ABCMdb

PMID: 16678503

Ngiam NS, Chong SS, Shek LP, Goh DL, Ong KC, Chng SY, Yeo GH, Goh DY
Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in Asians with chronic pulmonary disease: a pilot study.
J Cyst Fibros. 2006 Aug;5(3):159-64. Epub 2006 Mar 6., [PubMed]

Sentences

No. Mutations Sentence Comment

4 ABCC7 p.Ile556Val ABCC7 p.Ile125Thr ABCC7 p.Gln1352His Results: Three missense mutations (I125T, I556V, and Q1352H) and 1 splice site variant (intron 8 12TG5T) were identified in a total of 10 patients, representing a combined mutant/variant allele frequency of 0.25. Login to comment 6 ABCC7 p.Ile125Thr Furthermore, the I125T mutation was significantly associated with the idiopathic bronchiectasis sub-group ( P <0.05). Login to comment 8 ABCC7 p.Ile125Thr The association of I125T with idiopathic bronchiectasis alone suggests that different mutations predispose to different disease. Login to comment 34 ABCC7 p.Gln1352His Asian patients with congenital bilateral absence of vas deferens (CBAVD) have been investigated and in Japanese patients with CBAVD, missense mutations including Q1352H were detected [18]. Login to comment 78 ABCC7 p.Ile556Val ABCC7 p.Ile125Thr ABCC7 p.Gln1352His Three missense mutations (I125T in exon 4, I556V in exon 11, and Q1352H in exon 22) and one splice site variant (intron 8 12TG5T) were identified among the patients. Login to comment 83 ABCC7 p.Ile125Thr On subgroup analysis, the I125T mutation was found to be significantly associated with idiopathic bronchiectasis but not severe asthma. Login to comment 84 ABCC7 p.Ile125Thr Of the 6 patients with idiopathic bronchiectasis, 2 (33.3%) were heterozygous for I125T, compared to 1 in 40 normal controls (2.5%) and 2 in 96 unselected population samples (2.1%) (Table 1). Login to comment 85 ABCC7 p.Ile125Thr In marked contrast, I125T was not observed in the severe asthma group. Login to comment 86 ABCC7 p.Ile125Thr The I125T mutant allele frequency was 16.7% compared to 1.3% in the normal controls ( P <0.05) and an estimated population frequency of 1% ( P <0.02) (Table 2). Login to comment 88 ABCC7 p.Gln1352His ABCC7 p.Gln1352His The incidence of the Q1352H mutation was observed to be higher in the severe asthma patients, where 2 of 14 patients (14.3%) were heterozygous for Q1352H, compared to 1 of 40 normal controls (2.5%) and an estimated population heterozygote frequency of 4.2% (4 in 95) (Table 1). Login to comment 90 ABCC7 p.Ile556Val Similarly, 3 severe asthma patients were heterozygous for the I556V mutation (21.4%), compared to 10% (4 of 40) in the normal controls, and an estimated population frequency of 12.5% (12 of 96). Login to comment 93 ABCC7 p.Ile556Val ABCC7 p.Ile556Val ABCC7 p.Ile556Val ABCC7 p.Ile125Thr ABCC7 p.Ile125Thr ABCC7 p.Ile125Thr ABCC7 p.Gln1352His ABCC7 p.Gln1352His ABCC7 p.Gln1352His Table 1 Frequency of CFTR gene variants in the Singaporean Chinese Variation Genotype Unselected population samples (n =93-96) Healthy controls (n =40) Severe asthma (n =14) Idiopathic bronchiectasis (n =6) I125T I125T/WT 2 1 0 2 WT/WT 94 39 14 4 I556V I556V/WT 12 4 3 0 WT/WT 84 36 11 6 Q1352H Q1352H/WT 4 1 2 0 WT/WT 91 39 12 6 12TG5T 12TG5T/Other 9 1 2 1 Other/Other 84 39 12 5 Table 2 CFTR gene variant allele frequency comparisons between patient and population and normal control groups Variation Allele Unselected population (n =186-192) Healthy controls (n =80) Severe asthma (n =28) P-value Idiopathic bronchiectasis (n =12) P-value I125T Variant 2 1 0 1.000a 2 0.018a,* Wild-type 190 79 28 1.000b 10 0.044b,* I556V Variant 12 4 3 0.415a 0 1.000a Wild-type 180 76 25 0.372b 12 1.000b Q1352H Variant 4 1 2 0.172a 0 1.000a Wild-type 186 79 26 0.163b 12 1.000b 12TG5T 12TG5T 9 1 2 0.640a 1 0.473a Other 177 79 26 0.164b 11 0.245b a P value for disease vs. unselected population. Login to comment 99 ABCC7 p.Ile125Thr Our study identified four CFTR mutations in the population and patients, with only the I125T mutation showing a significant association with idiopathic bronchiectasis. Login to comment 102 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* These are R117H (exon 4), 621UVG>T (intron 4), F508del (exon 10), 1717-1 G>A (intron 10), G542X (exon 11), G551D (exon 11), R553X (exon 11), R1162X (exon 19), W1282X (exon 20) and N1303K (exon 21). Login to comment 108 ABCC7 p.Ile125Thr Of the 4 mutations or variants that we found, only the I125T mutation was significant, showing an association with idiopathic bronchiectasis. Login to comment 109 ABCC7 p.Ile125Thr Interestingly, the I125T mutation was first described in a Chinese woman and reported by Mittre in the CF Genetic Analysis Consortium [21]. Login to comment 113 ABCC7 p.Gln1352His Although the higher proportion of the Q1352H mutation in our patient population was not statistically significant, it is likely that this mutation has a role to play in disease causation. Login to comment 114 ABCC7 p.Gln1352His In a study in a Korean population, it was found that the heterozygote frequency of Q1352H was significantly higher in patients with bronchiectasis and chronic pancreatitis. Login to comment 115 ABCC7 p.Gln1352His Q1352H was found on molecular studies to be a significant mutation. It is located in the sequence called the ''linker peptide`` of the CFTR. Login to comment 117 ABCC7 p.Gln1352His The change of the last glutamine into histidine (Q1352H) resulted in defects in protein expression and affected gating properties of single channel kinetics [22]. Login to comment 119 ABCC7 p.Gln1352His [18] Q1352H was also recently detected in a Korean patient with alcoholic chronic pancreatitis although it was not thought to predispose to the disease [23]. Login to comment 121 ABCC7 p.Arg31Cys ABCC7 p.Ile556Val The first description of I556V was made in a male French patient having atypical CF who was also compound heterozygous for another mutation, R31C in exon 2 [24]. Login to comment 123 ABCC7 p.Ile556Val One of his children inherited his I556V mutation, and had chronic bronchitis suggestive of CF, although the authors indicated that the diagnosis was not clear. Login to comment 124 ABCC7 p.Ile556Val In the Korean study, I556V was shown to reduce the current density in the whole-cell chloride current by reducing the open probability of the channel [22]. Login to comment 139 ABCC7 p.Ile556Val ABCC7 p.Gln1352His The mutations were the I556V and the Q1352H mutations. Login to comment 148 ABCC7 p.Ile125Thr There is a higher incidence of the I125T alleles in patients with idiopathic bronchiectasis. Login to comment