Increased proportion of exon 9 alternatively spliced CFTR transcripts in vas deferens compared with nasal epithelial cells

Teng, Hui; Jorissen, Mark; Poppel, H. Van; Legius, Eric; Cassiman, Jean‐Jacques; Cuppens, Harry

doi:10.1093/hmg/6.1.85

Cited by 81 publications

(47 citation statements)

References 24 publications

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“…In the presence of mild CFTR mutations, there might be enough CFTR protein to prevent disease in other organs, but the additive effect of the T5 allele specifically affects the reproductive tract and results in the production of a nonfunctional protein, thus explaining why CAVD does not necessarily coincide with pulmonary or pancreatic manifestations of CF. 9,45,46 Although a particular sequence variation may not have deleterious consequences when present in isolation, the combination of such variations in cis might result in a less functional or even insufficient CFTR protein. Studies have shown that intronic IVS8 poly(TG)m and exonic (M470V) cis-acting elements affect the splicing efficiency of the CFTR gene bearing the T5 allele.…”

Section: Discussionmentioning

confidence: 99%

Molecular characterization of the cystic fibrosis transmembrane conductance regulator gene in congenital absence of the vas deferens

Grangeia

Sá

Carvalho

et al. 2007

Genetics in Medicine

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Purpose: Approximately 20% of patients with congenital absence of the vas deferens remain without two mutations identified. We applied a strategy of serial screening steps to 45 patients with congenital absence of the vas deferens and characterized cystic fibrosis transmembrane conductance regulator gene mutations in all cases.Methods: DNA samples of 45 patients with congenital absence of the vas deferens were screened by successive different molecular genetics approaches. Results: Initial screening for the 31 most frequent cystic fibrosis mutations, IVS8 poly(TG)m, poly(T)n, and M470V polymorphisms, identified 8 different mutations in 40 patients (88.9%). Extensive cystic fibrosis transmembrane conductance regulator gene analysis by denaturing gradient gel electrophoresis, denaturing high-performance liquid chromatography, and DNA sequencing detected 17 further mutations, of which three were novel. Cystic fibrosis transmembrane conductance regulator gene rearrangements were searched by semiquantitative fluorescent multiplex polymerase chain reaction, which detected a CFTRdele2,3 (21 kb) large deletion and confirmed two homozygous mutations. Overall, 42 patients (93.3%) had two mutations and 3 patients (6.7%) had one mutation detected. Conclusions: The present screening strategy allowed a higher mutation detection rate than previous studies, with at least one cystic fibrosis transmembrane conductance regulator gene mutation found in all patients with congenital absence of the vas deferens. Genet Med 2007:9(3):163-172. Key Words: CAVD, CBAVD, CUAVD, CFTR mutations, CFTR rearrangements, cystic fibrosis, male infertilityCongenital absence of the vas deferens (CAVD) in otherwise healthy males is responsible for 1% to 2% of male infertility and 6% of obstructive azoospermia cases. The disease was classified as a primary genital form of cystic fibrosis (CF) because 67% to 85% of patients with CAVD have mutations and/or splicing variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Patients with CAVD with upper urinary tract malformations (20% of cases) have a normal frequency of CFTR mutations and are thus considered a distinct clinical entity with a different cause. [1][2][3][4][5][6][7][8] CFTR genotypes in patients with CAVD are markedly different from those found in patients with CF. Patients with CAVD are usually heterozygous for a mild mutation on one allele and a severe mutation on the second allele (88%), or for mild mutations on both CFTR alleles (12%). On the other hand, homozygosity or compound heterozygosity for two severe mutations is responsible for the classic CF phenotype. The most common CFTR mutations found in CAVD are T5 allele, deltaF508, and R117H, with the combination between the T5 allele and a severe CF mutation in the other allele being the main cause of CAVD. 9 The polymorphic polythymidine locus (Tn) is located within the 3= splice acceptor site of intron 8 (IVS8 poly[T]n). The length of the IVS8 poly(T)n tract (T5/T7/T9) is inversely correlated with the degree of ...

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Section: Discussionmentioning

confidence: 99%

Molecular characterization of the cystic fibrosis transmembrane conductance regulator gene in congenital absence of the vas deferens

Grangeia

Sá

Carvalho

et al. 2007

Genetics in Medicine

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“…The splicing efficiency of CFTR exon 9 is poor in the vas deferens compared with nasal epithelial cells, independently of the IVS 8-T genotype. Therefore, men with the 5T variant would produce abnormally low amounts of CFTR protein, which may affect the reproductive tract in CAVD specifically; however, there may be sufficient protein to prevent disease in other organs usually affected by CF (Mak et al, 1997;Teng et al, 1997;Wong et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Screening for cystic fibrosis transmembrane conductance regulator gene mutations in men included in an intracytoplasmic sperm injection programme

Boucher¹,

Creveaux²,

Grizard³

et al. 1999

Molecular Human Reproduction

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The present study was undertaken to evaluate the frequency and nature of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene in infertile patients undergoing intracytoplasmic sperm injection. A total of 90 patients were screened for a panel of 10 mutations in the CFTR gene frequently involved in congenital absence of the vas deferens (CAVD); the patients included 14 with azoospermia and CAVD, 39 patients with azoospermia without CAVD (n ⍧ 39) and 37 patients with severe oligozoospermia. The length of the polymorphic polypyrimidine tract (allele 5T, 7T and 9T) in the intron 8/exon 9 splice-acceptor site was also determined. In 10 out of 14 patients with CAVD, CFTR mutations were found; nine patients had one ∆ ∆F508 mutation and one patient had two CFTR mutations (N1303K/R117H). Allele 5T was present in eight of these patients. In six patients, 5T was the non-∆ ∆F508 allele and in two patients there was no known CFTR mutation. None of the CFTR mutations were observed in patients with azoospermia without CAVD or with severe oligozoospermia and the frequency of allele 5T was 3.6% (three out of 78 alleles) and 1.35% (one out of 74 alleles) respectively. Our observation suggests that the CFTR gene is not involved in either spermatogenesis or in the pathology of the genital tract, except for CAVD.

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“…CBAVD patients are frequently compound heterozygotes for a known disease-associated CFTR mutation and the T 5 allele. In some cases, the proportion of exon 9 − CFTR transcripts is increased in the adult vas deferens compared to nasal epithelial cells of the same individual (Teng et al 1997). A mild CFTR mutation may then become a disease-causing mutation in the vas deferens of CBVAD patients due to the overall decrease in full-length CFTR mRNA.…”

Section: Associated Disordersmentioning

confidence: 99%

The Phenotypic Consequences of CFTR Mutations

Rowntree¹,

Harris²

2003

Annals of Human Genetics

299

215

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SummaryCystic fibrosis is a common autosomal recessive disorder that primarily affects the epithelial cells in the intestine, respiratory system, pancreas, gall bladder and sweat glands. Over one thousand mutations have currently been identified in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene that are associated with CF disease. There have been many studies on the correlation of the CFTR genotype and CF disease phenotype; however, this relationship is still not well understood. A connection between CFTR genotype and disease manifested in the pancreas has been well described, but pulmonary disease appears to be highly variable even between individuals with the same genotype. This review describes the current classification of CFTR mutation classes and resulting CF disease phenotypes. Complex disease alleles and modifier genes are discussed along with alternative disorders, such as disseminated bronchiectasis and pancreatitis, which are also thought to result from CFTR mutations.

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Increased proportion of exon 9 alternatively spliced CFTR transcripts in vas deferens compared with nasal epithelial cells

Cited by 81 publications

References 24 publications

Molecular characterization of the cystic fibrosis transmembrane conductance regulator gene in congenital absence of the vas deferens

Molecular characterization of the cystic fibrosis transmembrane conductance regulator gene in congenital absence of the vas deferens

Screening for cystic fibrosis transmembrane conductance regulator gene mutations in men included in an intracytoplasmic sperm injection programme

The Phenotypic Consequences of CFTR Mutations

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