ABCMdb

PMID: 12404105

Schurmann M, Albrecht M, Schwinger E, Stuhrmann M
CFTR gene mutations in sarcoidosis.
Eur J Hum Genet. 2002 Nov;10(11):729-32., [PubMed]

Sentences

No. Mutations Sentence Comment

3 ABCC7 p.Arg75Gln 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. Login to comment 4 ABCC7 p.Arg75Gln 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). Login to comment 14 ABCC7 p.Arg75Gln ABCC7 p.Arg75Gln Two successive studies from Italy reported a high frequency of CFTR mutations in individuals suffering from sarcoidosis.7,8 The most frequent CFTR mutation was R75Q, which was present in three of 26 cases.8 These findings prompted us to screen the panel of 63 families with two or more patients for R75Q. Login to comment 23 ABCC7 p.Arg75Gln The complete panel (63 families) was genotyped for the CFTR gene mutation R75Q by PCR with primers 3i-5 and 3i-3 (according to ref9 ) and restriction enzyme digestion of the corresponding PCR products. Login to comment 24 ABCC7 p.Arg75Gln R75Q (G?A at nucleotide position 356) creates a new Bsr DI cleavage site in the mutated gene sequence. Login to comment 25 ABCC7 p.Arg75Gln DNA from a R75Q heterozygous subject from a previous study10 was used as control DNA. Login to comment 30 ABCC7 p.Tyr1092* ABCC7 p.Ile336Lys A list of the corresponding mutations with detailed frequencies in the German population is given in ref. 12 Finally, we tested all 54 samples for the presence of I336K, Y1092X, 3272-26A?G and CFTRdel2,3 (21 kb) by PCR and restriction enzyme digestion with the respective enzymes (for mutation references, refer to the Cystic Fibrosis Genetic Analysis Consortium database). Login to comment 31 ABCC7 p.Arg75Gln 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 Fisher´s exact test, and non-parametric linkage analysis was performed using Genehunter 2.0.14 Results R75Q was identified in eight patients, three parents and in one unaffected sibling from a total of seven families. Login to comment 32 ABCC7 p.Arg75Gln In these families, R75Q was not present in 13 patients, six parents, nor in three unaffected siblings. Login to comment 33 ABCC7 p.Arg75Gln In six of the seven families at least one affected sibling was negative for R75Q. Login to comment 34 ABCC7 p.Arg75Gln ABCC7 p.Arg75Gln The frequency of R75Q heterozygosity in the group of unrelated founders (parents) was 0.057 (three in 53), which was slightly higher but statistically not significantly different (P=0.5; Fisher`s exact test) from the frequency of 0.011 (four in 94) among healthy German controls.10 The frequency for R75Q among patients was 0.05 (eight in 138), which was statistically neither different compared to the group of healthy controls (P=0.43) nor to the parents (P=0.64) nor to the healthy siblings (P=0.35). Login to comment 37 ABCC7 p.Arg75Gln We conclude that R75Q is not associated with sarcoidosis in our study group. Login to comment 38 ABCC7 p.Arg75Gln In addition, we did not obtain any evidence for linkage between sarcoidosis and R75Q by linkage analysis. Login to comment 40 ABCC7 p.Arg75Gln To conclude it can be said that, R75Q and the sarcoidosis phenotype segregate as independent traits (Figure 1). Login to comment 50 ABCC7 p.Arg75Gln We identified the CFTR mutation R75Q in seven families but could not find any evidence, which would prove that this mutation has a predisposing effect on the disease, neither by association nor by linkage analysis. Login to comment 51 ABCC7 p.Arg75Gln Instead, R75Q segregated independently from the sarcoidosis phenotype in these families. Login to comment 52 ABCC7 p.Arg75Gln Previously, we and others reported a relatively high frequency of R75Q among patients with congenital absence of the vas deferens (CAVD),10,17,18 bronchiectasis,7,19 atypical mild cystic fibrosis,20 chronic idiopathic pancreatitis,21 allergic bronchopulmonary aspergillosis,22 and sarcoidosis.7,8 Bombieri et al. Login to comment 53 ABCC7 p.Arg75Gln concluded from their study that R75Q may be a CFTR gene mutation characteristic of sarcoidosis.8 Our results do not support this hypothesis. Login to comment 54 ABCC7 p.Arg75Gln Moreover, R75Q is listed as a polymorphism (356G/A) in the Cystic Fibrosis Genetic Analysis Consortium database. Login to comment 55 ABCC7 p.Arg75Gln ABCC7 p.Arg75Gln The exact role of R75Q still remains unclear, but the results from the studies mentioned above suggest that R75Q may be associated with mild CF symptoms. Login to comment 69 ABCC7 p.Arg75Gln Clearly, a concerted Europe-wide approach Figure 1 Detection of R75Q (356G/A) by PCR and restriction digestion in three families. Login to comment 71 ABCC7 p.Arg75Gln PCR products with primers encompassing R75Q were digested with the restriction enzyme Bsr DI and visualised by agarose gel electrophoresis. Login to comment 74 ABCC7 p.Arg75Gln In each of the three families, only one of the affected siblings is heterozygote for R75Q (three bands), while the other affected siblings are homozygous for the G allele (one band). Login to comment 75 ABCC7 p.Arg75Gln Lane C: Bsr DI digested PCR product from R75Q heterozygous control DNA. Login to comment