ABCMdb

PMID: 15480987

Hirtz S, Gonska T, Seydewitz HH, Thomas J, Greiner P, Kuehr J, Brandis M, Eichler I, Rocha H, Lopes AI, Barreto C, Ramalho A, Amaral MD, Kunzelmann K, Mall M
CFTR Cl- channel function in native human colon correlates with the genotype and phenotype in cystic fibrosis.
Gastroenterology. 2004 Oct;127(4):1085-95., [PubMed]

Sentences

No. Mutations Sentence Comment

63 ABCC7 p.Arg1162* ABCC7 p.Gln552* ABCC7 p.Ser1159Phe ABCC7 p.Ser1159Phe Original recordings of the effects of cAMP-dependent (100 ␮mol/L IBMX and 1 ␮mol/L forskolin, basolateral) and cholinergic (100 ␮mol/L carbachol and CCH, basolateral) activation on Vte and Rte in rectal tissues from (A) a control subject, (B) a CF patient with no detectable Cl- secretion (R1162X/Q552X), and (C) a CF patient expressing residual Cl- secretion (S1159F/S1159F), as evidenced by lumen-negative Vte responses. Login to comment 78 ABCC7 p.Arg117His ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Pro205Ser ABCC7 p.Glu585* ABCC7 p.Val520Phe ABCC7 p.Gly85Glu ABCC7 p.Thr338Ile ABCC7 p.Met1101Lys ABCC7 p.Met1101Lys ABCC7 p.Arg1066Cys ABCC7 p.Tyr1092* ABCC7 p.Gln39* ABCC7 p.Gln552* ABCC7 p.Phe1052Val ABCC7 p.Gly576Ala ABCC7 p.Gly576Ala ABCC7 p.Ile1234Val ABCC7 p.Val232Asp ABCC7 p.Ser108Phe ABCC7 p.Ser1159Phe ABCC7 p.Ser1159Phe ABCC7 p.Ala561Glu ABCC7 p.Ala561Glu ABCC7 p.Ala561Glu ABCC7 p.Met1137Arg ABCC7 p.Gln637* ABCC7 p.Ile148Asn Relationship Between the CFTR Genotype and Cl- Channel Function in Native Rectal Epithelia CFTR genotype Number of individuals Sweat Cl-concentration (mmol/L)a cAMP-mediated response Carbachol-induced plateau response or maximal lumen-negative response Isc-cAMP (␮A/cm2) Cl- secretion (% of control) Isc-carbachol (␮A/cm2) Cl- secretion (% of control) Cl- secretion absent R1162X/Q552X 1 71 17.1 0 0.7 0 W1282X/3121-2AϾG 1 112 1.9 0 0.6 0 1898 ϩ 1G Ͼ T/1609delCA 2b 114, 118 25.4, 13.4 0, 0 0, 0.7 0, 0 ⌬F508/Q39X 2b 127, 129 2.6, 4.4 0, 0 1.7, 3.7 0, 0 ⌬F508/G542X 1 102 29.0 0 6.6 0 ⌬F508/R553X 3 112, 102, 109 13.1, 4.5, 23.8 0, 0, 0 1.5, 4.4, 1.0 0, 0, 0 ⌬F508/E585X 1 115 1.4 0 1.1 0 ⌬F508/Q637X 1 100 2.9 0 1.2 0 ⌬F508/Y1092X 1 119 0.0 0 -0.3 0 ⌬F508/120del23c 1 72 20.1 0 3.3 0 ⌬F508/182delT 1 116 10.8 0 5.2 0 ⌬F508/3905insT 2 88, 96 8.4, 5.6 0, 0 2.3, -1.1 0, 1 ⌬F508/V520F 1 68 1.2 0 1.7 0 ⌬F508/A561E 3 113, 146, 100 17.0, 17.0, 16.0 0, 0, 0 2.1, 1.5, 3.7 0, 0, 0 ⌬F508/R1066C 1 138 0.0 0 0.0 0 ⌬F508/N1303K 3 100, 117, 94 1.7, 4.1, 1.5 0, 0, 0 -0.6, 2.2, 0.8 0, 0, 0 A561E/A561E 2 101, 116 6.6, 2.0 0, 0 7.3, 3.3 0, 0 Residual Cl- secretiond G542X/I148N 1 75 -50.1 54 -22.2 12 1898 ϩ 3A Ͼ G/1898 ϩ 3A Ͼ G 1 82 -36.8 39 -12.9 7 ⌬F508/3272-26A Ͼ G 1 116 -17.8 19 -27.2 14 ⌬F508/S108F 1 118 -15.8 17 -12.3 7 ⌬F508/R117H 1 90 -35.9 38 -207.7 109 ⌬F508/Y161Cc 1 44 -35.1 37 -45.9 25 ⌬F508/P205S 1 80 -23.3 25 -10.4 5 ⌬F508/V232D 1 120 -16.9 18 -26.9 14 ⌬F508/R334W 1 92 -22.1 23 -21.1 11 ⌬F508/R334W 1 101 -24.5 26 -37.4 20 ⌬F508/T338I 1 73 -44.4 47 -79.4 42 ⌬F508/G576A 1 40 -16.9 18 -115.5 61 ⌬F508/I1234V 1 113 -13.6 15 -8.6 5 G576A/G85E 1 95 -26.1 28 -61.6 32 F1052V/M1137R 1 47 -36.7 39 -146.6 77 M1101K/M1101K 1 94 -11.1 12 -4.8 3 S1159F/S1159F 1 67 -47.9 51 -38.7 21 N1303K/R334W 1 91 -30.3 32 -47.7 25 NOTE. CFTR Cl- channel function was determined in rectal epithelia from Cl- secretory responses induced by IBMX/forskolin (Isc-cAMP) and after co-activation with carbachol (Isc-carbachol). Login to comment 84 ABCC7 p.Gly542* ABCC7 p.Ser108Phe One patient had TG10-9T/TG11-5T with G542X/1148N; the second patient had TG10-9T/TG12-5T with ⌬F508/S108F. Login to comment 87 ABCC7 p.Tyr161Cys By extensive genotyping, 2 disease-causing CFTR mutations were identified in all 45 CF patients studied, including 2 novel mutations (120del23 and Y161C). Login to comment 101 ABCC7 p.Arg117His ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Pro205Ser ABCC7 p.Glu585* ABCC7 p.Val520Phe ABCC7 p.Gly85Glu ABCC7 p.Thr338Ile ABCC7 p.Met1101Lys ABCC7 p.Arg1066Cys ABCC7 p.Tyr1092* ABCC7 p.Gln39* ABCC7 p.Gln552* ABCC7 p.Phe1052Val ABCC7 p.Gly576Ala ABCC7 p.Ile1234Val ABCC7 p.Val232Asp ABCC7 p.Ser108Phe ABCC7 p.Ser1159Phe ABCC7 p.Ala561Glu ABCC7 p.Met1137Arg ABCC7 p.Gln637* ABCC7 p.Ile148Asn Functional Classification and Protein Location of CFTR Mutations Mutation type Severe mutations (protein location) Mild mutations (protein location) Missense V520F, A561E (NBD1) G85E (MSD1, TM1) R1066C (MSD2, CL4) S108F, R117H (MSD1, EL1) N1303K (NBD2) I148N, Y161Ca (MSD1, CL1) P205S (MSD1, TM3) V232D (MSD1, TM4) R334W, T338I (MSD1, TM6) G576A (NBD1) I1234V (NBD2) F1052V, M1101K (MSD2, CL4) M1137R (MSD2, TM12) S1159F (pre-NBD2) Splice 1898 ϩ 1G Ͼ T (R domain) 1898 ϩ 3A Ͼ G (R domain) 3121-2A Ͼ G (MSD2, TM9) 3272-26A Ͼ G (MSD2, TM10) Single amino acid deletion ⌬F508 (NBD1) Nonsense Q39X (N-terminus) G542X, Q552X, R553X, E585X (NBD1) Q637X (R domain) Y1092X (MSD2, CL4) R1162X (pre-NBD2) W1282X (NBD2) Frameshift 120del23a 182delT (N-terminus) 1609delCA (NBD1) 3905insT (NBD2) NOTE. Severe mutation, Cl- secretion absent; mild mutation, residual cAMP-mediated Cl- secretion. Login to comment 114 ABCC7 p.Arg1066Cys ABCC7 p.Ala561Glu CFTR-mediated Cl- secretion was absent (or below the level of detection) in all CF patients compound heterozygous for class I and II mutations, including ⌬F508, nonsense, frameshift, and missense mutations that result in defective processing (A561E, R1066C, Table 3. Login to comment 122 ABCC7 p.Arg117His ABCC7 p.Arg334Trp ABCC7 p.Asn1303Lys ABCC7 p.Phe1052Val ABCC7 p.Ser108Phe N1303K).8,9,11,34 -36 Mutants that have been shown previously to form plasma membrane Cl- channels with altered single-channel properties in heterologous cells (S108F, R117H, R334W, F1052V)10,34,35,37 were associated with residual cAMP-mediated Cl- secretion of ϳ12%-54% of control rectal epithelia. Login to comment 123 ABCC7 p.Pro205Ser ABCC7 p.Met1101Lys ABCC7 p.Gly576Ala ABCC7 p.Met1137Arg Residual function also was observed for mutants, which are expected to form membrane Cl- channels that are reduced in number, either owing to improper protein maturation (P205S, M1137R) or owing to reduced levels of full-length CFTR messenger RNA (3272-26AϾG, G576A).32,38 - 40 The only exception was M1101K, which was reported as a loss of function mutation in heterologous cells34 and was associated with residual CFTR function in the 1 homozygous patient studied (Table 1). Login to comment 125 ABCC7 p.Val520Phe ABCC7 p.Thr338Ile ABCC7 p.Ile1234Val ABCC7 p.Val232Asp ABCC7 p.Ser1159Phe ABCC7 p.Tyr161Cys ABCC7 p.Ile148Asn According to our functional data, 3121-2AϾG, 1898ϩ1GϾT, and V520F constitute severe mutations, whereas 1898ϩ3AϾG, I148N, Y161C, V232D, T338I, I1234V, and S1159F confer residual CFTR Cl- channel function (Table 1). Login to comment 127 ABCC7 p.Ser108Phe ABCC7 p.Ile148Asn Previous studies have shown that the 5T allele, especially in conjunction with a high number of adjacent TG repeats, results in enhanced skipping of exon 9 and thus decreased levels of CFTR protein.41,42 It is therefore possible that reduced posttranscriptional processing of messenger RNA transcripts from mild CFTR mutations (S108F and I148N) contributed to reduced CFTR-mediated Cl- secretion, and the disease phenotype observed in these patients. Login to comment