ABCMdb

ABCC7 p.Leu15Pro

CF databases:	c.44T>C , p.Leu15Pro (CFTR1) ? , This change has been detected by SSCP/HD analysis and direct sequencing in one CF allele from Ecuador
Predicted by SNAP2:	A: D (53%), C: N (61%), D: D (80%), E: D (75%), F: N (78%), G: D (75%), H: D (66%), I: N (87%), K: D (80%), M: N (61%), N: D (71%), P: D (80%), Q: D (66%), R: D (75%), S: D (63%), T: D (63%), V: N (78%), W: D (59%), Y: N (72%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: N, G: D, H: D, I: N, K: D, M: N, N: D, P: D, Q: D, R: D, S: D, T: D, V: N, W: D, Y: N,

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Publications
[hide] Association of cystic fibrosis genetic modifiers w... Fertil Steril. 2010 Nov;94(6):2122-7. Epub 2010 Jan 25. Havasi V, Rowe SM, Kolettis PN, Dayangac D, Sahin A, Grangeia A, Carvalho F, Barros A, Sousa M, Bassas L, Casals T, Sorscher EJ
Association of cystic fibrosis genetic modifiers with congenital bilateral absence of the vas deferens.
Fertil Steril. 2010 Nov;94(6):2122-7. Epub 2010 Jan 25., [PMID:20100616]

Abstract [show]
OBJECTIVE: To investigate whether genetic modifiers of cystic fibrosis (CF) lung disease also predispose to congenital bilateral absence of the vas deferens (CBAVD) in association with cystic fibrosis transmembrane conductance regulator (CFTR) mutations. We tested the hypothesis that polymorphisms of transforming growth factor (TGF)-beta1 (rs 1982073, rs 1800471) and endothelin receptor type A (EDNRA) (rs 5335, rs 1801708) are associated with the CBAVD phenotype. DESIGN: Genotyping of subjects with clinical CBAVD. SETTING: Outpatient and hospital-based clinical evaluation. PATIENT(S): DNA samples from 80 subjects with CBAVD and 51 healthy male controls from various regions of Europe. This is one of the largest genetic studies of this disease to date. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Genotype analysis. RESULT(S): For single nucleotide polymorphism (SNP) rs 5335, we found increased frequency of the CC genotype among subjects with CBAVD. The difference was significant among Turkish patients versus controls (45.2% vs. 19.4%), and between all cases versus controls (36% vs. 15.7%). No associations between CBAVD penetrance and polymorphisms rs 1982073, rs 1800471, or rs 1801708 were observed. CONCLUSION(S): Our findings indicate that endothelin receptor type A polymorphism rs 5335 may be associated with CBAVD penetrance. To our knowledge, this is the first study to investigate genetic modifiers relevant to CBAVD.

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No. Sentence Comment
68 Portuguese CFTR alleles Spanish CFTR alleles Turkish CFTR alleles 5T 22 F508del 11 5T 20 F508del 14 5T 9 D1152H 14 R334W 5 D443Ya 3 D110H 3 R117H 3 G576Aa 3 F508del 2 S1235R 3 R668Ca 3 3041-11del7 2 N1303K 2 G542X 2 1767del6 2 P205S 2 R117H 2 2789þ5G>A 2 D614G 2 V232D 2 CFTRdele2(ins186) 2 G542X 1 L997F 1 3120þ1G>A 1 L206W 1 H609R 1 G1130A 1 V562I 1 N1303H 1 M952I 1 I507del 1 L206W 1 365insT 1 3272-26A>G 1 3272-26A/G 1 E585X 1 2789þ5G>A 1 L15P 1 2752-15C>G 1 G576Aa 1 R347H 1 R334Q 1 R668Ca 1 2689insG 1 R347H 1 CFTRdele2,3 1 R1070W 1 E831X 1 L1227S 1 I 1027T 1 R1070W 1 E831X 1 3272-26A>G 1 L997F 1 I853F 1 A349V 1 6T 1 Note: CFTR ¼ cystic fibrosis transmembrane conductance regulator. Login to comment

[hide] Cystic fibrosis transmembrane conductance regulato... J Biol Chem. 2010 May 28;285(22):17156-65. Epub 2010 Mar 29. Playford MP, Nurminen E, Pentikainen OT, Milgram SL, Hartwig JH, Stossel TP, Nakamura F
Cystic fibrosis transmembrane conductance regulator interacts with multiple immunoglobulin domains of filamin A.
J Biol Chem. 2010 May 28;285(22):17156-65. Epub 2010 Mar 29., 2010-05-28 [PMID:20351098]

Abstract [show]
Mutations of the chloride channel cystic fibrosis transmembrane conductance regulator (CFTR) that impair its apical localization and function cause cystic fibrosis. A previous report has shown that filamin A (FLNa), an actin-cross-linking and -scaffolding protein, interacts directly with the cytoplasmic N terminus of CFTR and that this interaction is necessary for stability and confinement of the channel to apical membranes. Here, we report that the CFTR N terminus has sequence similarity to known FLNa-binding partner-binding sites. FLNa has 24 Ig (IgFLNa) repeats, and a CFTR peptide pulled down repeats 9, 12, 17, 19, 21, and 23, which share sequence similarity yet differ from the other FLNa Ig domains. Using known structures of IgFLNa.partner complexes as templates, we generated in silico models of IgFLNa.CFTR peptide complexes. Point and deletion mutants of IgFLNa and CFTR informed by the models, including disease-causing mutations L15P and W19C, disrupted the binding interaction. The model predicted that a P5L CFTR mutation should not affect binding, but a synthetic P5L mutant peptide had reduced solubility, suggesting a different disease-causing mechanism. Taken together with the fact that FLNa dimers are elongated ( approximately 160 nm) strands, whereas CFTR is compact (6 approximately 8 nm), we propose that a single FLNa molecule can scaffold multiple CFTR partners. Unlike previously defined dimeric FLNa.partner complexes, the FLNa-monomeric CFTR interaction is relatively weak, presumptively facilitating dynamic clustering of CFTR at cell membranes. Finally, we show that deletion of all CFTR interacting domains from FLNa suppresses the surface expression of CFTR on baby hamster kidney cells.

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No. Sentence Comment
5 Point and deletion mutants of IgFLNa and CFTR informed by the models, including disease-causing mutations L15P and W19C, disrupted the binding interaction. Login to comment
113 Amino acid changes reflecting known CF mutations within this peptide (S13F, L15P, or W19C) prevented FLNa binding (Fig. 5C). Login to comment
125 Red and blue amino acids indicate residues mutated in CF patients (P5L, S13F, L15P, and W19C). Login to comment
137 The model also predicted that CF-causing L15P and W19C but not P5L mutants of CFTR perturb the interaction with FLNa. Login to comment
138 Indeed, L15P and W19C synthetic CFTR1-20 peptides did not or barely bound FLNa (Fig. 5C). Login to comment
142 The wild-type, L15P, and W19C peptides were soluble at least at concentration of 1 mg/ml in PBS. Login to comment
153 C, effect of CF-causing point mutations of CFTR on FLNa binding.OnemlofPBSwasaddedto1mgofbiotinylatedCFTR1-20peptides(wild-type,P5L,L15P,andW19C), andthesolutionwascentrifugedat15,000ϫgfor10minatroomtemperature.Allofthepeptidesweresoluble except for P5L mutant peptide (asterisk). Login to comment
227 Structural Basis for Mutations That Impair the FLNa-CFTR Interaction-Three missense mutations in the FLNa-binding site of CFTR have been reported: S13F, L15P, and W19C. Login to comment
229 The model also predicts that CF-causing L15P and W19C mutations in CFTR perturb the interaction with FLNa. Login to comment
230 Mutation of Leu-15 to Pro dramatically changes the structure of the CFTR peptide. Login to comment

[hide] Cytoskeleton and CFTR. Int J Biochem Cell Biol. 2014 Jul;52:68-72. doi: 10.1016/j.biocel.2014.03.018. Epub 2014 Mar 28. Edelman A
Cytoskeleton and CFTR.
Int J Biochem Cell Biol. 2014 Jul;52:68-72. doi: 10.1016/j.biocel.2014.03.018. Epub 2014 Mar 28., [PMID:24685681]

Abstract [show]
Cystic Fibrosis Transmembrane conductance Regulator, CFTR, is a membrane protein expressed in epithelia. A protein kinase A (PKA)-regulated Cl(-) channel, it is a rate-limiting factor in fluid transport. Mutations in CFTR are responsible for cystic fibrosis, CF, an autosomal recessive disease. The most frequent mutation is deletion of phenylalanine at position 508, DeltaF508. The regulation of trafficking and degradation of CFTR/DeltaF508CFTR as well as its function(s) is a complex process which involves a number of proteins including chaperones and adaptors. It is now known that cytoskeletal proteins, previously considered only as structural proteins, are also important factors in the regulation of cellular processes and functions. The aim of the present review is to focus on how microfilaments, microtubules and intermediary filaments form a dynamic interactome with CFTR to participate in the regulation of CFTR-dependent transepithelial ion transport, CFTR trafficking and degradation.

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No. Sentence Comment
872 Importantly, two CF disease-causing mutations, L15P and W19C, disrupt the interaction between filamin A and CFTR (Playford et al., 2010). Login to comment