CFTR gene mutations - including three novel nucleotide substitutions - and haplotype background in patients with asthma, disseminated bronchiectasis and chronic obstructive pulmonary disease

Tzetis, Maria; Efthymiadou, Alexandra; Strofalis, Stefanos; Psychou, Photini; Dimakou, Aikaterini; Pouliou, Evi; Doudounakis, Stavros; Kanavakis, Emmanuel

doi:10.1007/s004390100467

Cited by 130 publications

(123 citation statements)

References 27 publications

(32 reference statements)

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“…Prior studies have demonstrated that some individuals who carry T5 with a severe CF-causing mutation may have non-classic CF; others may have male infertility due to CBAVD [5,[17][18][19][20] , lung disease such as bronch iectasis [6,21,22] and chronic pancreatitis [23,24] ; and approximately 40% may be healthy and fertile as a consequence of incomplete penetrance [5,17] . In our study, the frequency of the T5 allele in the Chinese population was 3.8%, which is similar to the Vietnamese (3.7%) [14] , but lower than that in Caucasians (7.0%) [5,13] , and higher than in Japanese (0.6-1.0%) [14,15] and Koreans (1.7%) [16] . The main TG-repeat was (TG)11/11, with 61 (46.21%) individuals having the (TG)11/11 haplotype.…”

Section: Discussionsupporting

confidence: 61%

“…The TGrepeats, 5' of the poly-T, also influence splicing of exon 9 [12] , and when present on the same allele as a 5T repeat, the longer the TG-repeats, the higher the proportion of CFTR transcripts that will lack exon 9. On the other hand, the M470V polymorphism on exon 10 affects the intrinsic chloride activity, and thereby affects the function of the CFTR protein [12,13] . Although mutations and polymorphisms of CFTR have been extensively studied in Western populations, their importance is less well studied in East Asia because of the rare presentation of classical CF.…”

Section: Rapid Communicationmentioning

confidence: 99%

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Comparative analysis of common CFTR polymorphisms poly-T, TG-repeats and M470V in a healthy Chinese population

Qin¹,

Ding²,

Wei³

2008

WJG

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Huang Q, Ding W, Wei MX. Comparative analysis of common CFTR polymorphisms poly-T, TG-repeats and M470V in a healthy Chinese population. World J Gastroenterol 2008; 14(12): 1925-1930 INTRODUCTIONThe cystic fibrosis transmembrane conductance regulator (CFTR) gene on chromosome 7q31 spans approximately 250 kb of DNA and encodes 27 exons encodes [1] . The CFTR gene encodes a cAMP-and ATP-dependent chloride channel that is present in the apical membrane of the epithelial cells that line most exocrine glands [2] . Phosphorylation of the regulatory domain by protein kinase A, followed by binding and hydrolysis of ATP at both nucleotide-binding domains, regulates the transport of chloride ions through the channel [3] . Absence, reduced levels, or malfunction of the CFTR protein results in cystic fibrosis (CF), and CF-like diseases such as congenital bilateral absence of the vas deferens (CBAVD) [4,5] , bronchiectasis [6] and chronic pancreatitis [7] . Since the discovery of the CFTR gene, more than 1000 mutations and 200 polymorphisms have been identified [8] . CF is one of the most common autosomal recessive disorders in Caucasians, with an incidence of approximately 1 in 2500 Caucasian births and a carrier frequency of approximately 1 in 25. However, in Asians, the prevalence of CF is very low, with an incidence of approximately 1 in 100 000, and in particular, the severe mutations, such as ∆F508, G542X and N1303K, are rarely found in Asians. Previous studies have demonstrated that polymorphisms outside the CFTR gene [9,10] , as well as within the gene, may affect transcription or function of the CFTR protein and modify the phenotype of some CF mutations. It has been mentioned that poly-T, TG-repeats and M470V polymorphisms play a role in the development of CF-like diseases. The poly-T tract located at the junction of intron Abstract AIM: To investigate the three important cystic fibrosis transmembrane conductance regulator (CFTR ) haplotypes poly-T, TG-repeats and the M470V polymorphisms in the Chinese population, and to compare their distribution with that in Caucasians and other Asian populations. RAPID COMMUNICATION METHODS:Genomic DNA was extracted from blood leukocytes. Exons 9 and 10 of the CFTR gene were obtained through polymerase chain reaction (PCR). Exon 9 DNA sequences were directly detected by an automated sequencer and poly-T and TG-repeats were identified by direct sequence analysis. Pure exon 10 PCRamplified products were digested by Hph Ⅰ restriction enzyme and the M470V mutation was detected by the AGE photos of digestion products.RESULTS: T7 was the most common (93.6%) haplotype and the (TG)11 frequency of 57.2% and (TG)12 frequency of 40.9% were dominant haplotypes in the junction of intron 8 (IVS-8) and exon 9. The frequency of T5 was 3.8% and all T5 allele tracts (10 alleles) were joined with (TG)12. Four new alleles of T6 (1.5%) were found in three healthy individuals. In exon 10, the V allele (56.1%) was slightly more frequent than the M allele (43.9%), and the M/V (45.5%) was the dominan...

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Section: Discussionsupporting

confidence: 61%

Section: Rapid Communicationmentioning

confidence: 99%

Comparative analysis of common CFTR polymorphisms poly-T, TG-repeats and M470V in a healthy Chinese population

Qin¹,

Ding²,

Wei³

2008

WJG

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“…Single allele CFTR mutations have been identified at a higher frequency in patients with CFTR-related diseases, such as CBAVD, DB, pancreatitis and ABPA, than in the general population. Of these, heterozygosity for the CFTR M470V allele has been implicated in the development of asthma, DB and COPD of unknown aetiology [Casals, et al, 2004;Tzetis, et al, 2001]. Also, heterozygosity for other CFTR mutations, such as ∆F508, R117H and R75Q, has been linked to the development of CBAVD and bronchiectasis [Wilschanski, et al, 2006;Ziedalski, et al, 2006].…”

Section: Discussionmentioning

confidence: 99%

“…Also, individuals that are heterozygous for a CF disease-causing mutation are predisposed to a range of complex diseases in which multiple genetic and environmental factors play a role. These complex CFTR-related diseases (CFTR-RD) include: (i) congenital bilateral absence of vas deferens (CBAVD) [Casals, et al, 2000;Jarvi, et al, 1998], (ii) disseminated bronchiectasis (DB) [Bombieri, et al, 1998;Casals, et al, 2004;Girodon, et al, 1997;King, et al, 2004], (iii) pancreatitis [Chen and Ferec, 2009;Cohn, et al, 2005;Noone, et al, 2001], and (iv) allergic bronchopulmonary aspergillosis (ABPA) [Miller, et al, 1996;Tzetis, et al, 2001] of unknown aetiology.…”

Section: Introductionmentioning

confidence: 99%

Disrupted posttranscriptional regulation of the cystic fibrosis transmembrane conductance regulator (CFTR) by a 5′UTR mutation is associated with a cftr-related disease

2011

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Cystic fibrosis (CF) is characterised as a single-gene disorder with a simple, autosomal recessive mode of inheritance. However, translation of CFTR genotype into CF phenotype is influenced by nucleotide sequence variations at multiple genetic loci, and individuals heterozygous for CFTR mutations are predisposed to a range of CFTR-related conditions, such as Disseminated Bronchiectasis. CF disease severity and CFTR-related conditions are more akin to complex, multifactorial traits, which are increasingly being associated with mutations that perturb gene expression. We have identified a patient with Disseminated Bronchiectasis, who is heterozygous for a single nucleotide substitution in the CFTR 5´UTR (c.-34C>T). The c.-34C>T mutation creates an upstream AUG codon and upstream open reading frame that overlaps, and is out of frame with, the CFTR protein coding sequence. Using luciferase reporter constructs, we have shown that the c.-34C>T mutation decreases gene expression by 85%-99%, by reducing translation efficiency and mRNA stability. This is the first CFTR regulatory mutation shown to act at a post-transcriptional level that reduces the synthesis of normal CFTR (Class V), and reaffirms the importance of regulatory mutations as a genetic basis of multifactorial phenotypes.

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“…Yapılan bir çalışmada bronkoalveolar lavaj sıvısında aktif VDBP düzeyleri, KOAH'lı ve asemptomatik sigara içicilerinde, sigara içmeyenlere oranla daha yüksek bulunmuştur. 39 Yapılan çeşitli çalışmalarda Gc2 allelinin KOAH gelişimi için koruyucu, Gc1F allelinin ise KOAH için risk faktörü olduğu ileri sürülmüştür. 42 b) Tümör nekrozis faktör: Tümör nekrozis faktörler (TNF) pek çok enflamatuar mediatörün üretimini ve salgılanmasını sağlayan, sistemik enflamatuar yanıttan sorumlu anahtar sitokinlerdir.…”

Section: D) Hem Oksijenazunclassified

Genetic Risk Factors in Chronic Obstructive Pulmonary Disease

Mutlu¹,

Gülbaş²,

Günen³

2012

Solunum

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ÖZETKronik obstrüktif akciğer hastalığı (KOAH) oluşumunda genetik faktörlerin rolünün önemli olduğu fikri genel olarak kabul edilmektedir. Bununla birlikte, yarım asırdan uzun süredir yapılan birçok çalışmadan α-1 antitripsin eksikliğinin tek başına KOAH'a yol açabileceği bilgisi dışında kesin bir sonuç elde edilememiştir. Elimizdeki veriler ışığında, birçok gen bozuklukları arasındaki etkileşimlerin üstüne eklenen sigara dumanı gibi çevresel faktör-lerin KOAH oluşumdan sorumlu olduğu söylenebilir. Şüphesiz gelecekte de KOAH oluşumunda genetik risk faktörleri, üzerinde en fazla çalışılan konulardan biri olmaya devam edecektir. Anah tarkelimeler: KOAH, risk faktörleri, genetik ABST RACTThe role of genetic factors in development of chronic obstructive pulmonary disease (COPD) is accepted in general. However, other than α-1 antitrypsin deficiency which alone can lead to COPD, the studies performed longer than half a century did not yield any certain result on the genetics of COPD. Regarding the data available, it can be said that addition of environmental factors like cigarette smoking on interrelations between genetic abnormalities are responsible for COPD development. No doubt that the role of genetics on COPD development will continue to be one of the important research issues in future too. Solunum Dergisi t Levent Cem Mutlu ve ark. Keywords: COPD, risk factors, genetic

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CFTR gene mutations - including three novel nucleotide substitutions - and haplotype background in patients with asthma, disseminated bronchiectasis and chronic obstructive pulmonary disease

Cited by 130 publications

References 27 publications

Comparative analysis of common CFTR polymorphisms poly-T, TG-repeats and M470V in a healthy Chinese population

Comparative analysis of common CFTR polymorphisms poly-T, TG-repeats and M470V in a healthy Chinese population

Disrupted posttranscriptional regulation of the cystic fibrosis transmembrane conductance regulator (CFTR) by a 5′UTR mutation is associated with a cftr-related disease

Genetic Risk Factors in Chronic Obstructive Pulmonary Disease

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