BACKGROUND: Cystic fibrosis (CF; OMIM #219700) is a common autosomal recessive disease caused by pathogenic variants (henceforward mutations) in the cystic fibrosis transmembrane conductance regulator gene (CFTR). The spectrum and frequencies of CFTR mutations vary among different populations. Characterization of the specific distribution of CFTR mutations can be used to optimize genetic counseling, foster reproductive choices, and facilitate the introduction of mutation-specific therapies. Chechens are a distinct Caucasian ethnic group of the Nakh peoples that originated from the North Caucasus. Chechens are one of the oldest ethnic groups in the Caucasus, the sixth largest ethnic group in the Russian Federation (RF), and constitute the majority population of the Chechen Republic (Chechnya). The spectrum of CFTR mutations in a representative cohort of Chechen CF patients and healthy individuals was analyzed. METHODS: Molecular genetic analysis of 34 CFTR mutations (representing approx. 80-85% of mutations in multiethnic CF populations of the RF) was performed in 32 CF patients from 31 unrelated Chechen families living in Chechnya. One hundred randomly chosen healthy Chechens were analyzed for the 15 most common "Russian" mutations. The clinical symptoms in Chechen CF patients with different CFTR genotypes were investigated. RESULTS: High frequencies of c.1545_1546delTA (p.Tyr515X; 1677delTA) (52 out of 64 CFTR alleles tested; 81.3%) and c.274G > A (p.Glu92Lys, E92K) (8/64, 12.5%) mutations were found. Twenty patients were homozygous for the c.1545_1546delTA mutation, and eight were compound heterozygous for the c.1545_1546delTA and c.274G > A mutations. Three carriers of the c.1545_1546delTA mutation were also found in the cohort of 100 apparently healthy Chechens (frequency - 0.015). The c.1545_1546delTA and c.274G > A mutations are linked to the same haplotype (22-7-16-13) of intragenic Short Tandem Repeat markers, i.e., IVS1CA, IVS6aGATT, IVS8CA, and IVS17bCA. CONCLUSIONS: The distribution of CFTR mutations in the Chechen CF population is unique regarding the high frequency of mutations c.1545_1546delTA and c.274G > A (more than 90% of the mutant alleles). The c.274G > A mutation is associated with a less severe course of CF than that observed in c.1545_1546delTA homozygotes. Testing for these two variants can be proposed as the first step of CF DNA diagnosis in the Chechen population.

• MeSH
• bodová mutace * MeSH
• časná diagnóza MeSH
• cystická fibróza etnologie   genetika   MeSH
• dítě MeSH
• frekvence genu MeSH
• genetická predispozice k nemoci MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• protein CFTR genetika   MeSH
• sekvenční delece * MeSH
• studie případů a kontrol MeSH
• stupeň závažnosti nemoci MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Rusko MeSH

• Klíčová slova
• Keltové,
• MeSH
• biologická evoluce MeSH
• cystická fibróza dějiny   etnologie   MeSH
• DNA MeSH
• financování organizované MeSH
• lidé MeSH
• Check Tag
• lidé MeSH

BACKGROUND: On the basis of previous findings on random individuals, we hypothesized a preferential association of CF causing mutations with the M allele of the M470V polymorphic site of the CFTR gene. METHODS: We have determined the M/V-CF mutation haplotype in a series of 201 North East Italian and 73 Czech CF patients who were not F508del homozygotes, as F508del was already known to be fully associated with the M allele. RESULTS: Out of 358 not F508del CF genes, 84 carried the V allele and 274 the less common M allele. In the N-E Italian population, MM subjects have a risk of carrying a CF causing mutation 6.9x greater than VV subjects when F508del is excluded and 15.4x when F508del is included. In the Czech population a similar, although less pronounced, association is observed. CONCLUSIONS: Besides the possible biological significance of this association, the possibility of exploiting it for a pilot screening program has been explored in a local North East Italian population for which CF patients were characterized for their CF mutation. General M470V genotyping followed by common CF mutation screening limited to couples in which each partner carries at least one M allele would need testing only 39% of the couples, which contribute 89% of the total risk, with a cost benefit.

• MeSH
• běloši genetika   MeSH
• cystická fibróza etnologie   genetika   MeSH
• frekvence genu genetika   MeSH
• genetické testování metody   MeSH
• heterozygot MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• lidé MeSH
• mutace MeSH
• mutační analýza DNA MeSH
• pilotní projekty MeSH
• protein CFTR genetika   MeSH
• riziko MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Itálie MeSH

• Klíčová slova
• Keltové,
• MeSH
• cystická fibróza * epidemiologie   etnologie   MeSH
• lidé MeSH
• mutace MeSH
• protein CFTR genetika   MeSH
• Check Tag
• lidé MeSH
• Geografické názvy
• Česká republika MeSH
• Evropa MeSH
• Francie MeSH
• Irsko MeSH
• Německo MeSH
• Spojené království MeSH

No large-scale studies of the incidence or disease severity of cystic fibrosis (CF) in black patients have been reported to date. In this study, the CF Foundation National Patient Registry was used to establish new incidence figures and to compare the clinical status of U.S. black (n = 601) and white patients (n = 17,755) with CE Results indicate that the incidence of CF is approximately 1 in 3,200 white and 1 in 15,000 black live births in the United States. Black patients with CF are currently, and were at diagnosis, younger and have poorer nutritional status and pulmonary function than white patients with CF. Fewer have meconium ileus, but more have distal intestinal obstruction syndrome. To control for genotype, each black deltaF508 homozygote (n = 47) was compared with four age- and sex-matched white deltaF508 homozygotes. Only the difference in nutritional status remained. The deltaF508 mutation is associated with higher levels of meconium ileus than other genotypes, independent of race. In conclusion, the clinical manifestations of CF are similar in black and white patients except for poorer nutritional status in black patients, which appears to be independent of age and genotype.

• MeSH
• běloši genetika   MeSH
• černoši * genetika   MeSH
• cystická fibróza * etnologie   genetika   patofyziologie   MeSH
• dítě MeSH
• fenotyp MeSH
• genotyp MeSH
• incidence MeSH
• kojenec MeSH
• lidé MeSH
• nutriční stav MeSH
• předškolní dítě MeSH
• průřezové studie MeSH
• respirační funkční testy MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH
• srovnávací studie MeSH
• Geografické názvy
• Spojené státy americké MeSH

More than 500 mutations have been identified in the CFTR gene, making it an excellent system for testing mutation scanning techniques. To assess the sensitivity of denaturing gradient gel electrophoresis (DGGE), we collected a representative group of 202 CFTR mutations. All mutations analyzed were detected by scanning methods other than the DGGE approach evaluated in this study. DGGE analysis was performed on 24 of the 27 exons and their flanking splice site sequences. After optimization, 201 of the 202 control samples produced an altered migration pattern in the region in which an alteration occurred. The remaining sample was sequenced and found not to have the reported mutation. The ability of DGGE to identify novel mutations was evaluated in three Asian CF patients with four unknown CF alleles. Three novel Asian mutations were detected-K166E, L568X, and 3121-2 A-->G (in homozygosity)-accounting for all CF alleles. These results indicate that an optimized DGGE scanning strategy is highly sensitive and specific and can detect 100% of mutations.

• MeSH
• alely MeSH
• Asijci * genetika   MeSH
• cystická fibróza etnologie   genetika   MeSH
• DNA primery MeSH
• elektroforéza v polyakrylamidovém gelu * metody   MeSH
• exony MeSH
• lidé MeSH
• modely genetické MeSH
• mutace * genetika   MeSH
• mutační analýza DNA * metody   MeSH
• polymerázová řetězová reakce MeSH
• protein CFTR * genetika   MeSH
• retrospektivní studie MeSH
• senzitivita a specificita MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene but the association between mutation (genotype) and disease presentation (phenotype) is not straightforward. We have been investigating whether variants in the CFTR gene that alter splicing efficiency of exon 9 can affect the phenotype produced by a mutation. A missense mutation, R117H, which has been observed in three phenotypes, was found to occur on two chromosome backgrounds with intron 8 variants that have profoundly different effects upon splicing efficiency. A close association is shown between chromosome background of the R117H mutation and phenotype. These findings demonstrate that the genetic context in which a mutation occurs can play a significant role in determining the type of illness produced.

• MeSH
• běloši genetika   MeSH
• černoši genetika   MeSH
• cystická fibróza etnologie   genetika   MeSH
• DNA MeSH
• etnicita genetika   MeSH
• fenotyp MeSH
• genotyp MeSH
• introny MeSH
• lidé MeSH
• membránové proteiny * genetika   MeSH
• molekulární sekvence - údaje MeSH
• mutace * MeSH
• protein CFTR MeSH
• sekvence nukleotidů MeSH
• sestřih RNA MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH