ABCMdb

PMID: 19359437

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., [PubMed]

Sentences

No. Mutations Sentence Comment

0 ABCC7 p.Ala1087Pro ABCC7 p.Met348Val 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 ABCC7 p.Ala1087Pro ABCC7 p.Met348Val 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 3 ABCC7 p.Met348Val The M348V mutation was found in a woman diagnosed with chronic pancreatitis at the age of 63. Login to comment 5 ABCC7 p.Ala1087Pro 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 ABCC7 p.Ala1087Pro 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 ABCC7 p.Ala1087Pro 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 ABCC7 p.Ala1087Pro 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 ABCC7 p.Ala1087Pro 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 ABCC7 p.Ala1087Pro 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 ABCC7 p.Ala1087Pro 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 ABCC7 p.Ala1087Pro Another implication of the functional analysis of the A1087P mutant is that monomers of CFTR may affect each others` functions. Login to comment 22 ABCC7 p.Ala1087Pro 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 23 ABCC7 p.Met348Val How mild CFTR mutants such as M348V predispose to pancreatitis is currently being investigated in transgenic animal models. Login to comment 24 ABCC7 p.Ala1087Pro 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 ABCC7 p.Ala1087Pro 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