardium characterized by remarkable diversity in clinical presentations, ranging from no symptoms to severe heart failure and sudden cardiac death. 2Over the past 15 years, at least 11 genes have been identified, defects of which cause FHC. Most of these genes encode proteins that comprise the basic contractile unit of the heart (i.e. the sarcomere). 3Genetic studies are now beginning to have a major impact on the diagnosis in FHC, as well as in guiding treatment and preventative strategies. Although much is known about which genes cause disease, relatively little is known about the molecular steps leading from the gene defect to the clinical phenotype and what factors modify the expression of the mutant genes. 4Concurrent studies in cell culture and animal models of FHC are now beginning to shed light on the signalling pathways involved in FHC and the role of both environmental and genetic modifying factors. Calcium dysregulation appears to be important in the pathogenesis of FHC. 5Understanding these basic molecular mechanisms will ultimately improve our knowledge of the basic biology of heart muscle function and will therefore provide new avenues for diagnosis and treatment not only for FHC, but also for a range of human cardiovascular diseases. [source] | ||||||||||||||||||||||