ABCMdb

PMID: 19734299

Comer DM, Ennis M, McDowell C, Beattie D, Rendall J, Hall V, Elborn JS
Clinical phenotype of cystic fibrosis patients with the G551D mutation.
QJM. 2009 Nov;102(11):793-8. Epub 2009 Sep 4., [PubMed]

Sentences

No. Mutations Sentence Comment

10 ABCC7 p.Gly551Asp ABCC7 p.Arg117His Conclusions: Mutations on different chromosomes are not independent of each other for the overall impact on the amount of functional CFTR. This study suggests that patients with the G551D mutation and a second severe mutation have a milder clinical phenotype than F508del homozygous patients, but the phenotype is not as mild as patients with the R117H mutation. Login to comment 20 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp Furthermore, the high degree of clinical variability for any given mutation (as illustrated by CF siblings) supports the concept that factors in addition to CFTR function alone are important.4 The G551D (Glycine to Aspartate change in nucleotide 1784 in exon 11) mutation is a Gly to Asp substitution at amino acid position 551. Login to comment 21 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp There is considerable current interest in treating patients with the G551D mutation with drugs that potentiate its function.5,6 These pharmacological agents have shown promise in phase 2 clinical trials leading to changes in nasal potential difference and improved lung function.7 The prevalence of this particular mutation is high in Northern Ireland.8 Data on whether the phenotype of patients with compound heterozygocity for G551D differs from patients with F508del (Deletion phenylalanine in codon 508 in chromosome 7) homozygous mutations are divergent. Login to comment 22 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp No difference was shown between the G551D mutation and the F508del mutation for age at diagnosis, sweat chloride, measures of nutritional status, lung function, Pseudomonas aeruginosa infection and exocrine pancreatic function.9 At an early age, G551D patients had pancreatic insufficiency (PI).10 In contrast, a case study of two CF patients, who were heterozygous with the G551D mutation and a second severe mutation, showed a mild pulmonary and intestinal phenotype.8 More recently in a large study of the 11 most common CF mutations using US CF Registry data, the severity of the G551D mutation was similar to F508del for lung function, exocrine pancreatic status and P. aeruginosa infection but significant differences for age at diagnosis, sweat chloride, height and weight were demonstrated. Login to comment 23 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp There was a nonsignificant trend towards better survival for the G551D/F508del patients than homozygotes for F508del.11 In this study, we hypothesized that CF patients with the G551D mutation would have less severe disease than those F508del homozygotes. Login to comment 24 ABCC7 p.Gly551Asp ABCC7 p.Arg117His To address this, we compared the clinical phenotype of patients with a G551D mutation, a Class 3 mutation, with patients homozygous for F508del and those with the missense mutation R117H (Arginine to histidine mutation of residue 117), a Class 2 and 4 mutation, respectively. Login to comment 25 ABCC7 p.Arg117His Including the R117H mutation, a missense mutation in exon 4 and the most common mutation in its class, allowed a comparison across three groups to be established. Login to comment 26 ABCC7 p.Gly551Asp ABCC7 p.Arg117His Compound heterozygotes for the G551D and R117H were studied as a separate group. Login to comment 30 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His Group 1 included F508del homozygote patients, Group 2 with the G551D on either chromosome (and without the R117H mutation), Group 3 with the R117H mutation on either chromosome (and without the G551D mutation) and Group 4 compound heterozygotes for the R117H and G551D mutation. Login to comment 36 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Arg117His Results Group 1 (F508del homozygote patients) included 61 patients, Group 2 (patients heterozygous for G551D) 13 patients, Group 3 (patients heterozygous for R117H) 23 patients and Group 4 (compound R117H/G551D patients) 4 patients. Login to comment 39 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Glu60* Two patients in Group 2 (G551D/621+1G!T, G551D/3659delC) and 1 in Group 3 (R117H/ E60X) were heterozygous with a CFTR mutation other than F508del. Login to comment 54 ABCC7 p.Gly551Asp ABCC7 p.Arg117His Discussion Comparing F508del homozygous CF patients to those heterozygous for G551D and R117H, we have shown that the latter two groups individually have better lung function, slower rate of decline in FEV1, older age at diagnosis, better nutritional status, reducing infection with P. aeruginosa and B. cepacia complex, reduced burden of care and improved pancreatic status and glucose tolerance. Login to comment 55 ABCC7 p.Gly551Asp McKone et al.`s study, in contrast to our data, showed no significant difference in pancreatic status and FEV1 for those heterozygous for the G551D mutation compared with the F508del homozygous patients. Login to comment 56 ABCC7 p.Gly551Asp The trend for reduced infection with P. aeruginosa and the statistically better nutritional status that we have shown for G551D patients compared to F508del homozygous is in keeping with McKone et al.`s findings. Login to comment 60 ABCC7 p.Gly551Asp Recent interest in drugs that potentiate CFTR expression in G551D patients and the inconsistency in previous reports as to the overall severity of this particular phenotype make further study important. Login to comment 61 ABCC7 p.Arg117His The R117H mutation is commonly associated with the genetic polymorphism of the polypyrimidine tract in intron 8 giving rise to variable amounts of functional CFTR. This polymorphism exists on an intron-8 polythymidine sequence (IVS8) as a 5-, 7- or 9-thymidine (T) variant. Login to comment 62 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Glu60* These alleles cause intron Table 1 Genotype details of the 101 CF patients Group Genotype Patients (n) 1 F508del/F508del 61 2 G551D/F508del 11 G551D/621+1G!T 1 G551D/3659delC 1 3 R117H/F508del 22 R117H/E60X 1 4 G551D/R117H 4 8 to be incorrectly spliced leading to mRNA lacking exon 9 and so a reduced amount of normal CFTR transcript. Login to comment 63 ABCC7 p.Arg117His ABCC7 p.Arg117His R117H with the 5T variant are most severely affected.3 Each mutation, the missense mutation R117H in exon 4 and the 5T polymorphism in intron 8, have a mild phenotypic effect unless they are present on the same chromosome. Login to comment 65 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117Cys ABCC7 p.Arg117Cys In contrast to the number of T repeats, high numbers of TG repeats will result in a reduced amount of functional CFTR.16 The incidence of R117H on an IVS8-5T background was much higher in our cohort in comparison to a multicentre study of patients with the R117H/C mutation (39 with the R117H and 2 with the R117C mutation). Login to comment 66 ABCC7 p.Arg117His In this study of 41 patients, 16 had the R117H mutation on an IVS8-5T background, and 25 on an IVS8-7T background.17 TG repeats were not determined in this study. Login to comment 68 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Arg117His In our study, the lack of any significant CF phenotype in patients compound for R117H/G551D compared with R117H/F508del mutations is intriguing. Login to comment 69 ABCC7 p.Gly551Asp ABCC7 p.Arg117His Compound heterozygosity for G551D/R117H mutations was associated with normal spirometry, BMI, no chronic infection and no symptoms. Login to comment 72 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp Previous published data support this concept as homozygotes for G551D have an older age at diagnosis, reduced amount of exocrine PI and intestinal complications than those compound for G551D/F508del mutations.8 The correlation between genotype and phenotype is strongest for exocrine pancreatic function; however, this relationship is not consistent. Login to comment 73 ABCC7 p.Arg117His Only 52% of patients who are compound heterozygotes for R117H, where the second mutation was a severe mutation, were pancreatic sufficient. Login to comment 74 ABCC7 p.Arg117His In the Cystic Fibrosis Genotype-Phenotype Consortium, 87% of patients with the R117H/F508del mutation had pancreatic sufficiency2 ; however, the older age in our cohort may account for this difference (31.7 Æ 1.8 vs. 23.5 Æ 9.6 years). Login to comment 76 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Arg117His In addition, the particularly high incidence of R117H on an IVS8-5T background in our centre, with its associated Table2PhenotypicvariablesforGroups1-4(genderratio,meanvalueÆSDandrangeforcontinuousvariables,percentagewithORforcategoricalvariables) Group1:F508del homozygote Group2:G551D+ severemutation Group3:R117H+ severemutation Group4: R117H/G551D Male/Female41/207/614/92/2 Age(years)27.6Æ6.9(17.7to48.2)26.3Æ4.5(20.1to35.5)31.7Æ13.3(19.8to76.6)35.3Æ3.2(31.3to39) Ageatdiagnosis(years)3.9Æ8.1(3to26)3.9Æ5.7(0.1to19)16.4Æ19.1(0to73.4)ÃÃ 13.8Æ16.7(0to29.3) PercentagepredictedFEV156.3%Æ22(19to110)77.5%Æ18.8(50to110)Ã 83.4%Æ21.2(27to116)ÃÃ 100%Æ2.4(97to102) YearlyrateofdeclineofFEV1(%/year)1.6Æ0.9(À0.5to4.0)0.9Æ0.7(À0.3to2.4)Ã 0.5Æ0.7(À0.7to1.8)Ã 0Æ0.1(0to0.1) BMI(kg/m2 )21.4Æ2.8(15.1to29.9)23.7Æ3.0(17.5to28.4)Ã 24.7Æ3.5(18.3to30.6)ÃÃ 26.6Æ1.1(25.2to28) InfectionwithP.aeruginosa75%62%(OR:0.5)26%(OR:0.1)ÃÃ 0% CultureofB.cepaciacomplex16%0%0%0% Useofazithromycin56%54%(OR:0.9)35%(OR:0.4)0% UseofrhDNase61%39%(OR:0.4)22%(OR:0.2)Ã 0% NumberofdaysofIVAb21.8Æ24.3(0to98)8.7Æ17.4(0to60)4.7Æ12.3(0to42)Ã 0(0) IGT/CFRD23%8%4%0% Useofinhaledantibiotic74%31%(OR:0.5)26%(OR:0.4)0% Pancreaticinsufficient97%69%(OR:0.07)Ã 48%(OR:0.03)ÃÃ 25%(OR:0.02)Ã Ã ComparedtoGroup1(P<0.05);ÃÃ ComparedtoGroup1(P<0.001);OR:OddsratiorelativetoGroup1. Login to comment 82 ABCC7 p.Gly551Asp ABCC7 p.Arg117His Many of the patients in this study will have started taking pancreatic-enzyme supplementation immediately after diagnosis and so our data will be an overrepresentation of the overall amount of PI, particularly in G551D and R117H patients. Login to comment 84 ABCC7 p.Gly551Asp There is a high variability in phenotype within identical CFTR genotypes.11 However, as modifier genes remain to be identified, clinicians need to be mindful of consensus statements advising that genotype alone should not be used to predict clinical outcomes at the time of diagnosis.16 In conclusion, this study reports that patients with the G551D mutation and a second severe mutation have a milder clinical phenotype than F508del homozygous patients. Login to comment