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PubMed2000

Five missense variants in the amino-terminal domain of the glucocorticoid receptor: no association with puerperal psychosis or schizophrenia.

Steroid hormone administration causes behavior changes in many and psychosis in a few. The clinical features suggest that genetic variants of the glucocorticoid receptor or cofactors could produce susceptible subpopulations who react adversely to hormonal cascades. To investigate this possibility, coding and splice site sequences of the glucocorticoid receptor were scanned for single nucleotide polymorphisms in genomic DNA samples from 100 schizophrenics (86 Caucasians and 14 African-Americans) and 40 Caucasians with puerperal psychosis. Five amino acid substitutions were found in the amino-terminal domain at frequencies of 0.6 to 3.8% in Caucasians: R23K, F29L, L112F, D233N, and N363S. In addition, four silent nucleotide changes were found: E22E, K293K, D677D, and N766N; a transversion in intron 4 occurred beyond the splice junction. None of these variants can be linked to these disorders at present. However, the N363S variant contributes a new potential phosphorylation site and has been associated with increased body mass and reduced bone mineral density [Huizenga et al., 1998], so it is possible that the other missense variants confer traits that currently are unrecognized. Comparisons to natural glucocorticoid receptor mutants in the familial glucocorticoid resistance syndrome and steroid resistant leukemias suggest that amino acid substitutions at highly conserved residues may cause severe functional defects and serious illness, while changes at less conserved sites produce lesser alterations and milder disease.

Amino Acid Sequence↗
PubMed1997

Human cholecystokinin type A receptor gene: cytogenetic localization, physical mapping, and identification of two missense variants in patients with obesity and non-insulin-dependent diabetes mellitus (NIDDM).

The human CCKAR gene was previously mapped to chromosome 4 using a panel of human/hamster somatic cell hybrids. We now report the cytogenetic and physical localization of the CCKAR gene. Using fluorescence in situ hybridization, we determined that CCKAR maps to 4p15.1-p15.2. On the physical map, CCKAR was adjacent to the marker AFMa283yh5, between AFMb355ya5 and WI-4086. A simple sequence repeat (D4S391) with high heterozygosity was found in the database, and CCKAR and this genetic marker were colocalized on two YACs (933D9 and 928A5). We also characterized the genomic structure and determined the exon-intron boundaries of the gene. This provided the opportunity to screen the gene in patients with non-insulin-dependent diabetes mellitus and/or obesity for single nucleotide changes using a single-strand conformational polymorphism strategy. Five sequence variants were identified in the coding sequence of the gene, including two missense variants (G21R and V365I). The results of these studies provide (1) precise genetic and physical mapping data, (2) exon-intron sequences for single nucleotide analysis, and (3) identification of two missense mutations in the CCKAR gene. The contribution of these CCKAR variants to normal physiology, to obesity, and to diabetes can now be evaluated.

Animals↗
PubMed1975

Replication and expression of constructed plasmid chimeras in transformed Escherichia coli--a review.

EcoRI restriction-endonuclease-generated fragments of bacterial plasmids isolated from Staphylococcus aureus or Escherichia coli, or of amplified DNA coding for the 18S and 28S ribosomal RNA of Xenopus laevis, have been linked to the pSC101 plasmid replicon and introduced into E. coli by transformation. The constructed plasmid chimeras can be cloned as stable replicons in E. coli, where they synthesize RNA and/or protein products specified by their component genes.

Animals↗
PubMed1997

Glaucoma, apoptosis, and neuroprotection.

The demise of the retinal ganglion cell represents the final common pathway of glaucomatous vision loss. Various studies demonstrate that ganglion cells die by the mechanism of apoptosis in conditions such as experimental animal models of glaucoma and optic nerve transection, and in human glaucoma. Apoptosis is a basic cell death mechanism noted in a number of neurodegenerative conditions. It constitutes a genetically coded "suicide" program activated when cells are no longer needed or have been seriously damaged, and is typified by rapid phagocytosis without inflammation. These cells demonstrate characteristic morphological changes on electron microscopy: nuclear chromatin condensation, compaction of cytoplasmic organelles, and membrane blebbing. Neurotrophin withdrawal and excitotoxic neurotransmitters have been implicated in apoptosis in ganglion cells damaged by glaucoma. Understanding the cellular and molecular biological events involved in ganglion cell death may lead to novel approaches to the treatment of glaucoma.

Animals↗
PubMed1975

Extrachromosomal elements in a super-suppression system of yeast. III. Enhanced detection of weak suppressors in certain non-suppressed psi-strains.

Individual colonies of an adenine-requiring strain of the genotype ade 2-1, SUPQ5, [psi minus] exhibit high and uniform frequencies of ADE+ revertants (5-1 times 10-5). The frequencies for strains of the genotypes ade 2-1, SUPQ5+, [psi+] and ade 2-1 SUPQ5+, [psi minus] are by contrast 1-2 times 10-7 and 0-5 times 10-7 respectively. Mutation from [psi minus] to [psi+] can occur. This suggests that the original mutation from [psi+] to [psi minus] is not necessarily a physical loss of, or extensive deletion, the extrachromosomal elements. Although mutation from [psi minus] to [psi+] occurs, the majority of ADE+ revertants from ade 2-1, SUPQ5, [psi minus] strains contain other types of mutation. Crosses between most ADE+ revertants and ade 2-1, SUPO5+, [psi minus] strains yield adenine-requiring diploids and tetrad segregations of 0:4, 1:3 and 2:2 ADE+ :ade minus. It is argued that most mutations give rise to weak recessive suppressors (SUPX) which are themselves incapable of suppressing the ochre allele ade 2-1, unless the allele SUPQ5 is also present. Tests with two suppressors, S-theta and S-zeta, isolated by Dr R. A. Gilmore, which are themselves incapable of suppressing ade 2-1, show that they do not do so even in the presence of SUPQ5. Thus the set of suppressors isolated by us is a special class which can perhaps only be observed in the genetic background ade 2-1, SUPQ5, [psi minus]. There is evidence that some of the new suppressors are capable, in the absence of SUPQ5, of weakly suppressing trp 5-48 and perhaps can 1-100. All ochre alleles are, however, suppressed by the combination SUPQ5, SUPX. SUPQ5 is able to suppress trp 5-48, his 5-2, lys 1-1 and can 1-100 in a [psi minus] background, although it does so variably. It is incapable of suppressing ade 2-1 in such a background. It is argued that the alteration in the [psi] determinant results in a lowered efficiency of suppression by SUPQ5 rather than a changed specificity.

Adenine↗
PubMed1995

Rescue of measles viruses from cloned DNA.

A system has been established allowing the rescue of replicating measles viruses (MVs) from cloned DNA. On one hand, plasmids were constructed from which MV antigenomic RNAs with the correct termini are transcribed by phage T7 RNA polymerase. On the other hand, helper cells derived from the human embryonic kidney 293 cell line were generated constitutively expressing T7 RNA polymerase together with MV nucleocapsid protein and phosphoprotein. Simultaneous transfection of the helper cells with the MV antigenomic plasmid and with a plasmid encoding the MV polymerase under direction of a T7 promoter led to formation of syncytia from which MVs were easily recovered. A genetic tag comprising three nucleotide changes was present in the progeny virus. As a first application of reverse genetics, a segment of 504 nucleotides from the 5' non-coding region of the fusion gene was deleted, leading to an MV variant whose replication behaviour in Vero cells was indistinguishable from that of the laboratory Edmonston B strain. Since no helper virus is involved, this system, in principle, should be applicable to the rescue of any member of the large virus order Mononegavirales, i.e. viruses with a nonsegmented negative-strand RNA genome.

Base Sequence↗
PubMed2006

Myofiber degeneration in autosomal dominant Emery-Dreifuss muscular dystrophy (AD-EDMD) (LGMD1B).

UNLABELLED: Autosomal dominant Emery-Dreifuss muscular dystrophy is caused by mutations in the LMNA gene that code for the nuclear membrane protein lamin A/C. We investigated skeletal muscle fibers from several muscles for cytoplasmic degenerative changes in three patients with genetically confirmed Emery-Dreifuss muscular dystrophy. Methods included quantitative light and electron microscopy and PCR-based mutational analysis. RESULTS: The degenerative pathway was characterized by the gradual replacement of individual myofibers by connective tissue. Early stages of degeneration typically involved only a segment of the cross-sectional area of a myofiber. Intermediate stages consisted of myofiber shrinkage due to "shedding" of peripheral cytoplasmic portions into the endomysial space, and fragmentation of the myofibers by interposed collagen fibrils. Empty basement membrane sheaths surrounded by abundant deposits of extracellular matrix marked the end stage of the degenerative process. The nuclear number-to-cytoplasmic area in myofibers of one patient increased with increasing cross-sectional area, suggesting that satellite cell fusion with myofibers may have compensated for myofiber shrinkage. The pattern of degeneration described herein differs from muscular dystrophies with plasma membrane defects (dystrophinopathy, dysferlinopathy) and explains the frequently found absence of highly elevated serum creatine kinase levels in autosomal dominant Emery-Dreifuss muscular dystrophy.

Adult↗
PubMed2003

Discovery of gene function by expression profiling of the malaria parasite life cycle.

The completion of the genome sequence for Plasmodium falciparum, the species responsible for most malaria human deaths, has the potential to reveal hundreds of new drug targets and proteins involved in pathogenesis. However, only approximately 35% of the genes code for proteins with an identifiable function. The absence of routine genetic tools for studying Plasmodium parasites suggests that this number is unlikely to change quickly if conventional serial methods are used to characterize encoded proteins. Here, we use a high-density oligonucleotide array to generate expression profiles of human and mosquito stages of the malaria parasite's life cycle. Genes with highly correlated levels and temporal patterns of expression were often involved in similar functions or cellular processes.

Animals↗
PubMed1982

The adrenergic responsiveness of Down syndrome cells.

Platelets and cultured fibroblasts were used to examine the hormonal response of normal diploid and Down syndrome (trisomy 21) cells. An enhanced physiological response to catecholamine hormones was found in the trisomy 21 cells. This effect was specific for the adrenergic agonists since other hormones showed equivalent responses in the normal diploid and trisomy 21 cell types. Radioligand analysis of the alpha-adrenergic receptors in trisomy 21 platelets indicated no significant difference in receptor density or ligand affinity. Enzymatic analysis of the platelet adenylate cyclase activity in vitro showed no major changes in catecholamine sensitivity between the normal and Down syndrome preparations. Somatic cell genetic studies using human-hamster hybrids indicated that a gene coding for the beta-adrenergic receptor was not located on chromosome 21 but on human chromosome 5. These receptor, enzymic, and somatic cell genetic studies argue against a gene-dosage effect involving either the adrenergic hormone receptors or a component of the adenylate cyclase enzyme in the trisomy 21 cells. Identifying the gene(s) on chromosome 21 and the molecular mechanism(s) responsible for the exaggerated response of Down syndrome cells to catecholamines are the current objectives of this research program.

Cells, Cultured↗
PubMed1995

Direct interaction between amino acids and nucleotides as a possible physicochemical basis for the origin of the genetic code.

A study of the association of homocodonic amino acids and selected heterocodonic amino acids with selected nucleotides in aqueous solution was undertaken to examine a possible physical basis for the origin of codon assignments. These interactions were studied using 1H nuclear magnetic resonance spectroscopy (NMR). Association constants for the various interactions were determined by fitting the changes in the chemical shifts of the anomeric and ring protons of the nucleoside moieties as a function of amino acid concentration to an isotherm which described the binding interaction. The strongest association of all homocodonic amino acids were with their respective anticodonic nucleotide sequences. The strength of association was seen to increase with increase in the chain length of the anticodonic nucleotide. The association of these amino acids with different phosphate esters of nucleotides suggests that a definite isomeric structure is required for association with a specified amino acid; the 5'-mononucleotides and (3'-5')-linked dinucleotides are the favored geometries for strong associations. Use of heterocodonic amino acids and nonprotein amino acids supports these findings. We conclude that there is at least a physicochemical, anticodonic contribution to the origin of the genetic code.

Amino Acids↗
PubMed1992

Peptide mapping for detecting variants in protein products.

The genetic stability of biotechnology production systems is of importance in evaluating the safety and efficacy of protein products. The analysis methods currently available for assessing the genetic stability of such systems are limited by the complexity of the eukaryotic genome and by their inability to predict the effects of post-transcriptional and post-translational events, such as glycosylation or host cell protein level changes, on the protein produced. Therefore, it is important to focus attention on the protein product itself in evaluating product consistency rather than on nucleotide sequence analysis for genetic stability of the production systems involved. Peptide mapping has arisen as the best method for the analysis of proteins as a surrogate measure of genetic stability. This method uses known chemical reactions or enzymes to cleave the protein at specific sites, resulting in discrete peptides whose structure and composition can be readily compared to that of the theoretical protein coded for by the DNA sequence of its gene. Peptide mapping, which is capable of detecting single amino acid changes in a molecule, can also be used for determining glycosylation sites. Peptide mapping requires sophisticated chromatographic techniques and equipment, and is limited to molecules of m.w. of c. 100,000. The method also requires careful validation to limit the potential for misinterpretation of artifactual peaks. Despite its limitations, no better method currently exists to evaluate product consistency and, thereby, the genetic stability of recombinant products.

Amino Acid Sequence↗
PubMed1992

Alterations of the p53 gene in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a malignancy which is consistently associated with the Epstein-Barr virus (EBV). The structure of the EBV genome in NPC suggests that NPC is a clonal proliferation of epithelial cells which emerges after EBV infection. The disease develops with high incidence in specific populations in discrete geographic locations, implicating possible genetic or environmental cofactors. Mutations of the p53 gene are among the most frequent genetic changes found in a large variety of human tumors. Mutations in p53 have been shown to abrogate the suppressor function of wild-type p53 and thus contribute to the transformed phenotype. To determine if mutation in p53 participates in the development of the malignant clone in NPC, the structure and sequence of p53 in 42 primary, metastatic, and nude mouse-passaged NPC specimens was analyzed. A high frequency (6 of 9) of mutations was detected in the nude mouse-passaged tumors, while only 2 of 15 metastatic and 0 of the 18 primary tumors harbored mutant p53. The p53 mutations included single-point mutations and more extensive changes such as frame shifts, deletion, duplication, or complete loss of coding sequences. These data indicate that alterations of the p53 gene are unlikely to be involved in the initial genetic events leading to the clonal outgrowth in NPC. However, although it is a rare NPC which can be established in nude mice, this growth advantage appears to be conferred on tumors bearing a mutant p53.

Animals↗
PubMed1986

The development of the small intestine.

The remarkable degree of coordination between the development of various aspects of gastrointestinal function suggests that the process may be triggered by a single or a few central mechanisms, such as weaning and (or) hormones. Precocious development of enzyme and transport function can be induced by exogenous thyroxine and corticosteroids, while thyroidectomy and adrenalectomy abolish the normal pattern of postnatal development. These hormones may have a primary or a permissive role. Activation of the dormant hormonal mechanism could be controlled by a genetically coded biologic clock, such as chronologic age, or by a biological signal such as body size and oral intake. Generally speaking, shortly after birth, there are increases in the intestinal mucosal surface area, brush border membrane enzymes, and carrier-mediated transport. These adaptive changes occur as a result of the genetic endowment of the animal, but may be modified by environmental factors, particularly nutrient intake.

Aging↗
PubMed2003

ESEfinder: A web resource to identify exonic splicing enhancers.

Point mutations frequently cause genetic diseases by disrupting the correct pattern of pre-mRNA splicing. The effect of a point mutation within a coding sequence is traditionally attributed to the deduced change in the corresponding amino acid. However, some point mutations can have much more severe effects on the structure of the encoded protein, for example when they inactivate an exonic splicing enhancer (ESE), thereby resulting in exon skipping. ESEs also appear to be especially important in exons that normally undergo alternative splicing. Different classes of ESE consensus motifs have been described, but they are not always easily identified. ESEfinder (http://exon.cshl.edu/ESE/) is a web-based resource that facilitates rapid analysis of exon sequences to identify putative ESEs responsive to the human SR proteins SF2/ASF, SC35, SRp40 and SRp55, and to predict whether exonic mutations disrupt such elements.

Base Sequence↗
PubMed1994

Transfer RNA mutation and the malleability of the genetic code.

We propose that evolutionary reassignment of codons is facilitated by a translationally ambiguous intermediate. For example, recently discovered tRNA mutations that allow relatively efficient simultaneous cognate and near-cognate coding (sharing 2 contiguous nt) in vivo may speed reassignment of the near-cognate codon. As predicted by this notion, characterized codon reassignments are strikingly non-random, and half can be immediately explained by unusual tRNA activities already demonstrated. In addition, sequences of reassigned tRNAs contain sequences that promote ambiguity. tRNA structural change may provide a transitional pathway that allows rapid selection of a new specificity, rather than slow mutation toward a new codon-amino acid association.

Biological Evolution↗
PubMed1988

[Two allelic genes of human p53 code for proteins differing with respect to amino acid sequence].

Two allelic p53 genes were investigated. The allelic gene with BgIII site in the first intron codes for faster p53 protein variant, the other allelic gene coding for slower p53 protein variant (according to the mobility in SDS-PAAG). Exons and flanked regions of introns were sequenced. In coding regions allelic genes only differ by second nucleotides of codon 72 (G----C), which leads to the change in amino acid sequence (Arg----Pro). The relationship of these changes and the function of p53 is discussed.

Alleles↗
PubMed1993

Genetics of tumors of the head and neck.

Two uncommon tumors of the head and neck first revealed primary roles for two classes of cancer genes (oncogenes, tumor suppressor genes) in the origin of human cancer. In Burkitt's lymphoma the initiating event is a chromosomal translocation that leads to unregulated expression of an oncogene (MYCC), whereas retinoblastoma involves loss of function of both copies of a tumor suppressor gene (RB1). In osteosarcoma the RB1 gene is often affected, as is the gene (TP53) that codes for the p53 protein. TP53 is frequently mutated in carcinomas of the head and neck, as in one of the ras oncogenes. Multiple genetic changes typify carcinomas. Some carcinomas of the head and neck contain one of the human papilloma viruses that produce proteins that combine with and inactivate p53 and pRB proteins, rendering mutations in these genes unnecessary.

Burkitt Lymphoma↗
PubMed2005

Mutation screening and association analysis of six candidate genes for autism on chromosome 7q.

Genetic studies have provided evidence for an autism susceptibility locus (AUTS1) on chromosome 7q. Screening for mutations in six genes mapping to 7q, CUTL1, SRPK2, SYPL, LAMB1, NRCAM and PTPRZ1 in 48 unrelated individuals with autism led to the identification of several new coding variants in the genes CUTL1, LAMB1 and PTPRZ1. Analysis of genetic variants provided evidence for association with autism for one of the new missense changes identified in LAMB1; this effect was stronger in a subgroup of affected male sibling pair families, implying a possible specific sex-related effect for this variant. Association was also detected for several polymorphisms in the promoter and untranslated region of NRCAM, suggesting that alterations in expression of this gene may be linked to autism susceptibility.

Autistic Disorder↗