ABCC7 p.Tyr577Phe
| ClinVar: |
c.1731C>T
,
p.Tyr577=
D
, Likely pathogenic
c.1730A>T , p.Tyr577Phe ? , not provided |
| CF databases: |
c.1730A>T
,
p.Tyr577Phe
(CFTR1)
?
, Mutation Y577F and 1874insT were found together in another CF patient from Austria; this boy is also heterozygous for [delta]F508.
|
| Predicted by SNAP2: | A: D (59%), C: N (61%), D: D (71%), E: D (63%), F: N (82%), G: D (71%), H: N (78%), I: N (61%), K: D (63%), L: N (66%), M: N (53%), N: D (59%), P: D (80%), Q: N (57%), R: D (59%), S: D (63%), T: D (53%), V: N (66%), W: N (57%), |
| Predicted by PROVEAN: | A: N, C: N, D: N, E: N, F: N, G: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: N, |
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[hide] New type of disease causing mutations: the example... Hum Mol Genet. 2003 May 15;12(10):1111-20. Pagani F, Stuani C, Tzetis M, Kanavakis E, Efthymiadou A, Doudounakis S, Casals T, Baralle FE
New type of disease causing mutations: the example of the composite exonic regulatory elements of splicing in CFTR exon 12.
Hum Mol Genet. 2003 May 15;12(10):1111-20., 2003-05-15 [PMID:12719375]
Abstract [show]
The increase in genome scanning data, derived from clinical genetics practice, is producing a wealth of information on human sequence variability. The critical issue is to identify if a given nucleotide change results in a benign polymorphism or a disease-causing mutation. We have focused on one specific gene expression step, pre-mRNA processing, where we can functionally define the effect of nucleotide changes and in turn the patient's mutation can shed light on the basic pre mRNA splicing mechanisms. Our results show that several nucleotide changes in CFTR exon 12 induce a variable extent of exon skipping that leads to reduced levels of normal transcripts. This is the case in both natural mutations D565G and G576A (the latter having previously considered a neutral polymorphism) and several site-directed silent substitutions. We demonstrate here that this phenomenon is due to the interference with a new regulatory element that we have named composite exonic regulatory element of splicing (CERES). The effect of single nucleotide substitutions at CERES cannot be predicted by neither SR matrices nor enhancer identification. The recognition and characterization of splicing abnormalities, caused by exon sequence variations at CERES elements, may represent a frequent disease-causing mechanism that also relates to the phenotypic variability. Our results indicate that even the most benign looking polymorphism in an exon cannot be ignored as it may affect the splicing process. Hence, appropriate functional splicing assays should be included in genotype screenings to distinguish between polymorphisms and pathogenic mutations.
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No. Sentence Comment
89 We then studied the pattern of splicing of a minigene with the missense mutations D565G, G576A and Y577F, the latter associated to classical CF.
X
ABCC7 p.Tyr577Phe 12719375:89:99
status: NEW92 Instead, the nearby Y577F mutation found in classical CF did not produce aberrant skipping but surprisingly increased exon inclusion in comparison with WTB (Fig. 2C).
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ABCC7 p.Tyr577Phe 12719375:92:20
status: NEW93 This indicates that, unlike G565A and D565G, the disease-causing effect of Y577F cannot be attributed to a splicing abnormality but rather to a protein defect.
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ABCC7 p.Tyr577Phe 12719375:93:75
status: NEW97 To evaluate their role in CFTR exon 12 we transfected normal and the three D565G, G576A and Y577F minigenes in different cell lines (Fig. 3A).
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ABCC7 p.Tyr577Phe 12719375:97:92
status: NEW98 For each cell line tested, the three variants cause comparable changes in splicing efficiency, with D565G and G576A inducing exon skipping and Y577F exon inclusion.
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ABCC7 p.Tyr577Phe 12719375:98:143
status: NEW124 A total number of 26 hybrid minigenes were analysed containing site-directed mutations at two target sequences of the exon: the AAGATGC sequence at the 50 end from position 12 to 18, which includes D565G at position 15, and a central GGATAC sequence from position 47 to 52 which contains G576A and Y577F of position 48 and 51, respectively (Fig. 4).
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ABCC7 p.Tyr577Phe 12719375:124:298
status: NEW157 It is interesting to note that changes in the codon following G576A result in the classical CF mutation Y577F that produces a non-functional protein, but splicing is not significantly altered.
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ABCC7 p.Tyr577Phe 12719375:157:104
status: NEW[hide] Gender-sensitive association of CFTR gene mutation... Mol Hum Reprod. 2005 Aug;11(8):607-14. Epub 2005 Aug 26. Morea A, Cameran M, Rebuffi AG, Marzenta D, Marangon O, Picci L, Zacchello F, Scarpa M
Gender-sensitive association of CFTR gene mutations and 5T allele emerging from a large survey on infertility.
Mol Hum Reprod. 2005 Aug;11(8):607-14. Epub 2005 Aug 26., [PMID:16126774]
Abstract [show]
Human infertility in relation to mutations affecting the cystic fibrosis transmembrane regulator (CFTR) gene has been investigated by different authors. The role of additional variants, such as the possible forms of the thymidine allele (5T, 7T and 9T) of the acceptor splice site of intron 8, has in some instances been considered. However, a large-scale analysis of the CFTR gene and number of thymidine residues, alone and in combination, in the two sexes had not yet been addressed. This was the aim of this study. Two groups were compared, a control group of 20,532 subjects being screened for perspective reproduction, and the patient group represented by 1854 idiopathically infertile cases. Analyses involved PCR-based CFTR mutations assessment, reverse dot-blot IVS8-T polymorphism analyses, denaturing gradient gel electrophoresis (DGGE) and DNA sequencing. The expected 5T increase in infertile men was predominantly owing to the 5/9 genotypic class. The intrinsic rate of 5T fluctuated only slightly among groups, but some gender-related differences arose when comparing their association. Infertile men showed a significantly enriched 5T + CFTR mutation co-presence, distributed in the 5/9 and 5/7 classes. In contrast, females, from both the control and the infertile groups, showed a trend towards a pronounced reduction of such association. The statistical significance of the difference between expected and observed double occurrence of 5T + CFTR traits in women suggests, in line with other reports in the literature, a possible survival-hampering effect. Moreover, regardless of the 5T status, CFTR mutations appear not to be involved in female infertility. These results underline the importance of (i) assessing large sample populations and (ii) considering separately the two genders, whose genotypically opposite correlations with these phenomena may otherwise tend to mask each other.
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No. Sentence Comment
47 CFTR gene alterations were first scored by PCR and reverse dot blot (Chehab and Wall, 1992), targeted to the detection of the following mutations: ∆F508, G85E, 541∆C, D110H, R117H, 621+1G→T, 711+5G→A, R334W, R334Q, T338I, 1078∆T, R347H, R352Q, ∆I507, 1609∆CA, E527G, 1717-1G→A, 1717-8G→A, G542X, R347P, S549N, S549R A→C, Q552X, R553X, A559T, D579G, Y577F, E585X, 1898+3A→G, 2183AA→G, R709X, 2789+5G→A, 3132∆TG, 3272-26A→G, L1077P, L1065P, R1070Q, R1066H, M1101K, D1152H, R1158X, R1162X, 3849+10KbC→T, G1244E, W1282R, W1282X, N1303K and 4016∇T.
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ABCC7 p.Tyr577Phe 16126774:47:419
status: NEW101 Mutations Women (987) Men (867) N IVS8-T genotype N IVS8-T genotype ∆F508 16 15(7/9); 1(9/9) 26 15(7/9)*; 11(5/9) N1303K 4 4(7/9) 1 7/7 3849+10KbC→T 1 5/7 1 5/7 G542X 2 7/9 1 7/9† 2183AA→G 2 7/7 4 7/7 R553X 2 7/7 0 - R1162X 2 7/7 6 5(7/7)‡; 1(7/9) D1152H 0 - 3 2(7/7); 7/9† 711+5G→A 0 - 3 7/7 1717-8G→A 0 - 1 5/7 1717-1G→A 1 7/7 0 - Y577F 0 - 1 7/7 R117H 1 7/7 1 7/9* 621+3A→G 1 7/9 0 - W1282X 1 7/7 0 - deltaI1507 1 7/7 0 - T3381 1 7/7 1 7/9 R1066H 0 - 1 7/7§ R334Q 0 - 1 7/9 2789+5G→A 1 7/7 2 7/7‡§ Total 36¶ 53¶ records, all these mutations are normally found in trans with respect of 5T.
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ABCC7 p.Tyr577Phe 16126774:101:396
status: NEW[hide] Nucleotide binding domains of human CFTR: a struct... Cell Mol Life Sci. 2005 Sep;62(18):2112-23. Eudes R, Lehn P, Ferec C, Mornon JP, Callebaut I
Nucleotide binding domains of human CFTR: a structural classification of critical residues and disease-causing mutations.
Cell Mol Life Sci. 2005 Sep;62(18):2112-23., [PMID:16132229]
Abstract [show]
Defective function of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) causes CF, the most frequent lethal inherited disease among the Caucasian population. The structure of this chloride ion channel includes two nucleotide-binding domains (NBDs), whose ATPase activity controls channel gating. Recently, the experimental structures of mouse and human CFTR NBD1 and our model of the human CFTR NBD1/NBD2 heterodimer have provided new insights into specific structural features of the CFTR NBD dimer. In the present work, we provide a structural classification of CF-causing mutations which may complement the existing functional classification. Our analysis also identified amino acid residues which may play a critical role in interdomain interaction and are located at the NBD1-NBD2 interface or on the surface of the dimer. In particular, a cluster of aromatic amino acids, which includes F508 and straddles the two NBDs, might be directly involved in the interaction of the NBD1/NBD2 heterodimer with the channel-forming membrane-spanning domains.
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No. Sentence Comment
189 The Y577F mutation has been shown to be associated with severe lung disease and elevated sweat chloride levels (http: //www.genet.sickkids.on.ca/cftr).
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ABCC7 p.Tyr577Phe 16132229:189:4
status: NEW[hide] Functional properties and evolutionary splicing co... Nucleic Acids Res. 2010 Jan;38(2):647-59. Epub 2009 Nov 12. Haque A, Buratti E, Baralle FE
Functional properties and evolutionary splicing constraints on a composite exonic regulatory element of splicing in CFTR exon 12.
Nucleic Acids Res. 2010 Jan;38(2):647-59. Epub 2009 Nov 12., [PMID:19910374]
Abstract [show]
In general, splicing regulatory elements are defined as Enhancers or Silencers depending on their positive or negative effect upon exon inclusion. Often, these sequences are usually present separate from each other in exonic/intronic sequences. The Composite Exonic Splicing Regulatory Elements (CERES) represent an extreme physical overlap of enhancer/silencer activity. As a result, when CERES elements are mutated the consequences on the splicing process are difficult to predict. Here, we show that the functional activity of the CERES2 sequence in CFTR exon 12 is regulated by the binding, in very close proximity to each other, of several SR and hnRNP proteins. Moreover, our results show that practically the entire exon 12 sequence context participate in its definition. The consequences of this situation can be observed at the evolutionary level by comparing changes in conservation of different splicing elements in different species. In conclusion, our study highlights how it is increasingly difficult to define many exonic sequences by simply breaking them down in isolated enhancer/silencer or even neutral elements. The real picture is close to one of continuous competition between positive and negative factors where affinity for the target sequences and other dynamic factors decide the inclusion or exclusion of the exon.
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No. Sentence Comment
137 Western blot analysis of recovered proteins after pulldown of two naturally occurring nonsense CFTR mutations (G48C/G576A and A51T/Y577F) compared with CFTR Ex. 12 wild type.
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ABCC7 p.Tyr577Phe 19910374:137:131
status: NEW[hide] Quantitative methods for the analysis of CFTR tran... J Cyst Fibros. 2004 Aug;3 Suppl 2:17-23. Amaral MD, Clarke LA, Ramalho AS, Beck S, Broackes-Carter F, Rowntree R, Mouchel N, Williams SH, Harris A, Tzetis M, Steiner B, Sanz J, Gallati S, Nissim-Rafinifa M, Kerem B, Hefferon T, Cutting GR, Goina E, Pagani F
Quantitative methods for the analysis of CFTR transcripts/splicing variants.
J Cyst Fibros. 2004 Aug;3 Suppl 2:17-23., [PMID:15463919]
Abstract [show]
In cystic fibrosis (CF), transcript analysis and quantification are important for diagnosis, prognosis and also as surrogate markers for some therapies including gene therapy. Classical RNA-based methods require significant expression levels in target samples for appropriate analysis, thus PCR-based methods are evolving towards reliable quantification. Various protocols for the quantitative analysis of CFTR transcripts (including those resulting from splicing variants) are described and discussed here.
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No. Sentence Comment
164 D565G, G576A and Y577Y induce exon skipping, while Y577F increases the percentage of exon 12 inclusion.
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ABCC7 p.Tyr577Phe 15463919:164:51
status: NEW174 Another missense mutation, Y577F, reported in a patient with severe CF [23], increased the amount of transcript with this exon in comparison to non-CF controls (Fig. 1c), suggesting that this amino acid substitution was directly responsible for the severe phenotype.
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ABCC7 p.Tyr577Phe 15463919:174:27
status: NEW