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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The autosomal recessive genetic disorder ataxia telangiectasia (AT) has been characterized in the RNA transcripts of cultured cells. Molecular species of poly (A)+ RNA that are present in AT fibroblasts (ATFs) at levels different from those in normal human fibroblasts (NHFs) were cloned in the form of cDNAs. Treatment with bleomycin, which transiently inhibits DNA synthesis in NHFs but not in ATFs, differentiated ATFs and NHFs in the above cloning. Two cDNA clones with an identical DNA sequence were isolated, the corresponding RNA transcript of which was induced approximately twofold after bleomycin treatment in NHFs, but not in ATFs. The DNA sequence of these two cDNA clones, except for its polyadenylation part, was identical to the heavy-strand replication origin sequence of human mitochondrial DNA. The results indicate the possibility that the induction of this RNA transcript is involved in bleomycin-induced inhibition of DNA synthesis in normal human cells, while it is defective in AT cells. In addition, the previous observation that much fibronectin is produced in AT cells was confirmed in this study in terms of RNA transcription.
Somat Cell Mol Genet 1992 Mar
PMID:Gene expression in ataxia telangiectasia cells as perturbed by bleomycin treatment. 137 97

Cystic fibrosis (CF) is a recessive hereditary disorder, requiring both parental cystic fibrosis conductance transmembrane regulator (CFTR) genes to carry mutations for clinical disease to manifest, i.e., only 50% of normal CFTR gene expression is required to maintain a normal phenotype. To help define the minimum amount of normal CFTR gene expression necessary to maintain normalcy, we have capitalized on our prior observation (Chu, C.-S., B. C. Trapnell, J. J. Murtagh, Jr., J. Moss, W. Dalemans, S. Jallat, A. Mercenier, A. Pavirani, J.-P. Lecocq, G. R. Cutting, et al. 1991. EMBO [Eur. Mol. Biol. Organ] J. 10:1355-1363) that normal individuals can have up to 66% of bronchial CFTR mRNA transcripts that are missing exon 9, a region representing 21% of the sequence coding for the critical nucleotide (ATP)-binding fold 1 (NBF1) of the predicted CFTR protein. The study population included 78 individuals with no prior diagnosis of CF. Evaluation of bronchial epithelial cells (obtained by bronchoscopy) revealed that exon 9 was variably deleted in all individuals. Remarkably, there were four individuals, all greater than or equal to 35 yr, in whom bronchial epithelial cells exhibited 73, 89, 90, and 92% CFTR transcripts with inframe deletion of exon 9, respectively, despite normal sweat Cl- and no clinical manifestation of CF. In the context that only 8% or less of bronchial CFTR transcripts need exon 9 to maintain normal airway function, these observations strongly suggest that either exon 9 is not necessary for CFTR structure and/or function or that only a very small fraction of bronchial epithelial cells need to express normal CFTR mRNA transcripts with exon 9 to perform the function of CFTR sufficient to maintain a normal phenotype in vivo.
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PMID:Extensive posttranscriptional deletion of the coding sequences for part of nucleotide-binding fold 1 in respiratory epithelial mRNA transcripts of the cystic fibrosis transmembrane conductance regulator gene is not associated with the clinical manifestations of cystic fibrosis. 138 23

Cystic fibrosis (CF) is a common genetic disorder in Caucasians, and in some populations 70% of cases are associated with a 3 base pair (bp) deletion (delta F508) in the CFTR gene. We have implemented a fluorescence-based, multiplex allele-specific polymerase chain reaction (MASPCR) assay for deletion of the delta F508 mutation. Different allele-specific fluorescently-tagged primers are used in the PCR reaction to distinguish between normal and delta F508 alleles. Fluorescent PCR products are then visualized in a single lane on an agarose gel following electrophoresis combined with real-time multicolour fluorescence detection. The approach simplifies diagnosis of the most common mutation in the CFTR gene, and holds promise for a multiplex allele-specific, fluorescence-tagged gene amplification strategy for detection of additional CF mutations which may result in more cost-effective testing without increasing the risk of missed or erroneous diagnoses.
Mol Cell Probes 1992 Aug
PMID:Fluorescence-based, multiplex allele-specific PCR (MASPCR) detection of the delta F508 deletion in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. 138 22

Familial hypoalphalipoproteinemias (HA) are a heterogenous group of disorders characterized by various degrees of HDL deficiency. Differential diagnosis involves clinical and biochemical evaluation after intervention designed to correct known secondary causes of low HDL. Two specific HAs are discussed in this report: 1. primary isolated HA (PIHA) is a poorly characterized entity with an apparent autosomal dominant transmission and distinct abnormalities in the structure and function of HDL. 2. Lecithin: cholesterol acyltransferase (LCAT) deficiency syndromes are caused by a number of different genetic defects that lead to at least two distinct clinical presentations i.e. familial LCAT deficiency and fish eye disease. PIHA is an example of a genetic disorder whose diagnosis would greatly be improved by the availability of molecular diagnostic tests. Conversely, the effect of the genetic heterogeneity of LCAT deficiency syndromes on diagnosis is best overcome by utilizing existing biochemical measurement of LCAT activity and the plasma cholesterol esterification rate.
Mol Cell Biochem 1992 Aug 18
PMID:Analysis of familial hypoalphalipoproteinemia syndromes. 151 5

While routinely mapping point mutations within the arginase locus of a collection of hyperargininemic patients, we discovered that a base immediately outside a restriction endonuclease recognition site (TaqI) can eliminate cleavage of this site by this enzyme. The genetic lesion lay in a base immediately flanking a TaqI recognition site within exon 8 of the arginase locus and abolished cutting by approximately 80%. We wish to emphasize the necessity of heeding subtle cues frequently encountered while generating restriction enzyme data, because neither Southern blot maps nor endonuclease digestion of polymerase chain reaction amplified products of exon 8 accurately predicted where the point mutation lay. To our knowledge, this is the first instance of inhibition of cleavage by flanking bases occurring on natural (nonsynthetic) DNA substrates, i.e., within the clinical setting of characterization of a human genetic disorder.
Somat Cell Mol Genet 1991 Jul
PMID:Effect of an adjacent base on detection of a point mutation by restriction enzyme digestion. 188 33

Pseudoxanthoma elasticum (PXE) is a heritable disorder of connective tissue that is characterized by redundant folds of skin in flexural areas. There is considerable evidence that suggests that the elastic fiber is the main site of the abnormality although the primary molecular defect has not been identified. The aim of this study was to identify differences between PXE and normal skin elastins. Elastins from normal, nonsolar-exposed skin, and pseudoxanthoma elasticum lesional skin were purified and their solubilization by pancreatic elastase was compared. Results demonstrated that elastin derived from normal skin was more susceptible to proteolytic cleavage than elastin purified from either pseudoxanthoma elasticum lesional skin or ligamentum nuchae. Pretreatment of the lesional elastin with testicular hyaluronidase increased its solubilization two-fold and generated a unique 15,000 Da molecular weight fragment. Elastin prepared from PXE skin may contain bound glycosaminoglycans which interfere with elastase activity. The susceptibility of normal skin elastin to proteolytic degradation may have implications in the study of aging skin.
Exp Mol Pathol 1991 Oct
PMID:Elastase digestion of normal and pseudoxanthoma elasticum lesional skin elastins. 193 14

Phenylketonuria (PKU) is a genetic disorder secondary to a deficiency of hepatic phenylalanine hydroxylase (PAH). Several mutations in the PAH gene have recently been reported, and linkage disequilibrium was observed between RFLP haplotypes and specific mutations. A new molecular lesion has been identified in exon 7 of the PAH gene in a Hungarian PKU patient by direct sequencing of PCR-amplified DNA. The C-to-T transition causes the substitution of Arg243 to a termination codon, and the mutant allele is associated with haplotype 4 of the PAH gene. The mutation is present in two of nine mutant haplotype 4 alleles among Eastern Europeans and is not present among Western Europeans and Asians. The rarity of this mutant allele and its restricted geographic distribution suggest that the mutational event occurred recently on a normal haplotype 4 background in Eastern Europe.
Somat Cell Mol Genet 1990 Jan
PMID:Molecular genetics of PKU in eastern Europe: a nonsense mutation associated with haplotype 4 of the phenylalanine hydroxylase gene. 230 42

Transthyretin (TTR, also called prealbumin) is a plasma protein produced in liver. The variant types of TTR are known to be closely associated with familial amyloidotic polyneuropathy (FAP), an autosomal dominant genetic disorder. This article summarizes, together with some new data, our current knowledge on FAP from the view point of molecular genetics. As an initial step towards understanding the disease at the DNA level, the complete nucleotide sequence of the human TTR gene (-7 kb to 7 kb; 1 kb = 10(3) bases) was determined and analyzed. The gene is located on chromosome 18 q12.1 and consists of four exons. Homology search revealed that there exist several possible regulatory signals in the 5' flanking region of the gene, including the binding sites for liver-specific nuclear factors HNF-1, 3, 4 and C/E BP, which have been previously identified in mouse TTR gene. Sequence analysis enabled us to identify all the mutations related to various types of FAP. The mutations were shown to be almost completely linked to FAP and it has become possible to diagnose FAP even at presymptomatic (prenatal) stages by recombinant DNA technology, with a high reliability. Haplotype analysis of FAP families using DNA polymorphic markers in the TTR locus suggested that the Val30----Met mutation closely related to type I FAP, the most common type of FAP, has frequently recurred in the human population to generate FAP families of independent origin. Although the primary cause of FAP has become clear, extensive screening of FAP families in various locations suggested that the expression of FAP is a complicated process and affected by some unknown factors (other than TTR).(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Biol Med 1989 Apr
PMID:Human transthyretin (prealbumin) gene and molecular genetics of familial amyloidotic polyneuropathy. 269 90

Recent developments in molecular biology technology have greatly facilitated the methods for detection of mutations responsible for genetic disorders in both humans and animals. In this article we review some of these new methods and present a diagnostic algorithm that facilitates the routine and rapid diagnosis of any genetic disorder for which the defective gene has been isolated.
Mol Biol Med 1989 Dec
PMID:Detection of new mutation disease in man and mouse. 269 10

Familial amyloidotic polyneuropathy (FAP) is a genetic disorder showing autosomal dominant inheritance. Amyloid fibrils of FAP patients from various origins have been shown to contain a prealbumin variant with Val30----Met30 substitution as a major component. However, the structure of the prealbumin gene responsible for the variation has not been characterized. We determined the complete nucleotide sequence of the prealbumin gene from a patient with the Japanese type of FAP. In comparison with a normal prealbumin gene sequence, the patient's gene was found to be carrying seven base substitutions. The substitution responsible for the Val----Met change was found in exon 2, as expected, and the others were in introns. Hybridization analyses of normal and FAP patient DNAs showed that the base substitution in exon 2 was specific for FAP but the others were polymorphic changes. It was concluded that the mutation responsible for the Val----Met change is the only base change specific for FAP in the prealbumin gene.
Mol Biol Med 1986 Aug
PMID:Structure of the mutant prealbumin gene responsible for familial amyloidotic polyneuropathy. 302 7


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