Biomedical subjects

M Super

Publications and source records attributed to M Super.

At least 19 recordsLinked to original sources

PubMed1992

Characterization of the murine macrophage mannose receptor: demonstration that the downregulation of receptor expression mediated by interferon-gamma occurs at the level of transcription.

The macrophage mannose receptor (MMR) is a 175-Kd cell-surface transmembrane glycoprotein that is expressed on tissue macrophages where it functions both to mediate the uptake of mannose-rich glycoproteins and as a phagocytic receptor for bacteria, yeasts, and other pathogenic microorganisms. In this report we describe the cloning of the full-length cDNA of the mouse macrophage mannose receptor and we investigate the level at which interferon gamma (IFN-gamma) downregulates mannose receptor expression. The latter is a marker of the functional state of the cell as high levels are expressed on resident and inflammatory macrophages, whereas cells activated by treatment with IFN-gamma have decreased-to-absent cell-surface mannose receptor expression. The murine MMR cDNA contains an open reading frame that predicts a protein of 1,456 amino acids. Transient expression of the protein in heterologous cells shows that this cDNA encodes a functional mannose receptor. The deduced amino acid sequence of this protein has an overall 82% homology with the human mannose receptor and as such, the ectodomain contains an N-terminus that is cysteine-rich followed by a fibronectin type II domain and eight carbohydrate recognition domains (CRDs). The ectodomain is linked to a hydrophobic transmembrane region and a 46-amino acid cytoplasmic tail. All of the eight CRDs are particularly well conserved, especially CRD4, which shows 92% homology with the equivalent region of the human protein. Steady-state levels of murine MMR mRNA were measured in the macrophage cell line J774E, which is known to express the protein at the cell surface. These levels were decreased by a 4- to 8-hour incubation with IFN-gamma, but were almost abolished by overnight treatment with this cytokine. Nuclear run-on experiments showed that IFN-gamma inhibits MMR gene transcription. Therefore, the regulation of mannose receptor expression by IFN-gamma provides a novel system in which to study the mechanisms by which this cytokine represses gene expression.

Amino Acid Sequence↗

PubMed1992

Screening for cystic fibrosis carriers.

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Cystic Fibrosis↗

PubMed1992

Mutations of the cystic fibrosis gene locus within the population of the Northwest of England.

A large group of patients with cystic fibrosis (CF) from the Northwest of England were analysed for mutations within the CF gene. Eleven separate mutations were identified comprising 91.5% of the responsible genes. Molecular confirmation of a CF diagnosis becomes possible in 84% of cases. Only 1.19% of cases negative for the nine mutations have CF. The results of molecular analysis in this population have useful implications in respect of diagnosis validation and population carrier screening.

Adolescent↗

PubMed1992

Distinct and overlapping functions of allelic forms of human mannose binding protein.

Human mannose binding protein (MBP) is a C-type serum lectin involved in first-line host defense against a variety of bacterial, fungal and viral pathogens. Recently an association was found between low levels of serum MBP and an increased frequency of recurrent infections in infants. A particular genotype, in which glycine is substituted by aspartic acid at codon 54 of MBP in the fifth collagen repeat, shows apparent concordance with the clinical phenotype. We report, however, that this genotype occurs in 5% of the population and encodes a functional protein. Our results indicate that the Gly54Asp allele does not account for a deficiency state, but instead suggest that MBP may have two predominant allelic forms that have overlapping function and differ only in their ability to activate the classical pathway of complement.

Alleles↗

PubMed1992

The fragile X syndrome.

An amplification of a highly unstable DNA element has been identified at the fragile X locus in Xq27.3. This sequence appears to be both the source of the primary mutation causing the fragile X syndrome, apparently having its causative effect through the methylation of the FMR-1 HTF island and the region of cytogenetic fragility. The direct analysis of the genotype of carrier and affected individuals can be used as a direct diagnosis tool which will improve both the accuracy and speed of diagnosis. The identification of hereditary unstable DNA in a disease with such a wide level of non-penetrance and variable phenotype may give clues as to the basis of non-penetrance in other human genetic disorders.

Chromosome Fragility↗

PubMed1992

Milestones in cystic fibrosis.

The study of cystic fibrosis (CF) provides a fascinating insight into developments in medicine in the 20th century. Milestones include the first clear clinical descriptions in the 1930s, discovery of a sweat electrolyte abnormality, establishing the autosomal recessive mode of inheritance and improvements in treatment. Microdissection experiments on sweat glands allowed the main defect to be delineated as one of chloride transport. Location of the gene to chromosome 7 made prenatal diagnosis feasible and carrier detection in siblings. The CF gene--its product being the cystic fibrosis transmembrane conductance regulator (CFTR), and its major mutation Delta F508 was discovered in 1989. World-wide collaboration has resulted in discovery of more than 150 further mutations. Incorporation of CFTR into non-chloride transporting insect cells by conferring chloride transport, proved it a chloride channel. CFTR incorporated into adenovirus results in correction of the chloride transport defect in airway cells, bringing gene therapy closer.

Cystic Fibrosis↗

PubMed1992

The role of mannose-binding proteins in host defense.

The human mannose-binding protein (MBP) appears to function as an "ante-antibody" as its physiological role is in first line host defense. Low baseline serum levels are rapidly increased as part of the acute phase reactant and circulating MBP can act as a direct opsonin or activate the classical alternative complement pathway. MBP appears to selectively recognize an array of apparently disparate oligosaccharides that decorate gram-negative and gram-positive bacteria as well as certain parasites, yeasts, and fungi. MBP may be considered a "pattern" recognition molecule that has homologs in primitive life forms. Its ability to distinguish self from nonself indicates that it may play an important role in innate immunity.

Amino Acid Sequence↗

PubMed1992

The gene defect in cystic fibrosis and clinical applications of the knowledge.

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Cystic Fibrosis↗

PubMed1992

Development, multiplexing, and application of ARMS tests for common mutations in the CFTR gene.

The amplification refractory mutation system (ARMS) is a simple, rapid and reliable method for the detection of any mutation involving single base changes or small deletions. We have applied ARMS methodology to the detection of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Single ARMS tests have been developed for 11 CFTR mutations found in the northwest of England. ARMS reactions for the most common mutations have been multiplexed to give a test which will detect the presence of the delta F508, G551D, G542X, and 621 + 1G----T mutations in a DNA sample. The multiplex test has been validated by the analysis of over 500 previously genotyped samples and has been found to be completely accurate. The rapid detection of the most common mutations has enabled early molecular confirmation of suspected cystic fibrosis in neonates, rapid typing of cystic fibrosis patients and their relatives, and testing of sperm and egg donors.

Base Sequence↗

PubMed1991

Preventing neural tube defects.

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Drug Therapy, Combination↗

PubMed1991

Molecular basis of opsonic defect in immunodeficient children.

Low serum mannose-binding protein (MBP) concentrations are associated with a common opsonic defect. Sequence analysis of the MBP gene in three children with recurrent infections, the opsonic defect, and low serum MBP concentrations showed a point mutation at base 230 of exon 1 causing a change of codon 54 from GGC to GAC. The replacement of glycine with an aspartic acid residue disrupts the fifth Gly-Xaa-Yaa repeat in the collagen-like domain of each 32 kD MBP peptide chain and probably prevents the formation of the normal triple helix. Study of sixteen members of the three families showed autosomal dominant co-inheritance of the mutation and low serum MBP concentrations.

Alleles↗

PubMed1991

A deletion mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) locus: Delta I507.

During the development of an amplification refractory mutation system (ARMS) assay for the detection of the Delta F508 mutation and corresponding normal locus in cystic fibrosis we discovered a family in which a further variant of the sequence exists. PCR amplification and direct sequencing of a region of exon 10 of the CFTR locus indicated the deletion of the three base pairs encoding isoleucine or isoleucine, or possibly the presence of a single base substitution in conjunction with the Delta F508 mutation. The resulting protein has a deletion of an isoleucine residue at position 507 as opposed to the previously described deletion of phenylalanine at position 508. We conclude that the loss of an isoleucine residue at position 507 (Delta I507) is another defective variant of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene product.

Amino Acid Sequence↗

PubMed1991

Use of the polymerase chain reaction to analyse sequence variation within a major neutralizing epitope of glycoprotein B (gp58) in clinical isolates of human cytomegalovirus.

The heterogeneity of low passage human cytomegalovirus (HCMV) strains was determined by HindIII typing of 28 clinical isolates from transplant patients. These data have shown that, in general, each patient's strain has a unique restriction profile, usually comprising combinations of HindIII sites present in one or more of the tissue culture-adapted strains AD169, Towne and Davis. To map sequence changes in a more refined manner we performed detailed analyses of 33 low passage clinical isolates, including those aforementioned, analysing a sequence within glycoprotein B containing a major neutralizing epitope. A 149 bp sequence containing the epitope (amino acids 608 to 625) was amplified using the polymerase chain reaction, the products were cloned and their DNA sequence was determined. Comparison of the DNA and deduced amino acid sequences with those of HCMV strain AD169 revealed that there was a high degree of conservation of the epitope between the 33 clinical isolates. However 10 of the isolates possessed silent mutations and three isolates contained mutations producing amino acid changes within the neutralizing epitope. The possible functional significance of these changes is discussed.

Amino Acid Sequence↗

PubMed1991