Detection of more than 50 different CFTR mutations in a large group of German cystic fibrosis patients

Dörk, Thilo; Mekus, Frauke; Schmidt, Karen; Bosshammer, J; Fislage, Rainer; Heuer, Thomas; Dziadek, Violetta; Neumann, Thomas; Kälin, Nanette; Wulbrand, Ulrich

doi:10.1007/bf00211022

Cited by 89 publications

(57 citation statements)

References 61 publications

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“…38 The comparable amino acid substitution, Q1291R, in CFTR was observed in patients with cystic fibrosis. 39 It has also been reported that the Q1291R CFTR shows no chloride channel function, although it reaches the plasma membrane as a fully glycosylated mature protein. However, the role of the glutamine in the Q-loop has been controversial because the correspondent glutamine residue in the malK molecule was suggested to be placed too far away from the nucleotide to coordinate Mg 2ϩ and the water molecule that attacks the ␥-phosphate bond.…”

Section: Discussionmentioning

confidence: 99%

Trafficking and functional defects by mutations of the ATP-binding domains in MRP2 in patients with Dubin-Johnson syndrome

et al. 2002

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Dubin-Johnson syndrome (DJS) is a hereditary disease characterized by hyperbilirubinemia.We investigated the consequences of 2 missense mutations, R768W and Q1382R, of nucleotidebinding domains (NBDs) of the multidrug resistance protein 2 (MRP2; ABCC2) that were previously identified in patients with DJS. Pulse chase analysis revealed that the precursor form of the wild-type and Q1382R MRP2 were converted to the mature form, which is resistant to endoglycosidase H (Endo H) in about 60 minutes. However, the precursor form of the R768W MRP2, which is sensitive to endoglycosidase H, was degraded within 120 minutes and did not mature to the fully glycosylated form. Proteasome inhibitors inhibited the degradation of the precursor form of the R768W MRP2. Unlike the R768W MRP2, the Q1382R MRP2 was mainly localized on the apical membrane in the wild-type form. However, efflux of glutathione monochlorobimane (GS-MCLB) and ATP-dependent leukotriene C 4 (LTC 4 ) uptake into plasma membrane vesicles from cells expressing the Q1382R MRP2 were markedly reduced, suggesting that the Q1382R MRP2 on the apical membrane was nonfunctional. Vanadateinduced nucleotide trapping with 8-azido-[␣-32P]ATP in the wild-type MRP2 was stimulated by estradiol glucuronide (E 2 17␤G) in a concentration-dependent manner but that in the Q1382R MRP2 was not. In conclusion, the R768W mutation causes deficient maturation and impaired sorting, and the Q1382R mutation does not affect maturation or sorting but impairs the substrate-induced ATP hydrolysis. (HEPATOLOGY 2002;36:1236-1245

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Section: Discussionmentioning

confidence: 99%

Trafficking and functional defects by mutations of the ATP-binding domains in MRP2 in patients with Dubin-Johnson syndrome

et al. 2002

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“…The set of assays that we used in our study normally detects approximately 90 of 100 mutated CFTR genes in the German population. 12,13 With the exception of DF508, we did not find any of the 34 pathogenic CFTR mutations amongst the sarcoidosis patients. The observed frequency of the DF508 mutation was close to the expected value, and the segregation pattern was compatible with that of independent segregation.…”

Section: Discussionmentioning

confidence: 61%

“…Using this method, we are normally able to detect more than 90% of CF mutations among German CF patients. 12,13 Differences in the genotype frequencies between patients and controls were assessed by Fisheŕs exact test, and non-parametric linkage analysis was performed using Genehunter 2.0. 14 …”

Section: Methodsmentioning

confidence: 99%

CFTR gene mutations in sarcoidosis

et al. 2002

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Sarcoidosis is a complex disease of multiorgan granulomatous inflammation. Genetic susceptibility is involved in the pathogenesis of the disorder. Two successive studies from Italy have shown a high frequency of mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in patients suffering from sarcoidosis. We have genotyped a panel of 63 families with two or more affected siblings for the CFTR gene mutation R75Q, which was found to be present in three of 26 cases of the Italian study. Although R75Q was present in seven families, it was neither associated with the sarcoidosis phenotype in the German population (P=0.5), nor was it linked to sarcoidosis (P=0.54). In addition, a screening for 34 functional CFTR mutations was performed in a subset of 54 patients from 25 families. These patients were known to be concordant for at least one parental copy of the CFTR gene. With the exception of the mayor CF mutation DF508, which was present in three patients and absent in one patient from two families, we did not find any other CF mutation in these 54 patients. Our results do not support the hypothesis that CFTR mutations have a major influence on the pathogenesis of sarcoidosis.

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“…F508del is the most frequent CFTR mutation in German patients (72%) [12]. The class II mutation is characterised by defective protein processing.…”

Section: Resultsmentioning

confidence: 99%

Cystic Fibrosis in 65- and 67-Year-Old Siblings

Mainz

Hammer²,

Rokahr³

et al. 2006

Respiration

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Cystic fibrosis (CF) is a recessive genetic disease caused by defects of the cystic fibrosis trans-membrane regulator (CFTR) gene with a median survival of less than 35 years. This work reports on the oldest living German siblings with CF. Besides clinical history, CF genotype and nasal potential difference (NPD) measurement results, the remarkably high exercise activity of the siblings is discussed as a disease-modifying factor. Both male patients have an overall mild pulmonary manifestation. They have suffered from abdominal symptoms since their early childhood, including recurrent pancreatitis and diffuse symptoms leading to partial gastric resection. They were diagnosed as having CF with positive sweat tests at the advanced ages of 45 and 43 years, respectively. Later on genotyping revealed compound heterozygosity for F508del and 2789+5G→A. Using NPD we demonstrated a CF-typical inhibition of the NPD by the Na channel blocker amiloride, although in both siblings the remaining CFTR function and alternate chloride channel function were detected during superfusion of the nasal epithelium with isoproterenol and ATP. Long-term survival with CF is basically influenced by the CFTR genotype. The patients’ genotype was discussed as a mild one with remaining CFTR function. We demonstrated this residual CFTR function in both siblings using NPD. Additionally the siblings’ continuous healthy lifestyle and their engagement in a remarkably high level of exercise activities from early childhood to the present possibly have an important effect on the long-term outcome of CF as disease-modifying factors. In this regard this report can encourage CF patients to maintain a high level of physical activity in their daily lives.

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Detection of more than 50 different CFTR mutations in a large group of German cystic fibrosis patients

Cited by 89 publications

References 61 publications

Trafficking and functional defects by mutations of the ATP-binding domains in MRP2 in patients with Dubin-Johnson syndrome

Trafficking and functional defects by mutations of the ATP-binding domains in MRP2 in patients with Dubin-Johnson syndrome

CFTR gene mutations in sarcoidosis

Cystic Fibrosis in 65- and 67-Year-Old Siblings

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