ABCMdb

PMID: 25797027

Bergougnoux A, Viart V, Miro J, Bommart S, Molinari N, des Georges M, Claustres M, Chiron R, Taulan-Cadars M
Should diffuse bronchiectasis still be considered a CFTR-related disorder?
J Cyst Fibros. 2015 Sep;14(5):646-53. doi: 10.1016/j.jcf.2015.02.012. Epub 2015 Mar 18., [PubMed]

Sentences

No. Mutations Sentence Comment

73 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg75Gln ABCC7 p.Arg75Gln ABCC7 p.Ala46Asp ABCC7 p.Ala46Asp Sequence variation Allelic frequency Distribution cDNA name Protein name Legacy name rs number DB group (n = 94) Control group (n = 94) General populationa CF groupb Databasesc Our study c.-1043dupT - -912dupT no rs 0.01 0 NA 0 (n1) UV NNV c.-966 T N G - -834 T N G rs4148682 0.051 0.0319 0.043-0.562 (19 studies) 0.02 (n1) P P c.-812 T N G - -680 T N G rs181008242 0.01 0 NA 0.015 (n1) UV NNV c.137C N A p.Ala46Asp A46D rs151020603 0.01 0 NA 0.00015 (n2) CF CF c.224G N A p.Arg75Gln R75Q rs1800076 0.021 0.018 0-0.11 (7 studies) 0 (n1) P NNV c.350G N A p.Arg117His R117H rs78655421 0.01 0 0-0.002-0.004 (3 studies) 0.003 (n2) 0.005 (n3) M M c.489 + 23C N G p. Login to comment 77 ABCC7 p.Arg668Cys ABCC7 p.Arg668Cys ABCC7 p.Gly576Ala ABCC7 p.Gly576Ala (=) IVS8-(T)n no rs NA NA NA NA UV UV (ND) c.1519_1521delATC p.Ile507del I507del/ƊI507 rs121908745 0.021 0 NA 0.0024 (n2) 0.0038 (n3) CF CF (ND) c.1521_1523delCTT p.Phe508del F508del/ƊF508 rs113993960 0.01 0 0.01 (calculated) 0.67 (n1) CF CF c.1584G N A p.Glu528Glu 1716G N A rs1800095 0.021 0.0638 0.005-0.042 (15 studies) 0 (n1) P NNV c.1727G N C p.Gly576Ala G576A rs1800098 0.0638 0.0213 0.003-0.33 (4 studies) 0 (n1) UV M c.2002C N T p.Arg668Cys R668C rs1800100 0.0638 0.0319 0.004-0.02 (14 studies) 0 (n1) UV M c.2620-26A N G p. Login to comment 78 ABCC7 p.Val754Met ABCC7 p.Val754Met ABCC7 p.Leu997Phe ABCC7 p.Leu997Phe (=) 2752-26A N G rs201716473 0.01 0 0.005 (1 study) 0 (n1) UV P c.2260G N A p.Val754Met V754M rs150157202 0.01 0 0.002 (1 study) 0 (n1) UV NNV c.2898G N A p.Thr966Thr T966T rs1800109 0.01 0.01 0.007-0.017 (5 studies) 0 (n1) UV NNV c.2991G N C p.Leu997Phe L997F rs1800111 0.021 0.01 0-0.003 (4 studies) 3.7.10-5 (n2) M M c.3139 + 42A N T p. Login to comment 88 ABCC7 p.Ala46Asp Three alterations were well-known CF mutations: p.Phe508del was found in two patients, whereas p.Ile507del and p.Ala46Asp were each detected in only one patient. Login to comment 89 ABCC7 p.Arg117His ABCC7 p.Leu997Phe The mild mutation p.Leu997Phe was found in two patients and one control, whereas p.Arg117His was associated with the c. Login to comment 93 ABCC7 p.Arg668Cys ABCC7 p.Gly576Ala The UVs p.Gly576Ala and p.Arg668Cys were found in six patients with DB and two controls. Login to comment 95 ABCC7 p.Gly576Ala [Gly576Ala;p.Arg668Cys] [8,17]; however no familial segregation was available for the present study. Login to comment 96 ABCC7 p.Arg668Cys Furthermore, p.Arg668Cys was found alone in one healthy control. Login to comment 110 ABCC7 p.Arg75Gln ABCC7 p.Arg668Cys ABCC7 p.Gly576Ala The results of this analysis and comparison, when possible, with the MAF range for the general population (dbSNP database) or the CF population (our laboratory cohort or previously published control cohorts [10,11]) indicated that the variants p.Arg75Gln, p.Gly576Ala and p.Arg668Cys were twice more present in the DB cohort than in the general population. Login to comment 115 ABCC7 p.Ser1235Arg In silico analysis predicted that among the variants exclusively found in the control group only p.Ser1235Arg could induce functional alterations. Login to comment 129 ABCC7 p.Gly551Asp ABCC7 p.Ala46Asp Two known CF mutations were used as controls: p.Ala46Asp and p.Gly551Asp. Login to comment 136 ABCC7 p.Arg668Cys ABCC7 p.Gly576Ala Splicing was altered in the minigenes containing the exonic variants p.Gly576Ala, p.Arg668Cys and, to a lesser extent, p.Thr966Thr. Login to comment 137 ABCC7 p.Gly576Ala For p.Gly576Ala, complete exon 13 skipping was observed, as previously described [19], although the bioinformatics analysis predicted no dramatic change. Login to comment 138 ABCC7 p.Arg668Cys Indeed, the in silico analysis predicted that only the p.Arg668Cys missense variants could lead to a splicing defect. Login to comment 139 ABCC7 p.Arg668Cys In agreement, when using the exon 14-WT and the c.2002C N T (p.Arg668Cys) minigenes, three transcript populations were identified, corresponding to complete exon 14 inclusion (upper band) or skipping (lower band), or inclusion of exon 14 lacking the first 248 nucleotides (middle band), as already described [20]. Login to comment 142 ABCC7 p.Arg668Cys ABCC7 p.Gly576Ala Moreover, for the variants p.Gly576Ala and p.Arg668Cys, the quantity of normal CFTR transcript was reduced by 57 and 37%, respectively, compared to the WT gene (Fig. 2C). Login to comment 148 ABCC7 p.Val754Met ABCC7 p.Arg75Gln ABCC7 p.Arg668Cys ABCC7 p.Gly576Ala Transfection of full length CFTR containing the mutation p.Arg75Gln, p.Gly576Ala/p.Arg668Cys (alone and together), p.Val754Met or p.Thr966Thr induced a 30-50% decrease in CFTR mRNA level, compared to WT CFTR (Fig. 2C). Login to comment 152 ABCC7 p.Ala46Asp Similar results were obtained for the p.Ala46Asp variant. Login to comment 153 ABCC7 p.Arg117His ABCC7 p.Val754Met ABCC7 p.Arg75Gln ABCC7 p.Arg668Cys ABCC7 p.Gly576Ala ABCC7 p.Leu997Phe Quantification of the blots indicated that the level of mature CFTR protein was decreased by 17%-26% in cells expressing the p.Arg75Gln, p.Arg117His, p.Gly576Ala, p.Arg668Cys (alone and together), p.Leu997Phe or p.Thr966Thr variant, and by 48% and 39% in cells expressing p.Glu528Glu and p.Val754Met, respectively (Fig. 2D, lower panel). Login to comment 154 ABCC7 p.Gly551Asp Conversely, p.Gly551Asp (used here as control) and p.Tyr1424Tyr CFTR were normally processed. Login to comment 159 ABCC7 p.Gly576Ala ABCC7 p.Leu997Phe [Gly576Ala;p.Arg668Cys] complex allele and the p.Leu997Phe missense mutation [22]. Login to comment 160 ABCC7 p.Val754Met ABCC7 p.Arg75Gln On the other hand, the functional data suggest that the exonic variants p.Arg75Gln, p.Glu528Glu, p.Val754Met and p.Thr966Thr and the promoter variants c.-1043dupT and c.- 812 T N G, which are usually categorized as neutral variants based on epidemiological data, could be considered as in vitro non-neutral variants (NNV). Login to comment 185 ABCC7 p.Arg668Cys ABCC7 p.Gly576Ala Minigene splicing assays in Beas-2B cells to compare the effect of the p.Gly576Ala, p.Arg668Cys and p.Thr966Thr and wild type (WT) CFTR minigenes on the splicing patterns of exons 13, 14 and 16, respectively. Login to comment 215 ABCC7 p.Val754Met ABCC7 p.Arg75Gln The functional data suggest that the exonic variants p.Arg75Gln, p.Glu528Glu, p.Val754Met and p.Thr966Thr and the promoter variants c.-1043dupT and c.-812 T N G, which are usually categorized as neutral variants based on epidemiological data, might be considered NNV. Login to comment