ABCMdb

ABCC7 p.Ser753Arg

ClinVar:	c.2259C>G , p.Ser753Arg ? , not provided c.2259C>T , p.Ser753= ? , not provided
CF databases:	c.2259C>G , p.Ser753Arg (CFTR1) ? , This mutation was identified on one Brazilian CBAVD chromosome.
Predicted by SNAP2:	A: N (82%), C: N (82%), D: N (82%), E: N (78%), F: N (61%), G: N (82%), H: N (82%), I: N (78%), K: N (72%), L: N (78%), M: N (72%), N: N (93%), P: N (78%), Q: N (82%), R: N (72%), T: N (93%), V: N (87%), W: D (71%), Y: N (66%),
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, T: N, V: N, W: D, Y: N,

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Publications
[hide] Influence of phosphorylation by protein kinase A o... Biochim Biophys Acta. 1999 Dec 6;1461(2):275-83. Seibert FS, Chang XB, Aleksandrov AA, Clarke DM, Hanrahan JW, Riordan JR
Influence of phosphorylation by protein kinase A on CFTR at the cell surface and endoplasmic reticulum.
Biochim Biophys Acta. 1999 Dec 6;1461(2):275-83., [PMID:10581361]

Abstract [show]
CFTR possesses a large cluster of strict dibasic consensus sites for phosphorylation by protein kinase A (PKA) in the R-domain and an obligatory dependence on phosphorylation is a hallmark of CFTR Cl(-) channel function. Removal of as many as 11 of these sites reduces the conformational change in the R-domain and the degree of channel activation in response to PKA. However, until recently a completely PKA-unresponsive CFTR variant has not been reported, leaving open the possibility that the residual response may be mediated by associating ancillary phosphoproteins. We traced the residual PKA-catalyzed (32)P-labelling of the variant with 11 sites mutagenized (11SA) to distinct CNBr phosphopeptides within the R-domain. Mutagenesis of 4 additional monobasic sites in these segments produced a 15SA variant in which Cl(-) channel response to PKA was abolished. Therefore, it can be concluded that ancillary phosphoproteins do not contribute to CFTR activation by PKA. Notably, however, the 15SA protein did exhibit a low level of constitutive channel activity not dependent on PKA, which might have reflected a down-regulating effect of phosphorylation of one or two of the 15 sites as suggested by others. However, this did not prove to be the case.Since immature CFTR has been claimed to be active in the endoplasmic reticulum (ER), we also examined whether it can be phosphorylated in cells and what influence if any this might have on its susceptibility to degradation. Teleologically, activation by phosphorylation of CFTR Cl(-) channels in the ER might be undesirable to the cell. Using various phosphorylation site mutants and kinase and phosphatase inhibitors in pulse-chase experiments, we have found that although nascent CFTR can be phosphorylated at the ER, this is without effect on its ability to mature and avoid proteolysis. Furthermore, we found that microsomes from cells expressing CFTR processing mutants such as DeltaF508 do not generate Cl(-) active channels when fused with planar bilayers unless maturation is promoted, e.g. by growth of cells at reduced temperature or other means. We conclude that the ER-retained mutant nascent chains which are incapable of maturation may be phosphorylated but do not form active channels. Stimulation by PKA of the insertion of CFTR containing vesicles into the plasma membrane as part of the mechanism of stimulation of chloride secretion has been reported, as has an influence of CFTR on the balance between endocytosis and exocytosis but these findings have not been universally confirmed.

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No. Sentence Comment
415 The 5.8 kDa fragment from all except the S753R version could still be phosphorylated by PKA. Login to comment
416 When tested in both e&#a5;ux experiments and by patch-clamping the chloride channel response to PKA of cells expressing 11SA- S753R was reduced a further 40% compared to the 10SA. Login to comment

[hide] Novel CFTR missense mutations in Brazilian patient... Clinics (Sao Paulo). 2007 Aug;62(4):385-90. Pieri Pde C, Missaglia MT, Roque Jde A, Moreira-Filho CA, Hallak J
Novel CFTR missense mutations in Brazilian patients with congenital absence of vas deferens: counseling issues.
Clinics (Sao Paulo). 2007 Aug;62(4):385-90., [PMID:17823699]

Abstract [show]
PURPOSE: Screening for mutations in the entire Cystic Fibrosis gene (CFTR) of Brazilian infertile men with congenital absence of vas deferens, in order to prevent transmission of CFTR mutations to offspring with the use of assisted reproductive technologies. METHOD: Specific polymerase chain reaction (PCR) primers were designed to each of the 27 exons and splicing sites of interest followed by single strand conformational polymorphism and Heteroduplex Analysis (SSCP-HA) in precast 12.5% polyacrylamide gels at 7 masculineC and 20 masculineC. Fragments with abnormal SSCP migration pattern were sequenced. RESULTS: Two novel missense mutations (S753R and G149W) were found in three patients (two brothers) together with the IVS8-5T allele in hetrozygosis. CONCLUSION: The available screenings for CF mutations do not include the atypical mutations associated to absence of vas deferens and thus, when these tests fail to find mutations, there is still a genetic risk of affected children with the help of assisted reproduction. We recommend the screening of the whole CFTR gene for these infertile couples, as part of the work-up before assisted reproduction.

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No. Sentence Comment
7 RESULTS: Two novel missense mutations (S753R and G149W) were found in three patients (two brothers) together with the IVS8-5T allele in hetrozygosis. Login to comment
34 The new mutation found in the patient is an AGC to AGG change in DNA leading to a serine-to-arginine substitution at position 753 (S753R) in the CFTR protein; S753 is a consensus phosphorylation site in the regulatory domain of CFTR protein.6 No other classical CFTR mutation was found, but a 5T allele was identified in intron 8 (IVS8-5T) together with an IVS8-9T in the other allele. Login to comment
46 Case 1 2a 2b Age 30y 32y 27y mutation S753R G149W G149W IVS8-Tn 5T/9T 5T/7T 5T/7T IVS8-TGm 10TG/12TG 10TG/11TG 10TG/11TG polymorphisms M470V M470V M470V 2694T>G 2694T>G Sweat chloride* 26nmol/L 24nmol/L 45nmol/L Seminal Vesicles right hypoplastic normal normal left hypoplastic agenesis agenesis *ref: normal<30nmol/L; borderline 30-60nmol/L; high >60nmol/L DISCUSSION Infertility is an important health problem, affecting 10% of all men in reproductive age around the world. Login to comment
54 In our study, we performed a screening of all the exons and splicing of sites of interest of the CFTR gene in eighteen CBAVD patients and two novel mutations were detected: a serine-to-arginine at an alternative phosphorylation site in the regulatory domain (S753R), and a glycine- to-tryptophan substitution at position 149 (G149W) in the second intracellular domain of the CFTR protein. Login to comment
56 Considering the clinical presentation of the patient, S753R might not be a polymorphism once CBAVD was present together with a clear pulmonary phenotype, although not together with sweat-chloride elevation. Login to comment
81 RESULTADOS: Foram identificadas duas muta&#e7;&#f5;es novas com altera&#e7;&#e3;o de amino&#e1;cidos (S753R and G149W) em 3 pacientes (dois irm&#e3;os) juntamente com o alelo IVS8-5T em heterozigose. Login to comment