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At least 433 records · Page 24Linked to original sources
PubMed2000

[Familial myopathy with desmin storage seen as a granulo-filamentar, electron-dense material with mutation of the alphaB-cristallin gene].

Two familial cases of a myopathy remarkable by the presence of a granulo-filamentar, electron dense material were reported in 1978. In a second step, in 1988, it was demonstrated that this material contained an abnormally-phosphorylated desmin. During the last twenty years, the occurrence of new cases in this family confirmed the autosomal dominant inheritance of the disease, and made it potentially informative for molecular genetics studies. This allowed first to map the disease on chromosome11q21-23, and afterwards to identify a mutation within a gene coding for a chaperone protein, alphaBcrystallin. An extensive clinical, pathological and genetic study of this princeps family is herein reported in detail. First, it showed the possible detection of histopathological changes in presymptomatic patients. Second, it allowed to demonstrate the simultaneous occurrence of both alphaBcrystallin and desmin in the granulo-filamentar aggregates. Third, this study provided a precise knowledge of the evolution rate of the disease. The analysis of similar observations reported in the literature clearly shows the clinical, pathological and genetic heterogeneity of this new neuro-muscular disorder.

Actin Cytoskeleton↗
PubMed1996

Acquisition of the ts phenotype by a chemically mutagenized cold-passaged human respiratory syncytial virus vaccine candidate results from the acquisition of a single mutation in the polymerase (L) gene.

A cold-passaged (cp) temperature-sensitive (ts) mutant of human respiratory syncytial virus designated RSV cpts-248 was previously derived by random chemical mutagenesis of the non-ts mutant cp-RSV that possesses one or more host range mutations. We previously demonstrated in rodents and seronegative chimpanzees that the cpts-248 virus is more attenuated than cp-RSV and is more stable genetically than previously isolated RSV ts mutants. In the present study, we determined that the acquisition of the ts phenotype and the increased attenuation of the cpts-248 virus are associated with a single nucleotide substitution at nucleotide 10,989 that results in a change in the coding region (amino acid position 831) of the polymerase gene. The identification of this attenuating ts mutation is important because cpts-248 was used as the parent virus for the generation of a number of further attenuated mutants that are currently being evaluated as candidate vaccine strains in clinical trials in infants. Furthermore, technology now exists to rationally design new vaccine candidates by incorporating multiple attenuating mutations, such as the one identified here, into infectious viruses that are genetically stable and appropriately attenuated.

Animals↗
PubMed2004

Association between bone mineral density and LDL receptor-related protein 5 gene polymorphisms in young Korean men.

Recently, It has been reported that the LDL receptor-related protein 5 (LRP5) regulates bone formation, and that mutations of the gene cause osteoporosis-pseudoglioma syndrome or high bone mass phenotypes. However, the mutations cannot explain a genetic trait for osteoporosis in the general population because of their rarity. From 219 Korean men aged 20-34 yr, we looked for six known polymorphisms causing amino acid changes in the LRP5 coding region, and investigated their association with bone mineral density (BMD) at the following anatomical sites: lumbar spine (L2-L4) and the left proximal femur (femoral neck, Ward's triangle, trochanter and shaft). We found that the Q89R polymorphism was significantly associated with BMD at the femoral neck and Ward's triangle (p=0.004 and <0.001, respectively). However, after adjusting for age, weight and height, a statistically significant association only occurred at the Ward's triangle (p=0.043), and a marginal association was observed at the femoral neck (p=0.098). No A400V, V667M, R1036Q and A1525V polymorphisms were found, and no statistically significant association was found between the A1330V polymorphism and BMD at any sites. Although we failed to demonstrate a clear association between the LRP5 polymorphism and peak bone mass in young men, the present study suggests that larger-scale studies on the Q89R polymorphism need to be performed.

Adult↗
PubMed1995

Site-directed mutagenesis with an expanded genetic code.

A biosynthetic method has been developed that makes possible the site-specific incorporation of a large number of amino acids and analogues within proteins. In this approach, an amber suppressor tRNA chemically aminoacylated with the desired amino acid incorporates this amino acid site specifically into a protein in response to an amber codon introduced at the corresponding position in the protein's DNA sequence. Using this method, precise changes within a protein can be made to address detailed structure-function questions. A series of fluorinated tyrosine analogues and linear, branched, and cyclic hydrophobic amino acids have been used to determine the impact of hydrogen bonding and hydrophobic packing, respectively, on protein stability. Glutamate analogues and conformationally restricted amino acids have been used to probe the mechanisms of staphylococcal nuclease and ras. In addition, this technique has been used to construct photocaged proteins and proteins containing photoaffinity labels, spin labels, and isotopic labels at specific positions in the protein sequence suitable for biophysical studies.

Amino Acids↗
PubMed2000

Physico-chemical constraints connected with the coding properties of the genetic system.

New insights on the origin of the genetic code, based on the analysis of the physico-chemical properties of its molecular constituents (RNA and amino acids), are reported in this paper. We point out a symmetry in the genetic code table and show that it can be explained by the nature of the anticodon-codon interaction. The importance of the strength of this interaction is examined and a correlation is found between the free-energy change (DeltaG(0)) of anticodon-codon association and the volume of the corresponding amino acids. This correlation is investigated in conjunction with the well-known one linking the hydrophobicity of the anticodons with that of the amino acids. We show that they can be considerated separately and that the energy vs. volume correlation may be explained by the process implicating the peptide bond formation between two successive amino acids during translation. This interpretation is supported by a statistical pattern of bases (purines or pyrimidines), observed in present coding genes, and by considerations involving the availability of the different kinds of amino acids. Finally, we try to explain the hydrophobicity correlation when reconstructing the events at the time of the so-called "RNA World". The whole of our investigation shows that the genetic code might be sufficiently robust to exist without the participation of pre-existing proteins, and that this robustness is a consequence of the physico-chemical properties of the four bases of the genetic system.

Amino Acids↗
PubMed2002

Frequency of missense mutations in the coding region of a eukaryotic gene transferred by retroviral vectors.

A relatively high mutation rate is probably a major factor in the evolutionary success of retroviruses, because it generates the genetic diversity that helps them to cope with changes in the environment. When using recombinant retroviruses as vectors for gene transfer and gene therapy, it is important to consider the implications of this biological characteristic. Until now, the mutation rate has been studied by using noneukaryotic genes as reporters. Here we report point mutations in the human glucose-6-phosphate dehydrogenase (hG6PD) gene transferred by Moloney murine leukemia virus-based vectors into murine bone marrow cells and NIH 3T3 murine fibroblasts. After bone marrow transplantation, we observed an hG6PD with abnormal electrophoretic mobility for 2 out of 34 mice. Next, we studied this phenomenon quantitatively and found 1 electrophoretically abnormal hG6PD variant among 93 independently isolated NIH 3T3 clones, from which we estimate a mutation rate of 1.4 x 10(-5) per base pair per replication cycle. Mutations in the transferred gene can thus contribute to the impairment of the effectiveness of retrovirus-mediated gene transfer.

3T3 Cells↗
PubMedDate not supplied

[Calcimimetics].

Current therapy for secondary hyperparathyroidism in uremia has relatively poor success in achieving the target levels of parathyroid hormone (PTH), calcium and phosphate established by the NKF-K/DOQI guidelines. The discovery and characterization of a new membrane receptor able to sense minimal Ca changes (CaSR) started intensive research in the attempt to characterize better its functions and its finding compounds, which could modulate its activity. CaSR is expressed not only in the cells that secrete calcium-regulating hormones (parathyroid cells and thyroid C-cells) and in cells involved in calcium transport mechanisms (ie intestinal cells, bone-forming osteoblasts, and cells of different nephron segments), but also in other tissues with, as yet, a not completely defined role. CaSR stimulation by the agonists is followed by the activation of a great number of G-proteins mediated intracellular signalling pathways (PLC, PLA, PLD, PKC, PKA, etc). At the level of parathyroid cells, the main effect is the increase in IP3, followed by a mobilization of intracellular Ca stores, which inhibit PTH secretion in a few seconds or minutes. Long-term CaSR stimulation is also able to induce a reduction in both PTH synthesis and parathyroid cell proliferation. More than 100 mutations of the gene coding for CaSR have been described. Some of these mutations are matched by a gain or reduction/loss of function. Notwithstanding, CaSR is widely represented on different tissue cells, the main clinical manifestations of the above genetic changes mainly involve PTH and calcium metabolism. A great number of inorganic and organic cations can interact with the Ca-sensitive N-terminus domain of CaSR, mimicking Ca effects (type I calcimimetics), but these substances have substantial limitations for use in clinical practice. A second class of compounds was produced (NPS R-467, S-467, R-568, S-568, AMG 073), for use in the clinical setting, type II calcimimetics. These compounds, after having interacted with the membrane-spanning domains of the CaSR, induce conformational changes in the N-terminus domain, increasing its affinity for Ca. The preclinical experiences with calcimimetics demonstrated that they were effective in reducing circulating PTH, preventing the progression of secondary hyperparathyroidism, suppressing parathyroid cell proliferation, and reversing osteitis fibrosa at least in animal models. Clinical studies were performed mainly using AMG 073, due to its greater bioavailability and more consistent pharmacokinetic profile. Clinical studies performed in primary hyperparathyroidism proved AMG 073 to be effective in reducing both PTH and Ca serum levels, with a good safety profile. Further studies, mainly focused on the efficacy of AMG 073 in the control of secondary hyperparathyroidism in uremia, confirmed the efficacy of this compound in reducing PTH levels >30% in about 50% of patients. Furthermore, the fall in PTH was matched by a reduction in both calcium and phosphate serum levels of about 5-7%, with a significant reduction in calcium x phosphate product (about 15%). The latter aspect represents a unique pharmacological profile, as compared to all the other available therapeutic means to control secondary hyperparathyroidism in uremia. In addition to their effectiveness, calcimimetics present a relatively safe profile, the only adverse events referred to consist of transient and easily remediable hypocalcemic episodes and some gastrointestinal discomfort symptoms. However, although calcimimetics represent a real advancement in the field of treating secondary hyperparathyroidism in uremic patients, their use should be matched by the awareness that previously the success of a high number of new drugs proposed have been flawed by negative consequences in the long term. Therefore, strict clinical control is necessary in the next few years when the use of these new compounds will widen.

Animals↗
PubMed2006

High resolution analysis and phylogenetic network construction using complete mtDNA sequences in sardinian genetic isolates.

For mitochondrial phylogenetic analysis, the best result comes from complete sequences. We therefore decided to sequence the entire mitochondrial DNA (mtDNA) (coding and D-loop regions) of 63 individuals selected in 3 small Ogliastra villages, an isolated area of eastern Sardinia: Talana, Urzulei, and Perdasdefogu. We studied at least one individual for each of the most frequent maternal genealogical lineages belonging to haplogroups H, V, J, K, T, U, and X. We found in our 63 samples, 172 and 69 sequence changes in the coding and in the D-loop region, respectively. Thirteen out of 172 sequence changes in the coding region are novel. It is our hypothesis that some of them are characteristic of the Ogliastra region and/or Sardinia. We reconstructed the phylogenetic network of the 63 complete mtDNA sequences for the 3 villages. We also drew a network including a large number of European sequences and calculated various indices of genetic diversity in Ogliastra. It appears that these small populations remained extremely isolated and genetically differentiated compared with other European populations. We also identified in our samples a never previously described subhaplogroup, U5b3, which seems peculiar to the Ogliastra region.

DNA, Mitochondrial↗
PubMed2005

Association of the -92C/G and 807C/T polymorphisms of the alpha2 subunit gene with human platelets alpha2beta1 receptor density.

OBJECTIVE: Platelet adhesion to the subendothelial tissue via the collagen receptor alpha2beta1 is a crucial event in vascular biology. Although evidence has been provided that the number of platelets alpha2beta1 copies is genetically determined, the molecular change primary responsible has not been yet elucidated. The aim of our present study was to investigate the effect of combined polymorphisms within both regulatory (-52C/T and -92C/G) and coding regions (807C/T and 1648A/G) of the alpha2 subunit gene on human platelets alpha2beta1 receptor density and/or susceptibility to coronary artery disease (CAD). METHODS AND RESULTS: Among 254 cardiac surgery patients, no evidence was found for an association between the alpha2 subunit gene polymorphisms and CAD. In contrast, in a subgroup of 113 patients, we observed a significant association between all polymorphisms except -52C/T and alpha2beta1 receptor level. Furthermore, when 3 groups of patients were defined according to the tertiles of platelets alpha2beta1 copies, the -92C/807T haplotype was more frequent in the group of patients with high alpha2beta1 receptor level. CONCLUSIONS: These results suggest that an individual effect of each polymorphism located either in the coding or promoter sequence of the alpha2 gene may act in combination to modulate variations in platelets alpha2beta1 receptor density.

Blood Platelets↗
PubMed1991

The spectrum of molecular alterations in the evolution of chronic myelocytic leukemia.

DNA from 135 patients with chronic myelogenous leukemia (CML) at various clinical stages and Philadelphia (Ph1) chromosome positive acute lymphoblastic leukemia was investigated for alterations in a variety of proto-oncogenes which have been implicated in the evolution of CML from its chronic phase to blast crisis. The most common genetic change found in the evolution of typical Ph1 chromosome positive CML to blast crisis was an alteration of the p53 gene involving either a rearrangement, a deletion, or a point mutation in the coding sequence of the gene. Alterations of the p53 gene were found in the myeloid and the rare megakaryocytic variant of blast crisis but were absent in the lymphoid leukemic transformants. Gross structural alterations were seen in 11 of 54 (20%) of myeloid or unknown phenotypes of blast crisis and in only 1 of 44 chronic phase cases. Eight examples of mutations in the open reading frame of the p53 gene at codons 49, 53, 60, 140, 202, 204, 238, and 239 were observed in blast crisis patients. Mutations in the N-RAS gene were rare in typical blast crisis (2 of 27 cases) but were found in megakaryocytic and Ph1 negative myeloid blast crisis. We concluded that heterogeneous alterations in the p53 gene and occasionally in the N-RAS genes accompany the evolution of chronic phase CML to blast crisis.

Blotting, Northern↗
PubMed2005

DNA methylation and demethylation as targets for anticancer therapy.

Cancer growth and metastasis require the coordinate change in gene expression of different sets of genes. While genetic alterations can account for some of these changes, it is becoming evident that many of the changes in gene expression observed are caused by epigenetic modifications. The epigenome consists of the chromatin and its modifications, the "histone code" as well as the pattern of distribution of covalent modifications of cytosines residing in the dinucleotide sequence CG by methylation. Although hypermethylation of tumor suppressor genes has attracted a significant amount of attention and inhibitors of DNA methylation were shown to activate methylated tumor suppressor genes and inhibit tumor growth, demethylation of critical genes plays a critical role in cancer as well. This review discusses the emerging role of demethylation in activation of pro-metastatic genes and the potential therapeutic implications of the demethylation machinery in metastasis.

Animals↗
PubMed2005

Histone modifications as a platform for cancer therapy.

Tumorigenesis and metastasis are a progression of events resulting from alterations in the processing of the genetic information. These alterations result from stable genetic changes (mutations) involving tumor suppressor genes and oncogenes (e.g., ras, BRAF) and potentially reversible epigenetic changes, which are modifications in gene function without a change in the DNA sequence. Mutations of genes coding for proteins that directly or indirectly influence epigenetic processes will alter the cell's gene expression program. Epigenetic mechanisms often altered in cancer cells are DNA methylation and histone modifications (acetylation, methylation, phosphorylation). This article will review the potential of these reversible epigenetic processes as targets for cancer therapies.

Chromatin↗
PubMed1995

An adult diagnosed as hyper-IgM immunodeficiency syndrome.

A 27-year-old male who visited our hospital because of pneumonia was diagnosed as hyper-IgM immunodeficiency syndrome. His serum IgM level was markedly elevated, while the serum level of IgD was normal with a markedly decreased level of serum IgG and IgA. The proportion of T and B cells of peripheral blood lymphocytes was normal. However, B cells bearing surface IgG or IgA were not detectable by immunofluorescence technique. There was a consanguineous marriage in his family, suggesting that his disorder was caused by a genetic abnormality such as X-linked recessive and also autosomal recessive inheritance, although further study is necessary. CD40 ligand cDNA did not appear to contain any abnormal changes within the coding region.

Adult↗
PubMed2002

Identification of differentially expressed genes in subcutaneous adipose tissue from subjects with familial combined hyperlipidemia.

Subjects with familial combined hyperlipidemia (FCHL) are characterized by a complex metabolic phenotype with hyperlipidemia, insulin resistance, and central obesity. FCHL is due to impaired adipose tissue function superimposed on hepatic overproduction of lipoproteins. We investigated adipose tissue as an interesting target tissue for differential gene expression in FCHL. Human cDNA expression array analyses, in which adipose tissue from five FCHL patients was compared with that from four age, gender, and BMI matched controls, resulted in the identification of 22 up-regulated and three down-regulated genes. The genes differentially expressed imply activation of the adipocyte cell cycle genes. Furthermore, the differential expression of the genes coding for tumor necrosis factor alpha, interleukin 6, and intracellular adhesion molecule 1 support a role for adipose tissue in insulin resistance in FCHL subjects. The observed changes represent a primary genetic defect, an adaptive response, or a contribution of both.

Adipose Tissue↗
PubMed1998

Evolution of a simian immunodeficiency virus pathogen.

Analysis of disease induction by simian immunodeficiency viruses (SIV) in macaques was initially hampered by a lack of molecularly defined pathogenic strains. The first molecularly cloned SIV strains inoculated into macaques, SIVmacBK28 and SIVmacBK44 (hereafter designated BK28 and BK44, respectively), were cases in point, since they failed to induce disease within 1 year postinoculation in any inoculated animal. Here we report the natural history of infection with BK28 and BK44 in inoculated rhesus macaques and efforts to increase the pathogenicity of BK28 through genetic manipulation and in vivo passage. BK44 infection resulted in no disease in four animals infected for more than 7 years, whereas BK28 induced disease in less than half of animals monitored for up to 7 years. Elongation of the BK28 transmembrane protein (TM) coding sequence truncated by prior passage in human cells marginally increased pathogenicity, with two of four animals dying in the third year and one dying in the seventh year of infection. Modification of the BK28 long terminal repeat to include four consensus nuclear factor SP1 and two consensus NF-kappaB binding sites enhanced early virus replication without augmenting pathogenicity. In contrast, in vivo passage of BK28 from the first animal to die from immunodeficiency disease (1.5 years after infection) resulted in a consistently pathogenic strain and a 50% survival time of about 1.3 years, thus corresponding to one of the most pathogenic SIV strains identified to date. To determine whether the diverse viral quasispecies that evolved during in vivo passage was required for pathogenicity or whether a more virulent virus variant had evolved, we generated a molecular clone composed of the 3' half of the viral genome derived from the in vivo-passaged virus (H824) fused with the 5' half of the BK28 genome. Kinetics of disease induction with this cloned virus (BK28/H824) were similar to those with the in vivo-passaged virus, with four of five animals surviving less than 1.7 years. Thus, evolution of variants with enhanced pathogenicity can account for the increased pathogenicity of this SIV strain. The genetic changes responsible for this virulent transformation included at most 59 point mutations and 3 length-change mutations. The critical mutations were likely to have been multiple and dispersed, including elongation of the TM and Nef coding sequences; changes in RNA splice donor and acceptor sites, TATA box sites, and Sp1 sites; multiple changes in the V2 region of SU, including a consensus neutralization epitope; and five new N-linked glycosylation sites in SU.

Amino Acid Sequence↗
PubMed1975

The origin of the genetic code.

A new approach to the origin of the genetic code is proposed based on some regularities in the nucleotide distribution pattern of the code. The relative amounts of various amino acids in primitive proteins were possibly different from those in organisms living today. The primordial ratio was supposed to shift to the modern one guided by the action of primitive nucleotides. Each primitive tRNA had a discriminator site and, distinguished from it, an anticodon site. It also postulated that primordially each amino acid could correspond to a wide variety of codons. During the course of the evolutionary change, a selective mechanism worked among the protobionts so that less frequent nucleotides became associated with more abundant amino acids in the primordial conditions,thus finally leading to the present codon catalogue.

Amino Acids↗
PubMed1999

Comparative genomics: the key to understanding the Human Genome Project.

The sequencing of the human genome is well underway. Technology has advanced, such that the total genomic sequence is possible, along with an extensive catalogue of genes via comprehensive cDNA libraries. With the recent completion of the Saccharomyces cerevisiae sequencing project and the imminent completion of that of Caenorhabditis elegans, the most frequently asked question is how much can sequence data alone tell us? The answer is that that a DNA sequence taken in isolation from a single organism reveals very little. The vast majority of DNA in most organisms is noncoding. Protein coding sequences or genes cannot function as isolated units without interaction with noncoding DNA and neighboring genes. This genomic environment is specific to each organism. In order to understand this we need to look at similar genes in different organisms, to determine how function and position has changed over the course of evolution. By understanding evolutionary processes we can gain a greater insight into what makes a gene and the wider processes of genetics and inheritance. Comparative genomics (with model organisms), once the poor relation of the human genome project, is starting to provide the key to unlock the DNA code.

Animals↗