ABCMdb

PMID: 15994263

de Gracia J, Mata F, Alvarez A, Casals T, Gatner S, Vendrell M, de la Rosa D, Guarner L, Hermosilla E
Genotype-phenotype correlation for pulmonary function in cystic fibrosis.
Thorax. 2005 Jul;60(7):558-63., [PubMed]

Sentences

No. Mutations Sentence Comment

185 ABCC7 p.Arg117His ABCC7 p.Ala455Glu Although there are a few rare mutations such as A455E and R117H which are clearly linked to a better pulmonary outcome,12 13 the effect on the lungs of F508del and most other mutations cannot be separated and attempts to link mutations in CFTR to severity of lung disease have been unsuccessful.14 Furthermore, genes other than CFTR and environmental factors such as access to specialised centres and treatment strategies may be more important factors in modifying the development, progression, and severity of pulmonary disease. Login to comment 209 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Trp1282* ABCC7 p.Trp1282* ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Arg347His ABCC7 p.Arg347His ABCC7 p.Arg347His ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Arg1162* ABCC7 p.Arg1162* ABCC7 p.Arg1162* ABCC7 p.Asp1270Asn ABCC7 p.Pro205Ser ABCC7 p.Pro205Ser ABCC7 p.Leu206Trp ABCC7 p.Leu206Trp ABCC7 p.Arg1066Cys ABCC7 p.Arg1066Cys ABCC7 p.Gln890* ABCC7 p.Gln890* ABCC7 p.Asp836Tyr ABCC7 p.Asp836Tyr To study the decline in pulmonary function between groups the ANOVA method (repeated measures) was used with baseline and current spirometric values as dependent variables, genotype groups as the independent variable, and age and evolution time as Table 1 CFTR mutation according to functional classification Class Molecular dysfunction Mutation I Defective protein production G542X, 711+1GRT, 1609delCA, R1162X, 1717-8GRA, W1282X, 1782delA, Q890X, 1898+3ARG, CFTRdele19, 936delTA II Defective protein processing F508del, N1303K, I507del, R1066C III Defective protein regulation D1270N, G551D IV Defective protein conductance L206W, R334W, R117H, R347H, D836Y, P205S V Partially defective production or processing 2789+5GRA, 1811+1.6kbARG, 3849+10kbCRT, 3272+26GRA Table 2 Groups based on genotype in CF adult patients Functional classes Genotype No of subjects I-I G542X/W1282X 1 R1162X/1898+3ARG 1 R1162X/CFTRdele19 1 I-II F508del/G542X 5 F508del/711+1GRT 2 F508del/1717-8GRA 1 F508del/936delTA 1 F508del/R1162X 1 N1303K/1609delCA 1 I-III G542X/D1270N+R74W 1 711+1G-T/G551D 1 I-IV G542X/P205S 1 Q890X/R334W 1 1609delCA/R347H 1 I-V G542X/2789+5GRT 2 G542X/1811+1.6kbARG 1 1782delA/2789+5GRA 1 1609delCA/1811+1.6kbARG 1 II-II F508del/F508del 21 F508del/N1303K 1 F508del/R1066C 1 II-III F508del/D1270N+R74W 1 I507del/D1270N+R74W 1 II-IV F508del/L206W 4 F508del/R334W 3 F508del/R117H 3 F08del/R347H 2 F508del/D836Y 1 II-V F508del/2789+5GRA 5 F508del/3849+10kbCRT 2 F508del/1811+1.6kbARG 2 F508del/3272+26GRA 1 N1303K/1811+1.6kbARG 1 N1303K/2789+5GRA 1 adjusted variables. Login to comment 220 ABCC7 p.Arg347His ABCC7 p.Asp836Tyr Sweat tests were positive (sweat chloride concentration >60 mEq/l) in all but three patients (pair of CFTR mutations: I507del/ D1270N+1274W, F508del/D836Y, and F508del/R347H, respectively). Login to comment 251 ABCC7 p.Arg117His ABCC7 p.Ala455Glu ABCC7 p.Pro67Leu The mild pulmonary phenotype seen in patients with genotype I-II/III-V is consistent with previous reports where a few rare mutations such as A455E, R117H, 3849+10kbCRT, 2789+5GRT, and P67L (all class IV or V mutations) are clearly linked to a better pulmonary outcome.13 14 26-28 The findings observed in this study support the hypothesis that differences in CF pulmonary phenotype could be related to the effect of the genotype on CFTR protein production and function. Nevertheless, it is important to recognise that specific mutations may have characteristics of more than one 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 20 30 40 50 60 Follow up (years) Events Lung transplant Dead I-II/I-II 9 6 I-II/III-V 1 0 Genotype I-II/III, IV or V I-II/I-II p<0.001 (Log-rank test for trend) Figure 3 Kaplan-Meier survival curves by genotype. Login to comment 264 ABCC7 p.Arg117His They found that patients who were homozygous for F508del have significantly higher overall mortality and higher crude mortality adjusted for sex and age than those who were homozygous for mutation class IV and V or heterozygous for F508del with R117H, 3849+10kbCRT and 2789+5GRT. Login to comment 272 ABCC7 p.Gly551Asp ABCC7 p.Asp1270Asn Only the mutations D1270N and G551D were analysed and they were associated with a more favourable outcome of pulmonary function. Nevertheless, previous studies have pointed out that, among functional class III mutations, there may exist a wide variability in their phenotypes that depends principally on the CFTR protein site for which they code.33 34 In summary, the results of this study suggest that the genotype, based on functional class mutation on the two chromosomes, seems to be one of the most decisive factors for pulmonary phenotype and for survival in relation to pulmonary damage. Login to comment