A New Mutation in the CFTR Gene, Composed of Two Adjacent DNA Alterations, Is a Common Cause of Cystic Fibrosis among Georgian Jews

Shoshani, Tzipora; Berkun, Yaakov; Yahav, Yaacov; Augarten, Arie; Bashan, Nurit; Rivlin, Y.; Gazit, Ephrayim; Sereth, Hagit; Kerem, Eitan; Kerem, Bat Sheva

doi:10.1006/geno.1993.1046

Cited by 17 publications

(16 citation statements)

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“…Patients homozygous for the W1282X mutation were found to have severe presentations of the CF disease, like patients homozygous for the AF508 mutation (28). The results of our study indicate that the severe clinical phenotype is not necessarily due to a null phenotype resulting from severe deficiency of mRNA.…”

Section: Discussionmentioning

confidence: 47%

“…The patients' diagnoses had been confirmed before this study. The disease presentation ofthe patients has been described previously (28). RNA Polymerase chain reaction (PCR).…”

Section: Methodsmentioning

confidence: 99%

“…20 Ml of each RT-PCR sample were subjected to electrophoresis on a 1.4% agarose gel. Blots were prepared as previously described (28). Filters were hybridized for 18 h with 5 X 106 cpm/ml of32P end-labeled oligonucleotides or 5 X 101 cpm/ml 32P random-primed specific genomic DNA-PCR products.…”

Section: Methodsmentioning

confidence: 99%

“…Among patients of Jewish Ashkenazi origin -25% are homozygous for this nonsense mutation. We recently compared the clinical presentation of patients homozygous for the W1282X mutation and patients heterozygous for both the AF508 and the WI 282X mutations (28). We found that patients in both groups have similar severe disease presentation as reflected by pancreatic insufficiency, high incidence of meconium ileus, early age at diagnosis, poor nutritional status, and variable pulmonary function.…”

Section: Introductionmentioning

confidence: 99%

“…Recently, a major mutation, W1282X, was found in 60% of the chromosomes carried by patients from this ethnic group (28). This mutation creates a stop codon in exon 20 of the CF gene, which is located in the second nucleotide binding fold of the CFTR protein.…”

Section: Introductionmentioning

confidence: 99%

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Similar levels of mRNA from the W1282X and the delta F508 cystic fibrosis alleles, in nasal epithelial cells.

Shoshani¹,

Kerem²,

Szeinberg³

et al. 1994

J. Clin. Invest.

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The effect of nonsense mutations on mRNA levels is variable. The levels of some mRNAs are not affected and truncated proteins are produced, while the levels of others are severely decreased and null phenotypes are observed. The effect on mRNA levels is important for the understanding of phenotype-genotype association. Cystic fibrosis (CF) is a lethal autosomal recessive disease with variable clinical presentation. Recently, two CF patients with mild pulmonary disease carrying nonsense mutations (R553X, W1316X) were found to have severe deficiency of mRNA. In the Jewish Ashkenazi CF patient population, 60% of the chromosomes carry a nonsense mutation, W1282X. Patients homozygous for this mutation have severe disease presentation with variable pulmonary disease. The presence of CF transcripts in a group of patients homozygous and heterozygous for this mutation was studied by reverse transcriptase PCR of various regions of the gene. Subsequent hybridization to specific CF PCR probes and densitometry analysis indicated that the CF mRNA levels in patients homozygous for the W1282X mutation are not significantly decreased by the mutation. mRNA levels were compared for patients heterozygous for the W1282X mutation. The relative levels of mRNA with the W1282X, and the AF508 or the normal alleles, were similar in each patient. These results indicate that the severe clinical phenotype of patients carrying the W1282X mutation is not due to a severe deficiency of mRNA. In addition, the severity, progression, and variability of the pulmonary disease are affected by other, as yet unknown factors. (J. Clin. Invest.

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Section: Discussionmentioning

confidence: 47%

“…The patients' diagnoses had been confirmed before this study. The disease presentation ofthe patients has been described previously (28). RNA Polymerase chain reaction (PCR).…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Similar levels of mRNA from the W1282X and the delta F508 cystic fibrosis alleles, in nasal epithelial cells.

Shoshani¹,

Kerem²,

Szeinberg³

et al. 1994

J. Clin. Invest.

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Analysis of 16 cystic fibrosis mutations in Mexican patients

Villalobos-Torres

Rojas-Martı́nez

Villareal-Castellanos

et al. 1997

Am. J. Med. Genet.

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We carried out molecular analysis of 80 chromosomes from 40 unrelated Mexican patients with a diagnosis of cystic fibrosis. The study was performed in two PCR steps: a preliminary one to identify mutation delta F508, the most frequent cause of cystic fibrosis worldwide, and the second a reverse dot-blot with allele-specific oligonucleotide probes to detect 15 additional common mutations in the Caucasian population. A frequency of 45% for delta F508 was found, making it the most common in our sample of Mexican patients. Another five mutations (G542X, 3,849 + 10 kb C-->T, N1303K, SN549N, and 621 + 1 G-->T) were detected, and those accounted for 11.25%. The remaining mutations (43.75%) were undetectable with the methodology used.

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Mutation spectrum in Jewish cystic fibrosis patients in Israel: Implication to carrier screening

Quint¹,

Lerer²,

Sagi³

et al. 2005

Am. J. Med. Genet.

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We have tested 144 unrelated Jewish patients suffering from the classical form of cystic fibrosis. The patients were screened for a panel of 12 mutations including the six Ashkenazi founder mutations (DeltaF508, W1282X, N1303K, G542X, 3849 + 10 kb C-->T, 1717-1G > A) and six mutations that were found in non-Ashkenazi Jewish patients (S549R (T-->G), G85E, 405 + 1G-->A, W1089X, Y1092, and D1152H). Patients of Georgian origin were tested also for the Q359K/T360K mutation. In addition, all the patients were tested for the IVS-8 variant (9T/7T/5T). Of all the cystic fibrosis (CF)-bearing chromosomes, 94% (264/281) were accounted for by one of the known mutations, and none of the patients had the 5T allele of the IVS-8 variant. Single strand conformation polymorphism (SSCP) analysis of the coding sequence of the CFTR gene followed by sequencing showed eight mutations on ten CF chromosomes, leaving seven chromosomes (2.5%) with unknown mutations. We identified three mutations in two or more CF chromosomes, 2571 + 1insT in Jews from Iraq, 3121-1G > A in patients from Kurdistan and I1234V in Yemenite Jewish patients. The other five mutations appeared on a single allele and are considered "private mutations." In this study we have identified 99% of CF alleles in Ashkenazi Jewish patients, 91% in Jews of North African origin and 75% in Jewish patients from Iraq. The significance of these findings to the population screening in Israel is discussed.

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A New Mutation in the CFTR Gene, Composed of Two Adjacent DNA Alterations, Is a Common Cause of Cystic Fibrosis among Georgian Jews

Cited by 17 publications

References 0 publications

Similar levels of mRNA from the W1282X and the delta F508 cystic fibrosis alleles, in nasal epithelial cells.

Similar levels of mRNA from the W1282X and the delta F508 cystic fibrosis alleles, in nasal epithelial cells.

Analysis of 16 cystic fibrosis mutations in Mexican patients

Mutation spectrum in Jewish cystic fibrosis patients in Israel: Implication to carrier screening

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