ABCMdb

PMID: 7472820

Wilschanski M, Zielenski J, Markiewicz D, Tsui LC, Corey M, Levison H, Durie PR
Correlation of sweat chloride concentration with classes of the cystic fibrosis transmembrane conductance regulator gene mutations.
J Pediatr. 1995 Nov;127(5):705-10., [PubMed]

Sentences

No. Mutations Sentence Comment

12 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Gly542* Abnormal function of the channel results in aber- cAMP CF CFTR NBF PI PS RT-PCR Cyclicadenosinemonophosphate Cysticfibrosis Cysticfibrosistransmembraneconductance regulator Nucleotidebindingfold Pancreaticinsufficiency Pancreaticsufficiency Restrictiontransferasepolymerasechainreaction rant chloride conductance across the apical membrane of epithelial cells in a variety of organs.l-5 Approximately 70% of the CF chromosomes harbor a three base-pair deletionre- 705 0 Wilschanski et al. The Journal of Pediatrics November 1995 I II Ill IV V Normal Nonsense Missense G542X Missense Missense Missense A455E Frameshift AA deletion G551D R117H Alternative 394delTT AF508 splicing Splice junction 3849+10kbC~T 1717-1G~A (a) (b) (c) (d) (e) (f) Figure. Login to comment 13 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Gly542* Abnormal function of the channel results in aber- cAMP CF CFTR NBF PI PS RT-PCR Cyclicadenosinemonophosphate Cysticfibrosis Cysticfibrosistransmembraneconductance regulator Nucleotidebindingfold Pancreaticinsufficiency Pancreaticsufficiency Restrictiontransferasepolymerasechainreaction rant chloride conductance across the apical membrane of epithelial cells in a variety of organs.l-5 Approximately 70% of the CF chromosomes harbor a three base-pair deletionre- 705 0 Wilschanski et al. The Journal of Pediatrics November 1995 I II Ill IV V Normal Nonsense Missense G542X Missense Missense Missense A455E Frameshift AA deletion G551D R117H Alternative 394delTT AF508 splicing Splice junction 3849+10kbC~T 1717-1G~A (a) (b) (c) (d) (e) (f) Figure. Login to comment 43 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Pro574His ABCC7 p.Ala455Glu ABCC7 p.Arg553* ABCC7 p.Arg347Pro ABCC7 p.Arg347His ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Ser1251Asn ABCC7 p.Ile148Thr ABCC7 p.Glu585* ABCC7 p.Gln493* ABCC7 p.Gly85Glu ABCC7 p.Arg560Thr ABCC7 p.Tyr1092* ABCC7 p.Gln552* ABCC7 p.Leu1077Pro ABCC7 p.Ala559Thr ABCC7 p.Asp614Gly ABCC7 p.Glu1104* Defined mutations (each mutation cited in references 8, 23, and 24; numerals in parentheses indicate number of patients): Nonsense mutations-----class I: Frameshift mutations---class I: Splice site mutations-class I: Missense mutations---class HI: Missense mutations---class IV: Partially defective processing---class V: Alternative spficing-----classV: R1162X (3), Y1092X (3), G542X (21), Q552X (2), Q493X (2), w1282x (2), E1104X (1), R553X (6), E585X (l), (all PI) 3659delC (5), 2184delA (4), 4010de14 (1), 556delA (1), 3002delG (1) 3905insT (1), 4016insT (3), 1154insTC (l), 441delA (1), 2184insA (2), 1078delT (1), 4326delTC (3) (all PI) I717-1G--~A (4), 621+lG--*T (10), 711+IG--~T (3), 875+1G-+C (2), 3120+IG-~A (1) (18 PI, 2 PS) G551D (25), N1303K (7), R560T (8), I148T (1), G85E (3), A559T (1), L1077P (2), T1234V (1), (47 PI, 1 PS) R117H (10), R347H (3), R347P (1), D614G (1), S1251N (2), (all PS) P574H (2), A455E (2), (all PS) 3272-26A-+G (4), 3849+10KbC---~T (2), 3120G-+A (1), (all PS) analysis, we further grouped the patients according to the molecular consequences conferred by the CFTR alleles. Login to comment 58 ABCC7 p.Gly85Glu Only one patient in class III (AF508/G85E) had a PS phenotype. Login to comment 79 ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro When channel function was examined by patch clamp studies, three missense CFFR gene mutations (Rll7H, R334W, R347P) were correctly processed and transported to the apical membrane. Login to comment 82 ABCC7 p.Gly85Glu In one patient homozygous for AF508 and one heterozygous for AF508/G85E, PS was diagnosed at the time of analysis. Login to comment 84 ABCC7 p.Gly85Glu ABCC7 p.Gly85Glu However, the G85E mutation (classified as class III in this study) has been associated with both PS and PI phenotypes.16 Complete sequencing of the coding region of the G85E alleles in the PI and PS patients did not reveal any second site mutations that might modify the molecular consequence. Login to comment 106 ABCC7 p.Arg117His Variation in the level of normal RNA splicing affects the clinical consequence of at least one common CFFR mutation (R117H).I8 Although the level of normal CFrR expression dictates the encoded chloride channel activity, the exocrine pancreatic function appears to be a good indicator of any residual activity. Login to comment 107 ABCC7 p.Pro574His ABCC7 p.Ala455Glu Electrophysiologic studies on the mild mutations A455E and P574H revealed that single-channel conductance was not different from the normal CFFR channel but that less protein reached the membrane. Login to comment 109 ABCC7 p.Arg117His ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* More recently, a multicenter study reported no significant differences in sweat chloride levels in 79 compound heterozygotes carrying the mutations G55ID with AF508 (class III), in comparison with those homozygous for AF508.21 In addition, no significantdifferences in sweat chloride values could be detected between those who were homozygous for AF508 and those who had other common "severe" mutations, including the nonsense mutations (G542X, R553X, and W1282X), missense mutation (N1303K), and splice site mutations (621 + 1G--->Tand 1717 - 1G--~A).22 In the latter study there was a significant difference in sweat chloride concentration between a group heterozygous for the mild missense mutation (AF508/R117H) and the reference group (AF508/AF508).22 These data were limited by the range of mutations and were defined by genotype rather than functional class, but the results are in complete agreement with the findings of the present study. 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