ABCMdb

PMID: 26087176

Dupuis A, Keenan K, Ooi CY, Dorfman R, Sontag MK, Naehrlich L, Castellani C, Strug LJ, Rommens JM, Gonska T
Prevalence of meconium ileus marks the severity of mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene.
Genet Med. 2015 Jun 18. doi: 10.1038/gim.2015.79., [PubMed]

Sentences

No. Mutations Sentence Comment

11 ABCC7 p.Gly551Asp ABCC7 p.Gly542* In this severe spectrum MIP scores further distinguished between mutation types, for example, G542X (0.31) with a high, F508del (0.22) with a moderate, and G551D (0.08) with a low MIP score. Login to comment 63 ABCC7 p.Gly551Asp ABCC7 p.Ala455Glu ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Arg347His ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Asp1270Asn ABCC7 p.Arg352Gln ABCC7 p.Ile148Thr ABCC7 p.Leu206Trp ABCC7 p.Gln493* ABCC7 p.Val520Phe ABCC7 p.Gly85Glu ABCC7 p.Pro67Leu ABCC7 p.Arg1158* ABCC7 p.Met1101Lys ABCC7 p.Arg1066Cys ABCC7 p.Tyr1092* ABCC7 p.Asp1152His ABCC7 p.Lys710* ABCC7 p.Ser489* ABCC7 p.Trp1089* ABCC7 p.Glu60* ABCC7 p.Gly330* ABCC7 p.Ala559Thr Canadian studies for CF modfier genes 2,492 3,153 43,432 3,596 1,788 2,230 23,397 16,023 3 716 3,438 860 15% (19%) 1,902 2,576 PIP and MIP derivation FEV1 and zBMI modeling MIP calculation following correction of MI variable 23,301 2,413 510 21% (25%) 20% (23%) 13% (15%) Total F508del/others MI prevalence uncorrected (estimated) Missing or incomplete genotype Available for analysis Canadian CF patient registry, born after 1980 US CF patient registry German CF patient registry CF patient registry, North Italy Table 1ߒ Meconium ileus prevalence scores for the most common cystic fibrosis-causing variants p. F508del/other variants Class PIP Canada, (n) MIP, (n) Canada United States Germany Italy HGVS Legacy name c.262_263delTT 394delTT I 0.38 (50) c.3472C>T R1158X I 0.37 (35) c.1558G>T V520F 0.35 (43) c.3484C>T R1162X I 0.34 (135) 0.17 (14) 0.22 (45) c.2012delT 2143delT I 0.33 (13) c.3276C>A or G Y1092X I 0.92 (13) 0.09 (12) 0.33 (55) c.3846G>A W1282X I 1.00 (13) 0.29 (13) 0.32 (442) 0.17 (20) c.1477C>T Q493X I 1.00 (11) 0.19 (11) 0.32 (102) c.3528delC 3659delC I 0.31 (139) c.579ߙ+ߙ1G>T 711ߙ+ߙ1G>T 0.97 (39) 0.30 (38) 0.31 (54) c.178G>T E60X I 0.30 (66) c.1657C>T R553X I 1.00 (16) 0.28 (16) 0.30 (415) 0.24 (107) c.1585-1G>A 1717-1G>A I 1.00 (12) 0.23 (12) 0.29 (367) 0.22 (38) 0.16 (22) c.1766ߙ+ߙ1G>A 1898ߙ+ߙ1G>A 0.29 (139) c.1624G>T G542X I 0.99 (73) 0.31 (72) 0.29 (976) 0.21 (79) 0.22 (33) c.1521_1523delCTT F508del II 0.99 (1292) 0.22 (1260) 0.27 (15391) 0.21 (1910) 0.20 (230) c.1679G>C R560T II 0.27 (123) c.3744delA 3876delA 0.27 (22) c.2128A>T K710X I 0.26 (12) c.1519_1521delATC I507del II 1.00 (20) 0.21 (19) 0.25 (162) c.3909C>G N1303K II 0.98 (40) 0.13 (39) 0.25 (534) 0.23 (80) 0.14 (62) c.489ߙ+ߙ1G>T 621ߙ+ߙ1G>T I 1.00 (90) 0.24 (88) 0.25 (369) 0.21 (11) c.3266G>A W1089X I 0.25 (17) c.1675G>A A559T 0.24 (21) c.988G>T G330X 0.24 (10) c.3773_3774insT 3905insT 0.23 (78) c.2988ߙ+ߙ1G>A 3120ߙ+ߙ1G>A 0.22 (121) c.443T>C I148T;3199del6 1.00 (15) 0.22 (15) c.2052delA 2184delA I 0.21 (89) 0.22 (10) c.2051_2052delAAinsG 2183AA>G 0.20 (73) 0.20 (42) c.948delT 1078delT 0.19 (20) c.1652G>A G551D III 0.96 (54) 0.08 (53) 0.15 (979) 0.09 (84) c.254G>A G85E 0.50 (24) 0.06 (24) 0.14 (137) 0.00 (10) c.3196C>T R1066C 0.14 (42) c.1466C>A S489X 1.00 (14) 0.14 (14) c.3808G>A D1270N 0.13 (19) c.1055G>A R352Q 0.12 (18) c.579ߙ+ߙ5G>A 711ߙ+ߙ5G>A 0.12 (30) c.2175_2176insA 2307insA 0.11 (24) c.349C>T R117C 0.10 (37) c.1040G>C R347P IV 0.18 (11) 0.19 (11) 0.10 (130) 0.02 (56) c.350G>A R117H IV 0.05 (21) 0.00 (21) 0.07 (666) 0.02 (19) c.2657ߙ+ߙ5G>A 2789ߙ+ߙ5G>A V 0.25 (20) 0.00 (20) 0.06 (271) 0.01 (21) c.1040G>A R347H 0.06 (55) c.2988G>A 3120G->A 0.06 (36) c.328G>C D1152H IV 0.06 (124) c.3717ߙ+ߙ12191C>T 3849ߙ+ߙ10kbC>T V 0.07 (14) 0.00 (14) 0.05 (299) 0.01 (42) 0.00 (15) c.1364C>A A455E V 0.16 (45) 0.01 (41) 0.05 (109) c.1000C>T R334W IV 0.18 (11) 0.00 (10) 0.05 (92) c.617T>G L206W 0.06 (18) 0.05 (17) 0.04 (52) c.3302T>A M1101K 0.04 (17) c.200C>T P67L V 0.07 (14) 0.00 (14) Meconium ileus prevalence (MIP) and pancreas insufficiency prevalence (PIP) scores are presented. Login to comment 74 ABCC7 p.Gly551Asp ABCC7 p.Gly542* The highest MIP scores were calculated for mutations with premature termination, such as G542X (class I mutation, MIP 0.31), followed by F508del (class II mutation, MIP 0.22); the lowest MIP score was for G551D (class III mutation, MIP 0.08) (P = 0.0009). Login to comment 75 ABCC7 p.Gly551Asp We were curious to determine whether the low MIP score noted for G551D was obtained for other class III CFTR mutations: those with gating deficiencies. Login to comment 76 ABCC7 p.Gly1244Glu ABCC7 p.Ser1251Asn ABCC7 p.Ser549Arg ABCC7 p.Ser549Asn ABCC7 p.Gly178Arg Using the US and Italian data, we calculated equally low MIP scores for G178R (0.09, n = 22), S549N (0.12, n = 39), S1251N (0.07, n = 14), and G1244E (0.0, n = 3), but not for S549R (0.21, n = 14) (Supplementary Table S1 online). Login to comment 79 ABCC7 p.Val520Phe This mutation is found more frequently in the Swedish CF population, where it is associated with lower lung function.23 Of interest is that the MIP score ranked the clinically unclassified missense mutation V520F into a similar severe range of CFTR mutations as other class I CF-causing nonsense variants. Login to comment 101 ABCC7 p.Arg347Pro ABCC7 p.Met1101Lys The mutations M1101K and R347P, however, showed no CFTR function, with a low MIP score and intermediate PIP score, suggesting that the functional consequences of these mutations may be very organ-specific and/or are greatly influenced by non-CFTR-modifying factors. Login to comment 102 ABCC7 p.Arg347Pro ABCC7 p.Met1101Lys This finding does seem to reflect previous reports of various outcomes of patients with M1101K or R347P, ranging from PI and an early decline in lung function to PS and only mild lung disease.25,26 MIP scores distinguished between the "molecular" classification of CFTR mutations, especially regarding the distinctive class III or gating mutations. Login to comment 103 ABCC7 p.Val520Phe The highest MIP scores were calculated for class I mutations, including nonsense variants, the missense variant V520F, and the Scandinavian variant 394delTT. Login to comment 104 ABCC7 p.Val520Phe Nonsense variants and c.262_263delTT have been associated with a more severe CF phenotype when compared with F508del.23,27 Little clinical information is available for V520F, but the location of the amino acid substitution may indicate impairment of channel function. Login to comment 105 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly1244Glu ABCC7 p.Ser1251Asn ABCC7 p.Ser549Asn ABCC7 p.Gly178Arg MIP scores were significantly different between the mutations F508del and G551D, which is in agreement with early studies of smaller numbers of patients with CF that reported a lower MI incidence in patients carrying F508del/G551D when compared with patients with CF with F508del/ F508del.28,29 We demonstrated equally low MIP scores for other class III CFTR mutations (G178R, S549N, G1244E, S1251N), further supporting the idea that class III CFTR mutations are not as severe as F508del, at least with respect to gastrointestinal development. Login to comment 106 ABCC7 p.Gly551Asp This difference in the clinical phenotype is somewhat remarkable given that G551D is classically viewed as a "nongating" and "nonfunctional" CFTR mutation. Login to comment 107 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp Defects in responsiveness to adenosine triphosphate regulation is thought to explain the low open probability of G551D channels.30,31 However, following expression in different heterologous cells, measurable G551D-mediated chloride currents have been reported.32 In Fisher rat thyroid cells G551D showed 1% of wild-type function, and human bronchial epithelial cells generated from G551D/F508del lung explants expressed 5% wild-type CFTR function.24 Our results suggest that, in contrast to classes I and II, class III CFTR mutations confer sufficient chloride channel function to maintain early intestinal fluid homeostasis and thus eliminate the risk for MI in patients with CF. Login to comment 109 ABCC7 p.Gly551Asp ABCC7 p.Ala455Glu ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Arg347His ABCC7 p.Asn1303Lys ABCC7 p.Leu206Trp ABCC7 p.Val520Phe ABCC7 p.Gly85Glu ABCC7 p.Pro67Leu ABCC7 p.Met1101Lys ABCC7 p.Arg1066Cys ABCC7 p.Ala559Thr While non-CFTR modifier genes as well as environmental factors largely influence the development and progression of lung disease and nutritional decline,33-36 we demonstrate that the severity of the underlying CFTR genotype Table 2ߒ Meconium ileus prevalence scores and CFTR function CFTR mutation MIP score CFTR function (%wt) High MIP score ߓ V520F 0.38 0.2 ߓ N1303K 0.25 0.5 ߓ F508del 0.27 0.4 ߓ R560T 0.27 0.1 ߓ A559T 0.24 0 ߓ G551D 0.15 1 ߓ G85E 0.14 0.8 ߓ R1066C 0.13 0 Low MIP score ߓ R347P 0.1 0 ߓ R117C 0.1 2.9 ߓ R117H 0.07 33 ߓ R347H 0.06 5 ߓ R334W 0.05 1.3 ߓ A455E 0.05 6 ߓ L206W 0.04 5 ߓ M1101K 0.04 0 ߓ P67L 0.0 8 The table compares meconium ileus prevalence (MIP) scores and measured cystic fibrosis transmembrane conductance regulator (CFTR) function in Fisher rat thyroid determined by VanGoor et al.24 for the major and missense cystic fibrosis-causing variants for which patient group size was ࣙ10 in at least the US group. 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