ABCMdb

PMID: 12732620

Pagani F, Buratti E, Stuani C, Baralle FE
Missense, nonsense, and neutral mutations define juxtaposed regulatory elements of splicing in cystic fibrosis transmembrane regulator exon 9.
J Biol Chem. 2003 Jul 18;278(29):26580-8. Epub 2003 May 5., 2003-07-18 [PubMed]

Sentences

No. Mutations Sentence Comment

83 ABCC7 p.Ala455Glu ABCC7 p.Asn418Ser ABCC7 p.Gly424Ser ABCC7 p.Gln414* ABCC7 p.Ile444Ser Four of the natural substitutions, C31T (Q414X), G61A (G424S), T122G (I444S), and C155A (A455E), significantly decreased exon 9 inclusion to 48, 30, 40, and 16%, respectively, whereas only a modest decrease was evident for N418S. Login to comment 84 ABCC7 p.Asp443Tyr ABCC7 p.Gln452Pro ABCC7 p.Val456Phe The G118T (D443Y) and G157T (V456F) mutations did not significantly affect the splicing pattern, whereas the A146C (Q452P) caused an almost complete inclusion on the exon (96%). Login to comment 91 ABCC7 p.Gln414* We have evaluated the possibility that some of the changes in the splicing pattern induced by the natural substitutions in exon 9, particularly the Q414X, might be related to nonsense mediated altered splicing. Login to comment 129 ABCC7 p.Gln414* On the other hand, in the F1 and F2 minigenes, C31T creates a stop codon (Q414X), whereas C155A does not. Login to comment 137 ABCC7 p.Ala455Glu ABCC7 p.Gln452Pro ABCC7 p.Val456Phe Identification of Regulatory Elements of Splicing in CFTR Exon 9-Three natural missense mutations with completely different effects on splicing (Q452P (A146C), which induces exon inclusion; A455E (C155A), causing exon exclusion; and V456F (G157T), with no effect) are located within 15 nucleotides. Login to comment 144 ABCC7 p.Val456Phe On the contrary, the 153C and the 157T (V456F) variants did not significantly affect the splicing pattern. Login to comment 145 ABCC7 p.Gln452Pro Extension of the mutagenesis in the 5Ј direction, including the Q452P (146C) variant showed that mutants from position 145 to 149, with the notable exception of the 148G, induced exon inclusion (Fig. 4, A and B). Login to comment 151 ABCC7 p.Gln452Pro The 146C natural missense substitution (Q452P) with 95% of exon inclusion was analyzed in association with the nearby exon-skipping mutations in position 154 (C or T) and 155 (G or T). Login to comment 198 ABCC7 p.Ala455Glu ABCC7 p.Val456Phe The natural mutations Q456P, A455E, and V456F correspond to A146C, C155A and G157T, respectively. Login to comment 221 ABCC7 p.Ala455Glu ABCC7 p.Asp443Tyr ABCC7 p.Gly424Ser ABCC7 p.Gln414* ABCC7 p.Ile444Ser ABCC7 p.Gln452Pro ABCC7 p.Val456Phe WT sequence position AA change Nucleotide mutants Exon 9ϩ SR protein matrices above thresholds Disruption of preexisting sites New sites created by the mutations SC35 SR40 SF2 SR55 % WT 65 A 15 C 65 T 16 ⌬ 96 T 18 G 95 3.38 (13) G 19 A 52 A 20 G 80 C 31 Q414X T 50 A 43 G 62 SR40 0.28 (41) A 44 N414S G 59 46t49t 67 SR40 1.43 (41) G 61 G424S A 31 C 58 66g67a69g 68 SR40-1.01 (66) 3.21 (63) 2.24 (64) C 72 G 18 2.20 (67) A 63 2.01 (69) G 118 D443Y T 68 A 65 120g122a123g 96 2.24 (118) T 122 I444S G 40 A 144 G 55 T 40 C 145 G 85 A 87 A 146 G 92 3.02 (146) 2.66 (141) T 94 3.23 (143) Q452P C 96 3.46 (143) ⌬ 97 2.81 (142) 3.03 (141) G 147 T 97 C 98 2.70 (142) 3.00 (144) 2.53 (143) T 148 G 26 2.99 (142) 4.05 (143) C 90 2.49 (143) 2.47 (145) A 93 3.46 (145) T 149 C 82 2.99 (144) 3.53 (145) G 150 A 50 3.38 (148) C 62 T 151 A 65 C 67 3.00 (146) 3.15 (148) G 153 C 65 T 42 2.76 (153) G 154 T 18 C 20 C 155 A455E A 15 1.98 (152) G 3 T 5 G 156 T 10 3.59 (153) C 40 3.82 (153) G 157 V456F T 65 G 164ϩ ins 14 regulatory sequences derived from SR-specific score matrices, and the creation of novel enhancer and silencer controlling elements. Login to comment 282 ABCC7 p.Ala455Glu For example, it appears that A455E can achieve adequate levels of chloride conduction at the cell surface (46, 47), causing only a partial CFTR protein processing defect (48). Login to comment 284 ABCC7 p.Ala455Glu Furthermore, the modulation by the concentration of splicing factors, which have an inhibitory effect on the CFTR exon 9 (26, 49) and a specific and possibly individual variation distribution, can provide an explanation for the phenotypic and tissue-specific variability in CF patients, particularly in those carrying the A455E substitution. Login to comment