"PL215"
Dotaz
Zobrazit nápovědu
Závěrečná zpráva o řešení grantu Interní grantové agentury MZ ČR
Přeruš. str. : il. ; 32 cm + 3 volné přílohy
- Konspekt
- Patologie. Klinická medicína
- NLK Obory
- embryologie a teratologie
- genetika, lékařská genetika
- NLK Publikační typ
- závěrečné zprávy o řešení grantu IGA MZ ČR
[1st ed.] 631 s. : obr., tab., grafy ; 22 cm
The etiology of allergic bronchopulmonary aspergillosis (ABPA) is not well understood. A clinical phenotype resembling the pulmonary disease seen in cystic fibrosis (CF) patients can occur in some individuals with ABPA. Reports of familial occurrence of ABPA and increased incidence in CF patients suggest a possible genetic basis for the disease. To test this possibility, the entire coding region of the cystic fibrosis transmembrane regulator (CFTR) gene was analyzed in 11 individuals who met strict criteria for the diagnosis of ABPA and had normal sweat electrolytes (< or = 40 mmol/liter). One patient carried two CF mutations (deltaF508/R347H), and five were found to carry one CF mutation (four deltaF508; one R117H). The frequency of the deltaF508 mutation in patients with ABPA was significantly higher than in 53 Caucasian patients with chronic bronchitis (P < .0003) and the general population (P < .003). These results suggest that CFTR plays an etiologic role in a subset of ABPA patients.
- MeSH
- aspergilóza alergická bronchopulmonální etiologie genetika MeSH
- bronchitida genetika MeSH
- chronická nemoc MeSH
- cystická fibróza genetika MeSH
- dospělí MeSH
- fenotyp MeSH
- genotyp MeSH
- heterozygot MeSH
- lidé středního věku MeSH
- lidé MeSH
- mutace * MeSH
- protein CFTR * genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, P.H.S. MeSH
Mutation G551D of exon 11 of the cystic fibrosis transmembrane conductance regulator gene is one of the most common mutations in patients of European origin. In order to test the hypothesis that the mutation is identical by descent in these patients, we have studied haplotypes for the three intragenic microsatellite markers IVS8CA, IVS17bTA and IVS17bCA from 92 patients bearing this mutation, who had been referred to laboratories in Ireland, Scotland, England, France (Brittany) and the Czech Republic. In all cases we found that only haplotype 16-7-17 is associated with mutation G551D. Our results support the hypothesis of identity by descent of all cystic fibrosis chromosomes bearing mutation G551D in these patient populations, and suggest that given the combined mutation rate of the microsatellite markers, there is a low probability (p < 0.05) that the haplotype where mutation G551D first occurred remained unaltered for more than 170 generations.
We have identified a novel CFTR missense mutation associated with a protein trafficking defect in mammalian cells but normal chloride channel properties in a Xenopus oocyte assay. The mutation, a cysteine for glycine substitution at residue 480 (G480C), was detected in a pancreatic insufficient, African-American, cystic fibrosis (CF) patient. G480C was found on one additional CF chromosome and on none of 220 normal chromosomes, including 160 chromosomes from normal African-American individuals. Western blot analysis and immunofluorescence studies revealed that, in 293T cells, the encoded mutant protein was not fully glycosylated and failed to reach the plasma membrane, suggesting that the G480C protein was subject to defective intracellular processing. However, in Xenopus oocytes, a system in which mutant CFTR proteins are less likely to experience an intracellular processing/trafficking deficit, expression of G480C CFTR was associated with a chloride conductance that exhibited a sensitivity to activation by forskolin and 3-isobutyl-1-methylxanthine (IBMX) that was similar to that of wild-type CFTR. This appears to be the first identification of a CFTR mutant with a single amino acid substitution in which the sole basis for disease is mislocalization of the protein.
- MeSH
- AMP cyklický farmakologie metabolismus MeSH
- bodová mutace * MeSH
- chloridové kanály fyziologie genetika MeSH
- cystein genetika MeSH
- cystická fibróza * genetika MeSH
- glycin genetika MeSH
- imunoblotting MeSH
- kultivované buňky MeSH
- lidé MeSH
- membránové proteiny * analýza fyziologie genetika MeSH
- molekulární sekvence - údaje MeSH
- oocyty fyziologie účinky léků MeSH
- proteinkinasy závislé na cyklickém AMP, podjednotka RIIbeta farmakologie MeSH
- savci genetika MeSH
- sekvence nukleotidů MeSH
- teplota MeSH
- Xenopus laevis MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
- Research Support, U.S. Gov't, P.H.S. MeSH
- MeSH
- cystická fibróza diagnóza MeSH
- dospělí MeSH
- lidé MeSH
- nemoci dýchací soustavy MeSH
- nosní polypy etiologie patologie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
delta F508 is the most frequent cystic fibrosis (CF) mutation and accounts for approximately 70% of CF chromosomes worldwide. Three highly polymorphic microsatellite markers have been used to study the origin and evolution of delta F508 chromosomes in Europe. Haplotype data demonstrate that delta F508 occurred more than 52,000 years ago, in a population genetically distinct from any present European group, and spread throughout Europe in chronologically distinct expansions, which are responsible for the different frequencies of delta F508 in Europe.
- MeSH
- biologická evoluce MeSH
- časové faktory MeSH
- cystická fibróza * genetika MeSH
- genetická variace MeSH
- genetické markery MeSH
- haplotypy MeSH
- lidé MeSH
- mutace * MeSH
- populační genetika MeSH
- repetitivní sekvence nukleových kyselin MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- Geografické názvy
- Evropa MeSH
Microsatellite analysis of chromosomes carrying particular cystic fibrosis mutations has shown different haplotypes in four cases: R334W, R347P, R1162X, and 3849 + 10kbC-->T. To investigate the possibility of recurrence of these mutations, analysis of intra- and extragenic markers flanking these mutations has been performed. Recurrence is the most plausible explanation, as it becomes necessary to postulate either double recombinations or single recombinations in conjunction with slippage at one or more microsatellite loci, to explain the combination of mutations and microsatellites if the mutations arose only once. Also in support of recurrence, mutations R334W, R347P, R1162X, and 3849 + 10kbC-->T involve CpG dinucleotides, which are known to have an increased mutation rate. Although only 15.7% of point mutations in the coding sequence of CFTR have occurred at CpG dinucleotides, approximately half of these CpG sites have mutated at least once. Specific nucleotide positions of the coding region of CFTR, distinct from CpG sequences, also seem to have a higher mutation rate, and so it is possible that the mutations observed are recurrent. G-->A transitions are the most common change found in those positions involved in more than one mutational event in CFTR.
- MeSH
- chromozomální aberace MeSH
- cystická fibróza * genetika MeSH
- haplotypy MeSH
- lidé MeSH
- mapování chromozomů MeSH
- membránové proteiny * genetika MeSH
- molekulární sekvence - údaje MeSH
- mutace * genetika MeSH
- polymerázová řetězová reakce MeSH
- polymorfismus genetický MeSH
- protein CFTR MeSH
- sekvence nukleotidů MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
