ABCMdb

ABCC7 p.Ala1087Pro

CF databases:	c.3259G>C , p.Ala1087Pro (CFTR1) ? , This mutation was found in a patient with a deltaF508 mutation on the other chromosome. Mutations were identified in a CFTR gene mutation screening of 60 Patients with idiopathic chronic pancreatitis recruited from the region of North Rhine Westfalia in Germany. The entire coding region of the CFTR gene was sequenced.
Predicted by SNAP2:	C: N (61%), D: N (53%), E: N (66%), F: D (66%), G: N (66%), H: D (75%), I: D (63%), K: N (53%), L: D (66%), M: D (59%), N: N (61%), P: D (66%), Q: N (78%), R: D (59%), S: N (78%), T: N (72%), V: N (66%), W: D (80%), Y: D (71%),
Predicted by PROVEAN:	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: D, Y: N,

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[hide] Complete cystic fibrosis transmembrane conductance... Gut. 2005 Oct;54(10):1456-60. Epub 2005 Jun 29. Weiss FU, Simon P, Bogdanova N, Mayerle J, Dworniczak B, Horst J, Lerch MM
Complete cystic fibrosis transmembrane conductance regulator gene sequencing in patients with idiopathic chronic pancreatitis and controls.
Gut. 2005 Oct;54(10):1456-60. Epub 2005 Jun 29., [PMID:15987793]

Abstract [show]
BACKGROUND: Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene-many of which cause cystic fibrosis-have also been reported in patients with chronic pancreatitis. The authors examine whether mild or severe CFTR mutations, homozygous or compound heterozygous CFTR mutations, or even simple cystic fibrosis carrier status alone increases the risk of developing pancreatitis. METHODS: After exclusion of patients with trypsinogen (PRSS1) mutations, cystic fibrosis, or pulmonary disease, and with known risk factors for pancreatitis 67 patients with idiopathic chronic pancreatitis (ICP) from northwest Germany and 60 geographically and ethnically matched controls were recruited. The entire coding region of the CFTR gene was sequenced in all patients and controls. ICP patients were also analysed for serine protease inhibitor Kazal type 1 (SPINK1) gene mutations. RESULTS: Abnormal CFTR alleles were found to be twice as frequent in ICP patients as in controls (25/134 v 11/120; p<0.05). Three of four severe CFTR mutations detected in patients were compound heterozygous with another abnormal CFTR allele, whereas among controls three severe CFTR mutations were found in heterozygous cystic fibrosis carriers. In ICP patients 19 uncommon/mild mutations, including combinations of the 5T allele with 12TG repeats, were identified compared with only five in controls (p = 0.012). Heterozygous SPINK1 mutations were detected in eight ICP patients (15% v 1% in controls) but only one also carried an additional mild CFTR mutation. CONCLUSIONS: These data show that not only compound heterozygosity, but also cystic fibrosis carrier status for different types of CFTR mutations, including uncommon/mild mutations, significantly increase the risk of developing pancreatitis. Although 45% of the study's ICP patients carried predisposing genetic risk factors (for example, mutations in CFTR or SPINK1), the authors found no evidence that the risk conveyed by CFTR mutations depends on co-inherited SPINK1 mutations.

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233 CFTR mutations in idiopathic pancreatitis www.gutjnl.com Three of the four compound heterozygous ICP patients carried one severe DF508 mutation (genotypes: DF508/ R117H, DF508/A1087P, DF508/D1152H) and one carried two mild mutations (S1235R/R668C). Login to comment
238 M348V and A1087P present novel molecular changes in the CFTR gene with so far undetermined consequences on CFTR function. Login to comment
239 A1087P affects the intracellular loop between the transmembrane domains M10 and M11 and is most probably a mild missense mutation whereas M348V is located in the sixth transmembrane domain of the protein, where the wild type sequence has been conserved during evolution. Login to comment
256 The reason why numbers for compound heterozygous ICP patients in these studies are diverse (4/67 = 6% in our study) may be due to differences Table 1 CFTR and SPINK1 sequence variations identified in 30 of the 67 ICP patients PatientSex CFTR mutation T allele TG repeats PSTI mutation 1 M DF508/R117H 7/7 9/10 -/- 2 W DF508/A1087P 7/9 10/11 -/- 3 M DF508/D1152H 7/9 10/10 -/- 4 M S1235R/R668C 7/7 11/12 -/- 5 M 2184insA/- 7/7 10/12 -/- 6 M R31C/- 7/7 10/11 -/- 7 M R75Q/- 7/7 11/11 -/- 8 M R347P/- 7/7 11/12 -/- 9 M S1235R/- 7/7 11/12 -/- 10 W S1235R/- 7/7 11/12 -/- 11 M G576A/- 7/7 10/10 -/- 12 W M348V/- 7/9 10/10 -/- 13 M V754M/- 7/7 10/11 -/- 14 M -/- 5/7 11/12 -/- 15 W -/- 5/7 11/12 -/- 16 M -/- 5/7 11/12 -/- 17 W -/- 5/9 11/12 -/- 18 M -/- 5/7 11/12 -/- 19 M -/- 5/7 10/10 -/- 20 W -/- 5/7 10/10 -/- 21 W -/- 5/7 11/12 N34S/- 22 W -/- 7/7 10/11 N34S/- 23 M -/- 7/9 10/11 N34S/- 24 M -/- 7/7 11/11 N34S/- 25 M -/- 7/7 11/11 N34S/- 26 W -/- 7/7 11/11 N34S/- 27 M -/- 7/7 11/11 N34S/- 28 W -/- 7/7 10/11 N34S/- 29 W -/- 7/7 11/11 P55S/- 30 W -/- 7/7 11/11 IVS3+2TC/- Table 2 CFTR sequence variations identified in 11 of 60 healthy controls Control group Number DF508/- 3 R117H/- 2 I148T/- 1 L997F/- 1 5T/12TG 1 5T/11TG 3 in patient recruitment, the catchment populations, or the stringency with which cystic fibrosis patients were excluded. Login to comment

[hide] Functional characterisation of the CFTR mutations ... Gut. 2009 May;58(5):733-4. Weiss FU, Simon P, Bogdanova N, Shcheynikov N, Muallem S, Lerch MM
Functional characterisation of the CFTR mutations M348V and A1087P from patients with pancreatitis suggests functional interaction between CFTR monomers.
Gut. 2009 May;58(5):733-4., [PMID:19359437]

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0 LETTERS Functional characterisation of the CFTR mutations M348V and A1087P from patients with pancreatitis suggests functional interaction between CFTR monomers In a recent study on the role of cystic fibrosis transmembrane conductance regulator (CFTR) mutations in idiopathic chronic pancreatitis (Gut 2005;54:1456-60) we sequenced the complete CFTR-coding region of 67 pancreatitis patients and 60 controls. Login to comment
2 Two patients with previously unknown CFTR mutations (M348V and A1087P) were identified, and their unexpected clinical course after conclusion of the trial prompted the functional studies below. Login to comment
5 The patient with the A1087P mutation was recruited to the study as a 19 year old with idiopathic chronic pancreatitis and exocrine pancreatic insufficiency. Login to comment
7 An ambiguous sweat chloride test together with the presence of a DF508 mutation (inherited from her healthy mother) and the novel A1087P mutation (inherited from her healthy father) suggest that this patient suffers from a mild variety of cystic fibrosis rather than from idiopathic chronic pancreatitis, as initially thought. Login to comment
10 In contrast, the residual Cl2 current of the A1087P mutant was only 6% (3%) (mean (SD), n = 9 of the wild-type CFTR, which is typical of a mutation associated with severe cystic fibrosis. Login to comment
11 In addition, the A1087P mutant acted as dominant-negative variant and reduced the activity of co-expressed wild-type CFTR by 78% (7%) (n = 6). Login to comment
16 The observed reduction of Cl2 and HCO3 2 fluxes without reduction of current by the M349V mutation may be related to impaired activation of other Cl2 and HCO3 2 transporters, such as members of the SLC26 Cl2 /HCO3 2 exchangers.2 The A1087P mutant supports minimal Cl2 and HCO3 2 transport and markedly inhibited the function of co-expressed wild-type CFTR. Login to comment
19 The residual CFTR function of the A1087P mutant may explain the late onset of cystic fibrosis symptoms in the second patient, its unusually mild clinical course and its original misclassification. Login to comment
20 The patient`s brother who inherited the A1087P but not the DF508 mutation has symptoms of neither pancreatitis nor cystic fibrosis. Login to comment
21 Another implication of the functional analysis of the A1087P mutant is that monomers of CFTR may affect each others` functions. Login to comment
22 The minimal functional unit of CFTR appears to be a monomer,3 but CFTR has also been shown to function as a dimer.4 Although, in vivo CFTR appears to function as a monomer, the dominant-negative function of the A1087P mutant would be consistent with functional interaction of CFTR monomers. Login to comment
24 Our findings regarding the A1087P mutant, on the other hand, suggest that this variant must be considered a severe cystic fibrosis mutation. Login to comment
25 The unusually mild clinical course of the A1087P mutation-affected patient and its misclassification in the original trial serve as a reminder that cystic fibrosis and pancreatitis can coexist and that a clear distinction between these CFTR-dependent disease entities is sometimes difficult. Login to comment

[hide] Analysis of conventional and unconventional traffi... Methods Mol Biol. 2015;1270:137-54. doi: 10.1007/978-1-4939-2309-0_11. Gee HY, Kim JY, Lee MG
Analysis of conventional and unconventional trafficking of CFTR and other membrane proteins.
Methods Mol Biol. 2015;1270:137-54. doi: 10.1007/978-1-4939-2309-0_11., [PMID:25702115]

Abstract [show]
The cystic fibrosis transmembrane conductance regulator (CFTR) is a polytopic transmembrane protein that functions as a cAMP-activated anion channel at the apical membrane of epithelial cells. Mutations in CFTR cause cystic fibrosis and are also associated with monosymptomatic diseases in the lung, pancreas, intestines, and vas deferens. Many disease-causing CFTR mutations, including the deletion of a single phenylalanine residue at position 508 (DeltaF508-CFTR), result in protein misfolding and trafficking defects. Therefore, intracellular trafficking of wild-type and mutant CFTR has been studied extensively, and results from these studies significantly contribute to our general understanding of mechanisms involved in the cell-surface trafficking of membrane proteins. CFTR is a glycoprotein that undergoes complex N-glycosylation as it passes through Golgi-mediated conventional exocytosis. Interestingly, results from recent studies revealed that CFTR and other membrane proteins can reach the plasma membrane via an unconventional alternative route that bypasses Golgi in specific cellular conditions. Here, we describe methods that have been used to investigate the conventional and unconventional surface trafficking of CFTR. With appropriate modifications, the protocols described in this chapter can also be applied to studies investigating the intracellular trafficking of other plasma membrane proteins.

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2366 Functional characterisation of the CFTR mutations M348V and A1087P from patients with pancreatitis suggests functional interaction between CFTR monomers. Login to comment