抄録
The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-regulated chloride channel present in epithelial membranes. In pancreatic ducts the CFTR plays the pivotal role in the apical bicarbonate transport. Loss of its function due to CFTR mutations causes cystic fibrosis (CF). Mild mutations may result in dysfunction of the CFTR that causes a variety of atypical diseases, such as chronic pancreatitis (CP). The sweat chloride concentration was elevated in about 50% of CP patients due to the failure of chloride reabsorption in sweat ducts. Therefore, we studied DNA of 65 CP patients and 162 healthy controls (C) for 29 CFTR mutations and 3 polymorphisms (poly T, TG repeats, and M470V). Compared with Caucasians, Japanese had a higher frequency of the (TG)12 with the (TG)11:(TG)12 of roughly 1:1. Genotype analysis revealed two major haplotypes, the (TG)12-M470 (31%) and (TG)11-V470 (51%); the former was known to express a smaller amount of intact CFTR proteins and the latter to produce proteins with lower intrinsic activity. These genetic backgrounds, together with a high association of Q1352H (12.3% in CP vs. 3.7% in C) or R1453W (6.2% vs. 3.1%), may explain the association of CFTR dysfunction and CP in Japan where CF is very rare. It remains to be studied how CFTR dysfunction leads to CP. As the CFTR regulates other ion transporters, such as the chloride-bicarbonate exchange and sodium-bicarbonate cotransport, the investigation on their molecular interaction with CFTR may provide a physiological background for understanding pathogenesis of CF and CP. [Jpn J Physiol 54 Suppl:S59 (2004)]
