ABCMdb

PMID: 15121783

Fujiki K, Ishiguro H, Ko SB, Mizuno N, Suzuki Y, Takemura T, Yamamoto A, Yoshikawa T, Kitagawa M, Hayakawa T, Sakai Y, Takayama T, Saito M, Kondo T, Naruse S
Genetic evidence for CFTR dysfunction in Japanese: background for chronic pancreatitis.
J Med Genet. 2004 May;41(5):e55., [PubMed]

Sentences

No. Mutations Sentence Comment

136 ABCC7 p.Arg1453Trp ABCC7 p.Gln1352His For example, polythymidine (poly-T) and TG dinucleotide repeats, (TG)n, at the junction of intron 8 and exon 9 influence transcription and thereby reduce the amount of normal CFTR protein.19 20 The M/V polymorphism at position 470 affects the function of the CFTR protein.20 In order to understand the genetic background for CFTR dysfunction in chronic pancreatitis in Japanese, we first analysed patients with chronic pancreatitis and healthy individuals for 20 CF mutations that are common in whites, along with 9 CF causing and 2 other non-CF causing (Q1352H and R1453W) mutations commonly found in Japanese. Login to comment 210 ABCC7 p.Arg1453Trp ABCC7 p.Gln1352His N These genetic backgrounds, together with a high association of Q1352H (12.3% in chronic pancreatitis patients v 3.7% in controls) or R1453W (6.2% v 3.1%), may explain the association of CFTR dysfunction and chronic pancreatitis in Japan where CF is very rare. Login to comment 218 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Ser1251Asn ABCC7 p.Glu60* The 20 most common CF mutations (E60X, R117H, R334W, R347P, A455E, DI507, DF508, G542X, G551D, R553X, 621+1GRT, 1078delT, R1162X, S1251N, W1282X, N1303K, 1717-1GRA, 2183AARG, 3659delC, and 3849+10kbCRT) were tested by an Elucigene CF20 kit (AstraZeneca Diagnostics, Abingdon, Oxfordshire, UK). Login to comment 219 ABCC7 p.Arg347His ABCC7 p.Asp979Ala ABCC7 p.His1085Arg ABCC7 p.Arg75* ABCC7 p.Arg1453Trp ABCC7 p.Gln98Arg ABCC7 p.Leu571Ser ABCC7 p.Gln1352His ABCC7 p.Thr1086Ile ABCC7 p.Met152Arg ABCC7 p.Leu441Pro The nine CF causing (R75X, Q98R, M152R, R347H, L441P, L571S, D979A, H1085R, and T1086I) and two non-CF causing (Q1352H and R1453W) mutations in Japanese6 22-24 were screened by SNP typing with a Masscode system (Shimadzu, Kyoto, Japan) and confirmed by sequence analysis in positive and equivocal cases. Login to comment 224 ABCC7 p.Arg1453Trp ABCC7 p.Gln1352His ABCC7 p.Gln1352His ABCC7 p.Gln1352His However, Q1352H and R1453W, both of which were originally identified in Japanese patients with diffuse panbronchiolitis,6 were found in one allele of both control and patients. Q1352H was found in eight patients with chronic pancreatitis (six alcoholic and two idiopathic); the frequency of Q1352H in chronic pancreatitis (12.3%) was significantly (p = 0.015) higher than that of controls (3.7%; 6 in 162 subjects). Login to comment 225 ABCC7 p.Arg1453Trp R1453W was present in five controls (3.1%) and four patients (6.2%) with chronic pancreatitis (two alcoholic and two idiopathic) but their frequencies were not significantly (p = 0.281) different. Login to comment 226 ABCC7 p.Arg1453Trp One patient with idiopathic chronic pancreatitis was homozygous for R1453W. Login to comment 248 ABCC7 p.Arg1453Trp ABCC7 p.Gln1352His Association of 5T, Q1352H, and R1453W with genotypes of (TG)m/n-M470V Fig 3 summarises the frequency distribution of normal subjects and patients with chronic pancreatitis based on the genotypes of the TG repeats and M470V. Login to comment 249 ABCC7 p.Gln1352His 5T was associated with (TG)12/13-M/V470 in two normal subjects and with (TG)12/12-M/V470 in two alcoholic patients. Q1352H was present in patients with (TG)11/11-V/V470 (three alcoholic and two idiopathic), (TG)11/12-M/V470 (6 normal and 2 alcoholic), and (TG)11/12-V/V470 (one alcoholic). Login to comment 250 ABCC7 p.Arg1453Trp R1453W was found in five normal subjects with (TG)11/11-V/V470 (n = 3), (TG)11/12-M/V470 (n = 1), and (TG)12/12-M/M470 (n = 1), and four patients with (TG)11/11-V/V470 (two alcoholic and two idiopathic). Login to comment 253 ABCC7 p.Gln1352His However, we found a significantly higher accumulation (12.3%) of the Q1352H allele in patients with chronic pancreatitis, though it was also observed in healthy subjects (3.7% in Japanese and 0.9% in Korean). Login to comment 254 ABCC7 p.Arg1453Trp ABCC7 p.Gln1352His Glutamine at 1352 is located in the second nucleotide binding fold of CFTR,1 and its change to histidine (Q1352H) causes reduction in both protein expression and channel activity of CFTR.25 This mutation has been found in Japanese patients with CBAVD (25%), and in Korean patients with chronic pancreatitis (14.3%) and bronchiectasis (11.8%).25 The other mutation, R1463W, affects channel activity but its overall effect on CFTR function appears to be mild.25 One patient homozygous for R1453W showed no clinical manifestations other than idiopathic pancreatitis. Login to comment 289 ABCC7 p.Gln1352His Indeed, the Q1352H allele was found in three alcoholic and two idiopathic pancreatitis patients with the (TG)11/11-V/V470 haplotype (fig 3). Login to comment 291 ABCC7 p.Gln1352His ABCC7 p.Gln1352His The Cl2 channel activity is almost completely abolished in cells that expressed the V470-Q1352H CFTR.25 As Q1352H was always present in the V470 background, this allele cannot produce functional CFTR proteins. Login to comment 292 ABCC7 p.Gln1352His Thus, we can estimate that the association of Q1352H in the V/V470 genotype reduces the total CFTR function to about 25% of the wild type. Login to comment 293 ABCC7 p.Arg1453Trp R1453W may not cause CF related disease by itself but its association in the V/V genotype may reduce the total CFTR function to less than 50%. Login to comment 301 ABCC7 p.Arg1453Trp ABCC7 p.Gln1352His Association of other mutations, such as Q1352H and R1453W, may further reduce CFTR function. Login to comment