ABCC7 p.Ala566Thr
| ClinVar: |
c.1696G>A
,
p.Ala566Thr
?
, not provided
|
| CF databases: |
c.1697C>A
,
p.Ala566Asp
(CFTR1)
D
, He originated from the Esfahan province in the centre of Iran.
c.1696G>A , p.Ala566Thr (CFTR1) ? , This mutation was detected by SSCP/HA analysis and confirmed by bi-directional sequencing. The patient's other mutation is deltaF508. Both the patient's parents are Swedish in origin. The patient was referred to Manchester for analysis from the Adult CF Centre at Papworth Hospital, Cambridge by Dr Bilton |
| Predicted by SNAP2: | C: N (72%), D: D (75%), E: D (75%), F: D (66%), G: N (53%), H: D (66%), I: D (59%), K: D (71%), L: D (63%), M: D (53%), N: N (78%), P: D (63%), Q: D (63%), R: D (66%), S: N (66%), T: N (53%), V: N (53%), W: D (75%), Y: D (66%), |
| Predicted by PROVEAN: | C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: N, T: D, V: D, W: D, Y: D, |
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[hide] An exon-specific U1 small nuclear RNA (snRNA) stra... Hum Mol Genet. 2012 Jun 1;21(11):2389-98. Epub 2012 Feb 23. Fernandez Alanis E, Pinotti M, Dal Mas A, Balestra D, Cavallari N, Rogalska ME, Bernardi F, Pagani F
An exon-specific U1 small nuclear RNA (snRNA) strategy to correct splicing defects.
Hum Mol Genet. 2012 Jun 1;21(11):2389-98. Epub 2012 Feb 23., [PMID:22362925]
Abstract [show]
A significant proportion of disease-causing mutations affect precursor-mRNA splicing, inducing skipping of the exon from the mature transcript. Using F9 exon 5, CFTR exon 12 and SMN2 exon 7 models, we characterized natural mutations associated to exon skipping in Haemophilia B, cystic fibrosis and spinal muscular atrophy (SMA), respectively, and the therapeutic splicing rescue by using U1 small nuclear RNA (snRNA). In minigene expression systems, loading of U1 snRNA by complementarity to the normal or mutated donor splice sites (5'ss) corrected the exon skipping caused by mutations at the polypyrimidine tract of the acceptor splice site, at the consensus 5'ss or at exonic regulatory elements. To improve specificity and reduce potential off-target effects, we developed U1 snRNA variants targeting non-conserved intronic sequences downstream of the 5'ss. For each gene system, we identified an exon-specific U1 snRNA (ExSpeU1) able to rescue splicing impaired by the different types of mutations. Through splicing-competent cDNA constructs, we demonstrated that the ExSpeU1-mediated splicing correction of several F9 mutations results in complete restoration of secreted functional factor IX levels. Furthermore, two ExSpeU1s for SMA improved SMN exon 7 splicing in the chromosomal context of normal cells. We propose ExSpeU1s as a novel therapeutic strategy to correct, in several human disorders, different types of splicing mutations associated with defective exon definition.
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No. Sentence Comment
43 In the CFTR exon 12, we studied five donor-site substitutions and, as models for exonic mutations that affect splicing, two codon changes (A566T and Y577Y) located in the previously reported CERES element (7) (Supplementary Material, Table S1).
X
ABCC7 p.Ala566Thr 22362925:43:139
status: NEW52 On the other hand, all mutations in CFTR exon 12, either located at the donor sites (in position 21, +3 and +5) or in the exon (A566T and Y577Y), induced exon skipping (Fig. 1D).
X
ABCC7 p.Ala566Thr 22362925:52:128
status: NEW53 In is worth noting that the A566T and Y577Y exonic variants affect exonic splicing regulatory elements (7), which are important for correct exon definition.
X
ABCC7 p.Ala566Thr 22362925:53:28
status: NEWX
ABCC7 p.Ala566Thr 22362925:53:128
status: NEW127 Intriguingly, we observed complete splicing correction by ExSpeU1 cf11 of the two exonic A566T and Y577Y mutations (Fig. 6B, lanes 1-4).
X
ABCC7 p.Ala566Thr 22362925:127:89
status: NEW44 In the CFTR exon 12, we studied five donor-site substitutions and, as models for exonic mutations that affect splicing, two codon changes (A566T and Y577Y) located in the previously reported CERES element (7) (Supplementary Material, Table S1).
X
ABCC7 p.Ala566Thr 22362925:44:139
status: NEW54 In is worth noting that the A566T and Y577Y exonic variants affect exonic splicing regulatory elements (7), which are important for correct exon definition.
X
ABCC7 p.Ala566Thr 22362925:54:28
status: NEW128 Intriguingly, we observed complete splicing correction by ExSpeU1 cf11 of the two exonic A566T and Y577Y mutations (Fig. 6B, lanes 1-4).
X
ABCC7 p.Ala566Thr 22362925:128:89
status: NEW