ABCMdb

PMID: 8863168

Parad RB
Heterogeneity of phenotype in two cystic fibrosis patients homozygous for the CFTR exon 11 mutation G551D.
J Med Genet. 1996 Aug;33(8):711-3., [PubMed]

Sentences

No. Mutations Sentence Comment

0 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp IMed Genet 1996;33:71 1-713 Heterogeneity of phenotype in two cystic fibrosis patients homozygous for the CFTR exon 1 1 mutation G551D Richard B Parad Abstract In the heterozygous state, the cystic fibrosis transmembrane conductance regulator (CFTR) exon 11 mutation G551D has been described as "severe," causing pancreatic insufficiency. Login to comment 4 ABCC7 p.Gly551Asp G551D, an exon 11 mutation in the first nucleotide binding fold (NBF) ofthe CFTR protein, is one ofthe most common non-AF508 mutations, occurring at a world wide frequency of 3%. Login to comment 7 ABCC7 p.Gly551Asp Reported here are the clinical courses of two patients homozygous for CFTR mutation G551D. Login to comment 10 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg560Thr R B Parad Received 27 December 1995 Revised version accepted for publication 15 March 1996 Methods Cheekbrush DNA for CFTR mutation analysis was collected and prepared according to Richards et al.1 CFTR mutation analysis was performed for 12 mutations (AF508, G551D, G542X, 621 + 1G->T, AI507, 1717-1G-4A, R117H, N1303K, W1282X, R560T, R553X, 3849 + 1Okb C-+T). Login to comment 12 ABCC7 p.Ser549Asn DNA from patient 1 was also assessed for 12 mutations by allele specific oligonucleotide analysis (ASO),4 but S549N was screened in addition, and 3849 + 1Okb was excluded. Login to comment 42 ABCC7 p.Gly551Asp Results Fig 1 shows the multiplex ARMS rea assessment of mutations AF508, G551D, and 621 + 1G-4T. Login to comment 43 ABCC7 p.Gly551Asp The pair labelled 1 was performed on a known] gote for mutation G551D. Login to comment 46 ABCC7 p.Gly551Asp patient 1 showed a single band in th( lane for mutation G551D in the lanes This result was confirmed by ASO (data not shown). Login to comment 50 ABCC7 p.Gly551Asp The allele frequency of G551D patients from Europe has been docum a north west to south east gradient,6 highest frequency reported in North land (8.3%) and less than 0.1% f southern European/Mediterranean tions. Login to comment 53 ABCC7 p.Gly551Asp ABCC7 p.Gly542* Lanes are paired to show both normal and abnormal alleles con; mutations 621 + JG-*T (normal band lane 1, abnormal band lane 2), G551D (abnormal band lane 1, normal band lane 2), G542X (abnormal band lane 1, n band lane 2), and AF508 (normal band lane 1, abnormal band lane 2) at these first pair oflanes shows the ARMS pattern ofa GSSJDIN heterozygote. Login to comment 59 ABCC7 p.Gly551Asp ABCC7 p.Ala455Glu Consistent pulmo- boplastin nary phenotype has only been suggested with were nor- two mutations, RI 17H and A455E.9 10 CF, and G551D has been characterised as a class III mutation8 through its presumed impact on ATP binding." Login to comment 60 ABCC7 p.Gly542* Recent studies have shown present (but diminished) chloride conduct- iction for ance, and absent CFTR inhibitory regulation G542X of the outwardly rectifying chloride channel. Login to comment 62 ABCC7 p.Gly551Asp e mutant G551D was originally categorised as a under 3. severe" mutation with respect to pancreatic analysis insufficiency (PI). Login to comment 63 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp '3 All 21 AF508/G551D het- show the erozygotes, five compound heterozygotes for Ler muta- G551D and other non-AF508 mutations, and one G551D homozygote fit criteria for PI. Login to comment 65 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp In a retrospective cohort xn at the study by Hamash et alt of 79 AF508/G551D xon ii.~ compound heterozygotes, no significant clini- iino acid cal differences from AF508 homozygotes could I of the be detected, with the exception of a lower risk for meconium ileus (MI) in the AF508/G551D in CF heterozygotes at birth. Login to comment 67 ABCC7 p.Gly551Asp Three ound in G551D homozygotes were alluded to in that popula- report, and they were briefly described with s from 1 minimal detail as PI with no history of MI. Login to comment 68 ABCC7 p.Gly551Asp A conflicting report by Curtis et al'4 documented 7m being three pancreatic sufficient G551D compound ogven a heterozygotes. Login to comment 71 ABCC7 p.Gly551Asp The ages of diagnosis and age at taining PI in patients 1 and 2 are much older than the 0ormal means proposed for AF508/G551D hetero- loci. Login to comment 73 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp The disparity in severity of idpattern respiratory disease of these patients could beThe third related to the absence of mucoid Pseudomonas aeruginosa (an organism known to be associ- Parad Phenotype ofCFTR mutation G551D Table 1 Clinical characteristics: comparison between reported homozygotesfor G551D andpreviously published heterozygous and homozygous series Genotype Ref No ofpatients Age at diagnosis (y) * No with PIt Age at PI (y) * No with MI, Heterozygotes G551D/AF508 5 79 1.9 (2.8) 79 2.7 (4.0) 5 12 21 NR 21 NR 0 13 5 NR 5 NR 1 G551D/other 12 3 NR 0 NR 0 Homozygotes G551D/G551D 5 1 NR 1 NR 0 12 3 NR 3 NR 0 Patient I 1 6 1 16 0 Patient 2 1 36 0 NA 0 * Mean (SD). Login to comment 82 ABCC7 p.Gly551Asp Fig 1 shows that both patients 1 and 2 have only mutant bands and no normal bands for the amplimer containing the G551D mutation locus. Login to comment 84 ABCC7 p.Gly551Asp Both methods suggest that there is only an abnormal, and no normal sequence at the G551D locus. Login to comment 85 ABCC7 p.Gly551Ser It is still possible that a similar mutation, such as G551S,'5 is present (rather than G55 1 D) on one or both alleles and is producing a false positive result. Login to comment 87 ABCC7 p.Gly551Asp Of course, the same criticism could be made of the genotypes reported for the other G551D carrying CF patients reviewed in table 1. Login to comment 88 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp Another explanation for phenotype modification, assuming the common genotype of G551D/G551D, is the presence of a second mutation or sequence variant elsewhere in either or both alleles ofthe CFTR gene. Login to comment 89 ABCC7 p.Gly551Asp '6 The disparate outcomes of these two patients shows both that severe pancreatic insufficiency is not necessarily a clinical feature of the G551D homozygous genotype, and thai a mild pulmonary phenotype is possible. Login to comment 128 ABCC7 p.Gly551Asp Nature Genet 1993;5:274-8. group.bmj.comon October 25, 2012 - Published byjmg.bmj.comDownloaded from doi: 10.1136/jmg.33.8.711 1996 33: 711-713J Med Genet R B Parad exon 11 mutation G551D. Login to comment