ABCC7 p.Gln207*
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c.619C>T
,
p.Gln207*
?
, not provided
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[hide] Newborn screening for cystic fibrosis: Polish 4 ye... Eur J Hum Genet. 2012 Aug 15. doi: 10.1038/ejhg.2012.180. Sobczynska-Tomaszewska A, Oltarzewski M, Czerska K, Wertheim-Tysarowska K, Sands D, Walkowiak J, Bal J, Mazurczak T
Newborn screening for cystic fibrosis: Polish 4 years' experience with CFTR sequencing strategy.
Eur J Hum Genet. 2012 Aug 15. doi: 10.1038/ejhg.2012.180., [PMID:22892530]
Abstract [show]
Newborn screening for cystic fibrosis (NBS CF) in Poland was started in September 2006. Summary from 4 years' experience is presented in this study. The immunoreactive trypsin/DNA sequencing strategy was implemented. The group of 1 212 487 newborns were screened for cystic fibrosis during the programme. We identified a total of 221 CF cases during this period, including, 4 CF cases were reported to be omitted by NBS CF. Disease incidence in Poland based on the programme results was estimated as 1/4394 and carrier frequency as 1/33. The frequency of the F508del was similar (62%) to population data previously reported. This strategy allowed us to identify 29 affected infants with rare genotypes. The frequency of some mutations (eg, 2184insA, K710X) was assessed in Poland for the first time. Thus, sequencing assay seems to be accurate method for screening programme using blood spots in the Polish population.European Journal of Human Genetics advance online publication, 15 August 2012; doi:10.1038/ejhg.2012.180.
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No. Sentence Comment
69 Based on this assumption, the previously published data of the frequency of this mutation in the Polish population (57%,15), the data from the Polish Cystic Fibrosis Patients Registry3 (56-62%) and the results of the clinical follow-up Table 1 Characteristic of the cases omitted in the screening for CF programme owing to IRT values o99.4 percentile Newborn Patients` genotype after first stage CFTR analysisa Sweat test (pilocarpine ionthoforesis (mmol/l)) Clinical history Patients` genotype after extended CFTR analysis (performed on physician`s request; sequencing of entire coding region) 1 [2183AA4G ];[ ¼ ] 116; 139 Recurrent diarrhoea, pneumonia, liver dysfunction [2183AA4G];[E92K] 2 [F508del];[ ¼ ] 80; 127; 136 Chronic diarrhoea, failure to thrive, pneumonia [F508del];[4218insT] 3 [ ¼ ];[ ¼ ] 118;140 Pneumonia, liver dysfunction [Q207X];[ ¼ ] 4 [ ¼ ];[ ¼ ] 56 Diarrhoea, pneumonia [L997F];[1210-12T[5] þ 1210-13G4T]b Abbreviations: CF, cystic fibrosis; IRT, immunoreactive trypsin; NBS CF, newborn screening for CF; ¼ , no mutation identified.
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ABCC7 p.Gln207* 22892530:69:860
status: NEW[hide] The cystic fibrosis V232D mutation inhibits CFTR m... Biochem Pharmacol. 2014 Mar 1;88(1):46-57. doi: 10.1016/j.bcp.2013.12.027. Epub 2014 Jan 9. Loo TW, Clarke DM
The cystic fibrosis V232D mutation inhibits CFTR maturation by disrupting a hydrophobic pocket rather than formation of aberrant interhelical hydrogen bonds.
Biochem Pharmacol. 2014 Mar 1;88(1):46-57. doi: 10.1016/j.bcp.2013.12.027. Epub 2014 Jan 9., [PMID:24412276]
Abstract [show]
Processing mutations that inhibit folding and trafficking of CFTR are the main cause of cystic fibrosis. Repair of CFTR mutants requires an understanding of the mechanisms of misfolding caused by processing mutations. Previous studies on helix-loop-helix fragments of the V232D processing mutation suggested that its mechanism was to lock transmembrane (TM) segments 3 and 4 together by a non-native hydrogen bond (Asp232(TM4)/Gln207(TM3)). Here, we performed mutational analysis to test for Asp232/Gln207 interactions in full-length CFTR. The rationale was that a V232N mutation should mimic V232D and a V232D/Q207A mutant should mature if the processing defect was caused by hydrogen bonds. We report that only Val232 mutations to charged amino acids severely blocked CFTR maturation. The V232N mutation did not mimic V232D as V232N showed 40% maturation compared to 2% for V232D. Mutation of Val232 to large nonpolar residues (Leu, Phe) had little effect. The Q207L mutation did not rescue V232D because Q207L showed about 50% maturation in the presence of corrector VX-809 while V232D/Q207A could no longer be rescued. These results suggest that V232D inhibits maturation by disrupting a hydrophobic pocket between TM segments rather than forming a non-native hydrogen bond. Disulfide cross-linking analysis of cysteines W356C(TM6) and W1145C(TM12) suggest that the V232D mutation inhibits maturation by trapping CFTR as a partially folded intermediate. Since correctors can efficiently rescue V232D CFTR, the results suggest that hydrophilic processing mutations facing a hydrophobic pocket are good candidates for rescue with pharmacological chaperones.
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105 These results suggest that the Q207X mutations likely had deleterious effects on mutant V232D, as the mutants could no longer be rescued with VX-809.
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ABCC7 p.Gln207* 24412276:105:31
status: NEW179 If V510D is a universal suppressor, then we predict that it would also promote maturation of the Q207X mutants.
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ABCC7 p.Gln207* 24412276:179:97
status: NEW180 Accordingly, the V510D mutation was introduced into mutants Q207X (X = A, L, C, E, F, W, N, and S) that were defective in maturation (Fig. 2).
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ABCC7 p.Gln207* 24412276:180:60
status: NEW195 The L305R(TM5) P-gp mutant resembles CFTR mutants V232D, V232E, and V232K The characteristics of the V232D/Q207X (Fig. 1) and V232X (Fig. 3) mutants suggest that the mechanism of the V232D mutation involves disruption of a hydrophobic pocket between TM segments.
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ABCC7 p.Gln207* 24412276:195:107
status: NEW215 To test if the rescued L305R mutant was active, histidine-tagged versions of the mutant and wild-type P-gp were expressed in HEK Fig. 6. Rescue of Q207X mutants with the V510D suppressor mutation.
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ABCC7 p.Gln207* 24412276:215:147
status: NEW216 (A) Whole cell extracts of cells expressing CFTR Q207X mutants in the absence () or presence (+) of VX-809 or were subjected to immunoblot analysis.
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ABCC7 p.Gln207* 24412276:216:49
status: NEW220 An asterisk indicates significant (P < 0.05) difference when compared to the Q207X mutant (without the V510D mutation) that was expressed in the absence of corrector.
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ABCC7 p.Gln207* 24412276:220:77
status: NEW