Exon 9 of the CFTR gene: splice site haplotypes and cystic fibrosis mutations

Dörk, Thilo; Fislage, Rainer; Neumann, Thomas; Wulf, Brigitte; Tümmler, Burkhard

doi:10.1007/bf00218916

Cited by 43 publications

(25 citation statements)

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“…However, interestingly, the M allele has been reported for some CF mutations, and particularly for ∆F508 [28][29][30] , most mutations have been found to be associated with the M470 allele, while the V470 allele shows an extended haplotype homozygosity [27,31,32] . The T7 allele tracts were combined with (TG)11 and (TG)12 repeats, but the T7-(TG)10 haplotype was not found in our study.…”

Section: Discussionmentioning

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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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: Discussionmentioning

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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“…†Data were obtained from Kiesewetter et al, 27 Dörk et al, 28 and Cuppens et al 29 ‡Includes pooled data from the Spanish population studied and the studies listed above under "Other populations." §PϽ0.001 for the comparison with the general population.…”

Section: Cftr Mutations and The 5t Allele In Patients With Cbavdmentioning

confidence: 99%

Mutations in the Cystic Fibrosis Gene in Patients with Congenital Absence of the Vas Deferens

Chillón¹,

Casals²,

et al. 1995

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Background. Congenital bilateral absence of the vas deferens (CBAVD) is a form of male infertility in which mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene have been identified. The molecular basis of CBAVD is not completely understood. Although patients with cystic fibrosis have mutations in both copies of the CFTR gene, most patients with CBAVD have mutations in only one copy of the gene.Methods. To investigate CBAVD at the molecular level, we have characterized the mutations in the CFTR gene in 102 patients with this condition. None had clinical manifestations of cystic fibrosis. We also analyzed a DNA variant (the 5T allele) in a noncoding region of CFTR that causes reduced levels of the normal CFTR protein. Parents of patients with cystic fibrosis, patients with types of infertility other than CBAVD, and normal subjects were studied as controls.Results. Nineteen of the 102 patients with CBAVD had mutations in both copies of the CFTR gene, and none of them had the 5T allele. Fifty-four patients had a mutation in one copy of CFTR, and 34 of them (63 percent) had the 5T allele in the other CFTR gene. In 29 patients no CFTR mutations were found, but 7 of them (24 percent) had the 5T allele. In contrast, the frequency of this allele in the general population was about 5 percent.Conclusions. Most patients with CBAVD have mutations in the CFTR gene. The combination of the 5T allele in one copy of the CFTR gene with a cystic fibrosis mutation in the other copy is the most common cause of CBAVD. The 5T allele mutation has a wide range of clinical presentations, occurring in patients with CBAVD or moderate forms of cystic fibrosis and in fertile men. (N Engl

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“…The mutations R117H, R347H, ∆F508, and 384910kb C>T exist in association with more than one intron 8 allele (Dörk et al, 1994;Chillón et al, 1995), but small numbers of any particular mutation-intron 8 combination make phenotypic conclusions difficult to establish. The variable phenotypes reported for certain mutations may correlate with the proportion of appropriate exon 9 splicing.…”

Section: Introductionmentioning

confidence: 99%

Rapid characterization of the variable length polythymidine tract in the cystic fibrosis (CFTR) gene: Association of the 5T allele with selected CFTR mutations and its incidence in atypical sinopulmonary disease

et al. 1997

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Exon 9 of the CFTR gene: splice site haplotypes and cystic fibrosis mutations

Cited by 43 publications

References 47 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

Mutations in the Cystic Fibrosis Gene in Patients with Congenital Absence of the Vas Deferens

Rapid characterization of the variable length polythymidine tract in the cystic fibrosis (CFTR) gene: Association of the 5T allele with selected CFTR mutations and its incidence in atypical sinopulmonary disease

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