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Thorax1999;54(Suppl 2):S19±S23S19

The pathogenicconsequences ofa

single mutatedCFTR gene

Uta Griesenbach,DuncanM Geddes, EricWFWAlton

Department ofGene Therapy, ImperialCollegeatthe NationalHeart &Lung

Institute, London,UK

Introductoryarticles

D F508 heterozygosityincystic ®brosis andsusceptibility toasthma

M Dahl,A Tybjaerg-Hansen, PLange,B GNordestgaard

Background

.Cystic®br osisis arecessivedisor dermainly characterizedby lungdisease.We testedthe hypothesis thatindividuals heterozygous forthecommoncystic ®brosis DF508 mutationar eatriskof obstructive pulmonarydisease. Methods.We studiedacross-sectional samplefr omthe general population ofCopenhagen, Denmark,aged 20years andolder .W edid spirometry tomeasurefor ced expiratory volumein 1s(FEV 1 ) andfor cedvitalcapacity(FVC), anddid genotypingon bloodsamples of 9141individuals. We askedforinformationon smokingand otherfactors thatcould havecontributed to obstructivepulmonary disease.Findings. Weidenti®ed250 carriersof theDF508 mutation(2.7% [95% CI2.5 to3.1]). 9%of carriersr eportedhaving asthmacompar edwith 6%ofnon-carriers(p

0.04). Theodds ratiofor asthmain participantsheter ozygousfor DF508 mutationswas 2.0(1.2 to3.5,

p

0.02). Furthermore,amongindividuals withairway obstruction,the percentage predicted FEV

1 and FVC weresigni®cantlylower inparticipants heterozygous forDF508 thanin non-carriers(49 vs58%, p

0.004; and70 vs82%, p<0.001,r espectively),mainly dueto aneffectinthose withself-r eported

asthma.Interpretation.Cystic®br osisDF508 heterozygositymaybe over-r epresented amongpeople with asthmaand seemsto beassociated withdecr easedpulmonary functionin peoplewith airway obstruction whoalso haveasthma. (Lancet1998;351:1911±3) Mutations ofthe cystic®br osisgene inpatientswithchr onicpancr eatitis N Sharer,MSchwarz,G Malone,A Howarth,J Painter, MSuper ,J Braganza

Background

.Thepancr eaticlesions ofcystic®brosis developin utero andclosely resemblethoseof chronicpancr eatitis.Therefore, wehypothesizedthatmutationsofthe cystic®br osistransmembrane conductance regulator(CFTR)gene maybe more commonthan expectedamong patientswithchronic pancreatitis.Methods.We studied134consecutivepatients withchr onicpancr eatitis(alcohol-r elated disease in71, hyperparathyroidism in2,hypertriglyceridemiain 1,and idiopathicdisease in60). We examined DNAfor 22mutations ofthe CFTRgene thattogether accountfor 95per centof allmutations in patientswith cystic®br osisin thenorthwestofEngland. We alsodetermined thelength ofthe noncoding sequenceof thymidinesin intron 8,since theshorterthesequence, thelower thepr oportion of normalCFTR messengerRNA. Results. The94 maleand 40female patientsranged inage from 16 to 86years. Nonehad amutation onboth copiesof theCFTR gene.Eighteen patients(13.4 percent), including 12without alcoholism,had aCFTR mutationon onechr omosome,as compared witha frequencyof 5.3per centamong 600localunrelated partnersof personswith afamily historyofcystic ®brosis(p<0.001). Atotal of10.4 percent ofthe patientshad the5Tallelein intron 8(14 of134), which is twicethe expectedfr equency(p

0.008). Fourpatients were heterozygousforboth aCFTRmutation

and the5T allele.Patients witha CFTRmutation were youngerthan thosewith nomutations (p

0.03). Nonehad thecombination ofsinopulmonary disease,high sweatelectr olyteconcentrations, and

low nasalpotential difference valuesthatare diagnosticof cystic®br osis.Conclusions.Mutationsof the CFTRgene andthe 5Tgenotype are associatedwith chronic pancreatitis.(N EnglJ Med1998;339:

645±52)

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nloaded from

S20Griesenbach, Geddes,Alton

Cystic ®brosis(CF) isa recessivesingle genedisorder forcedexpiratory volumein onesecond (FEV 1 ) and

forced vitalcapacity (FVC)were signi®cantlylower inwhich requiresboth copiesof thecystic ®brosisgene to

be mutated.Currently morethan 800mutations haveasthmatics whocarried aDF508 mutationthan innon-

carriers, suggestingthat thee Vect ofDF508 hetero-been detectedin thecystic ®brosistransmembrane con-ductance regulator( CFTR)gene.Mutations havebeen zygositybecomes more/onlyapparent incombination

with otherfactors involvedin theaetiology ofasthma. found inevery exon,as wellas inmany ofthe ¯ankingintron sequences,and includemissense, nonsense,One potentialcriticism ofthe studyrelates tothe self-

classi®cation ofthe participantsinto thepresence orframeshift andsplice sitemutations aswell asamino acid deletionsand substitutions.The majormutation, absenceof respiratorydisease, andwhether thiswas

asthma orCOPD. Further, theauthorsdiscussthat apresent inapproximately 70%of CFchromosomes worldwide, isa deletionof phenylalanineat position508 closeproximity betweenthe DF508 mutationand an

unidenti®ed asthmagene (linkagedisequilibrium) on(DF508). Therelative frequencyof theother mutations

varies amongdi V erent populations,but mostof themchromosome 7could bean alternativeexplanation, since sampleswere drawnonly fromthe Danishpopu- are veryrare.

CFTRmutations canbe dividedinto ®veclasses.

1 lation andthus havea highlikelihood forcommon

ancestry.Class Iare nonsense,frameshift, andsplice mutationsthat leadto truncationsor absenceof CFTRprotein Insupport oftheir conclusion,increased bronchial

hyperreactivity haspreviously beendemonstrated inone synthesis. ClassII mutations,including DF508, are

mutations thatinterfere withcorrect post-translationalstudy 10 in heterozygotecarriers. Further, anincreasein

atopic diseasein thispopulation hasalso beendocu- processing. Thevast majorityof mutantprotein doesnot reachthe apicalmembrane, althoughthe proteinmented.

11

Dahlet alpostulate thatthe increasein bron-

chial hyperreactivitymight explainthe associationitself islikely toretain normalfunction. 2

Class IIImut-

ations suchas G551D(glycine toaspartic acidchange betweenDF508 carriersand asthma.In contrast,a high

pro®le studyby Schroederet alsuggested thatobligate at position551) giverise tochloride channelsthat showa reducedresponse tocAMP stimulation.Class IVheterozygote carriers(n =100)inCF familiesin the

USA areprotected fromasthma inchildhood andearly mutations alterthe ionselectivity orconductance ofCFTR chloridechannels. ClassV mutationsinterfere adultlife.

12

This wasrapidly followedby astudy by

Mennieet al

13

who assessedsamples froma Britishwith correcttranscription ortranslation, resultingin reduced levelsof functionalCFTR. populationscreening programme(n =186)anddid not

®nd anyassociation betweenCFTRmutations andA verystrong genotype/phenotypecorrelation has been shownfor pancreaticfunction inpatients withCF; asthma,in keepingwith previouswork whichalso did not demonstratesuch anassociation. 14

85% ofpatients su

V er frompancreatic insu Y ciency(PI) while 15%are pancreaticsu Ycient (PS).Patients withDahl et alevaluated thegenetic statusof theirpar-

ticipants onlyfor theabsence orpresence ofthe DF508PI generallycarry ªsevereºCF mutationswhereas PSis associatedwith ªmildºmutations. Asa generalrule, mutation.However ,other geneticvariation suchas

the welldocumented thymidinetract polymorphismin mutations classi®edas nonsense,frameshift, splice-site,or aminoacid deletionsare ªsevereºmutations andintron 8m ayalso beinvolved. Thispolymorphism exists

as a9-, 7-or 5-thymidinevariant. The5-thymidine therefore conferthe PIphenotype. However, thereis no goodcorrelation betweenthe genotypeand thevariant (5T)signi®cantly reducesthe amountof normal

CFTRtranscript

15 because intron8 isine Y

cientlyseverity ofthe pulmonarydisease, whichsuggests thatthe lungphenotype mightbe modulatedby additionalspliced. The5T varianton oneallele, whencoupled

with aCFTRmutation onthe secondallele, hasbeen genetic orenvironmental factors.

CF heterozygotecarriers aregenerally diseasefree. associatedwith congenitalbilateral absenceof thevas

deferens (CBAVD)ininfertile males.This conditionis The carrierfrequency ofCFTRmutations inthe Cau- casian populationis 4±5%. 3

Founder e

V ects andin- themost extensivelystudied exampleof ªatypicalºCF .

Thus, ininfertile malesin whomrenal abnormalitiesbreeding havebeen shownto accountfor thehigh incidence ofCF insome populations.

4 A heterozygotewere excludedas acause forCBA VD,CFTRmutations are foundin 70%of a V ected males. 16

The combinationadvantage hasalso beenpostulated toexplain thishigh incidence ofCFTRmutations. Increasedfertility

5 and ofthe 5Tallele onone copyof theCFTRgene witha cystic ®brosismutation onthe otherallele, ortwo increased resistanceto tuberculosis, 6 cholera, 7 and typh- oid fever 8 of heterozygotecarriers havebeen suggesteddi Verent mutationson bothCFTRalleles, isthe most common causeof CBAVD. 17

Despite thefact thatmen and somehave beendemonstrated inanimal models.The papersreviewed hereby Dahlet aland Shareretwith CBAVDusuallyhave noneof theother signsof CF suchas decreasedpulmonary function,

18 pancreaticalnow suggestthat CFheterozygotes areover -rep-

resented inpatients withasthma andchronic idiopathici ns uYciency,oralt ered sweatelectrolyt econcentrati on,

19 this diseaseis classi®edas atypicalCF .It wouldhave pancreatitis, respectively. been interestingto knowwhether the5T variantis over- represented inasthmatic subjectsin thepopulation

studied byDahl et al.Giventhe discrepant®ndings toCF mutationsand asthmadate, weare notyet persuadedby theproposed linkDahlet al

9

suggest alink betweenDF508 heterozygositybetweenCFTRmutations andasthma. and anincreased susceptibilityto asthma.By studyinglung functionand thegenotype ofa crosssectional sample fromthe generalDanish population(n =9141),

theauthorsshowthatheterozygotecarriersoftheDF508CF mutationsand chronic pancreatitisAnother diseaserecently associatedwith mutationsin CFTRmutation areover -representedintheDanish

population ofasthmatics. Further, DF508 hetero-the CFTRgene ischronic pancreatitis.A linkbetween

thesediseaseshasbeensuggestedbecausethepancreaticzygosity islinked todecreased pulmonaryfunction inpatients withasthma, butnot insubjects withchronic lesionsseen insubjects withCF closelyresemble those

in chronicpancreatitis. Thestudy bySharer et al 20 obstructive pulmonarydisease (COPD).Thus, both

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nloaded from The pathogenicconsequences ofa singlemutated CFTRgene S21 screened 134patients withchronic pancreatitisfor 22

Table1 Non-CF diseasesassociatedwithCFTR

CFTRmutations aswell asthe lengthof thethymidine

mutations tract inintron 8.T ogetherthese alterationsaccountfor Congenital bilateralabsence ofthe vasdeferens (CBAVD)

95% ofCFTRmutations innorth-west England.The

Azoospermia

frequency ofCFTRmutations amongpatients withAsthma

Pancreatitis

pancreatitis wasabout 2.5times higherand the5T

Bronchiectasis

variant inintron 8was twiceas highas thatof theAllergicbronchopulmonary aspergillosis general population.None ofthe patientshad amutation on bothcopies ofthe CFTRgene. However,fourof the

18 patientswith aCFTRmutation alsohad the5T

variant The patientswith theCF mutationswere signi®cantly

younger atpresentation andincluded ahigher pro-CFTRmutations hasbeen determinedin anumber ofportion ofnon-smokers. Therewas nosigni®cant other diseasesthat presentwith isolatedfeatures ofthe diVerence inthe proportionof alcoholicsand non-classical CFphenotype (table1). Theprevalence ofalcoholics withmutations althoughnon-alcoholics hadCFTRmutations andthe 5Tvariant inmen withan approximatelytwofold greaterincidence. Inaddition CBAVDis welldocumented andhas alreadybeen dis-to themutation analysis,a numberof investigationscussed above.CFTRmutations havealso beenim- frequently usedin thediagnosis ofCF wereassessed. plicated inmen withazoospermia withoutCBA VD,These includedsinopulmonary evaluation,meas- suggesting animportant rolefor CFTRin sperm-urements ofbasal potentialdi Verences inthe nasalatogenesis andsperm maturation

2324
but notin spermepithelium, sweatchloride tests,and semenanalysis. malformations. 25

Milleret alfound anincreased fre-Based onthese parametersa diagnosisof atypicalCF quency ofCFTRmutation inpatients withaller giccould notbe con®rmedin anyof thepatients presentingbronchopulmonary aspergillosis.However, thisstudywith chronicpancreatitis. was carriedout ona smallnumber ofpatients (n=Alcoholism, smoking,and anumber ofmetabolic 11).

26

Twostudies determinedthe incidenceof CFTRdisorders aremajor riskfactors inthe aetiologyof mutations inpatients withnasal polyposisbut neitherchronic pancreatitis;no causecan beidenti®ed inthe found anincreased frequencyof CFTRmutations inremaining 40%or soof aVected patients.

20

In-these populations.2728

Finally,patients withbron- terpretation ofthe datain thepresent studyis com-chiectasis orCOPD havealso beenscreened forCFTRplicated bythe heterogeneousaetiology ofthe patientsmutations. Severalstudies reportevidence foran in-chosen. Pancreatitiswas relatedto alcoholismin 53%volvement ofCFTRin atleast somecases ofwhilst 74%of patientswere smokers,making itmore bronchiectasis

2930
but notin COPD, 3132

in agreementdiYcult todetermine therelative contributionof CFTRwith the®ndings ofDahl et aldiscussed above.mutations. Clearly,thein¯uence ofsmoking willalso be importantwith regardto theuse oflung functiontests inthe diagnosisof CFlung disease.Thus, ob-structive lungfunction wasfound in22% and25%, respectively,of patientswith andwithout CFTRmut-

centrations, thegold standardfor diagnosisof CF, are hampered bythe knowledgethat alcoholismincreases sweat electrolytelevels.

Despite thesepotential confoundingfactors, the

results presentedhere arein agreementwith arecent study whichalso determinedthe prevalenceof CFTR mutations andthe 5Tpolymorphism inpatients with chronic idiopathicpancreatitis. 21

Nine of27 patients

had aCFTRmutation orthe 5Tvariant, orboth. In three patientsboth CFTRalleles werea Vected; the genotypes werethe twomost commonin patientswith

CBAVD.As isthe casewith CBAVD subjects,none of

these patientsful®lled traditionaldiagnostic criteriafor the classicCF phenotype.Unlike thestudy bySharer et al , thisstudy didnot ®ndevidence foran increased frequency ofthe 5Tvariant inpatients withchronic idiopathic pancreatitis.However ,inarecent cor- respondence Shareret alrecognised amistake incal- culating thecarrier frequencyof the5T variantand con®rmed thatthe 5Tvariant isnot associatedwith chronic pancreatitis. 22

In ourview ,giventheconcordant

®ndings ofboth thesestudies withrespect tothe in- creased frequencyof CFTRmutations, thereis com- pelling evidencefor arole forCFTRmutations inthe

CFTR function

Residual CFTR functionDisease

<1%Classical CF with PI

5%Classical CF with PS

10%CBAVD

50%None

100%NonePancreatitis

Asthma?

aetiology ofchronic pancreatitis.

Figure1 CFTRmutations reduce thelevel ofnormalCFTRfunction. Diseasemanifestation dependson theamount ofresidualCFTR functionand there appearsto beatissue

Other non-CFdiseases associatedwith CFTR

speci®c threshold.PS=pancreaticsuf®ciency;PI=pancreatic mutations insuf®ciency; CBAVD=congenitalabsenceof thevas deferens.

Apart fromasthma andpancreatitis, thefrequency of

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nloaded from

S22Griesenbach, Geddes,Alton

LEARNING POINTS

*The pathogenicconsequences ofmutated CFTRcan befound indiseases otherthan classical cystic ®brosis. Chronicpancr eatitisappearstobe onesuch disease;the linkwith asthmais lesscertain. The presenceofthe 5Tvariant inintr on8 shouldbe considered inadditiontoªclassicalº

CF mutations.

2 DenningGM, AndersonMP ,Amara JF,et al.Processing ofmutant

How doesa mutation inoneCFTRallele cause

cystic ®brosistransmembrane conductanceregulator istemperature-

3 JohnsonJP ,LouieE,Lewiston NJ,et al. Beta-adrenergicsweatresponses

The relationshipbetween thebasic defectin CF(altered in cystic®brosis heterozygoteswith andwithout thedelta F508allele. transport ofchloride (Cl ) andsodium (Na ) ions)and

Pediatr Res1991;29:525±8.

4 SuperM. Factorsin¯uencing thefrequency ofcystic ®brosisin South

the pathologyof thedisease isnot wellunderstood, but

WestAfrica. Monogr Paediatr1979;10:106±13.

for lungdisease severalhypotheses areavailable. One

5 KnudsonAGJ, Wagner L,HallettWY. Onthe selectiveadvantage of

cystic ®brosisheterozygotes. Am JHum Genet1998;19:388±92. simplistic suggestionrelates toimpaired mucociliary

6 MeindlRS. Hypothesis:a selectiveadvantage forcystic ®brosishetero-

clearance inthe airways,since eYcient clearanceof zygotes.Am JPhysical Anthropol 1987;74:39±45.

7 MorralN, BertranpetitJ, EstivillX, et al.The originof themajor cystic

mucus andinhaled micro-organisms islikelytodepend ®brosis mutation(delta DF508) inEuropean populations.Nature on anoptimal volumeof airwaysurface ¯uidin which

Genet1994;7:169±75.

the ciliainvolved inmucociliary clearancebeat. Thus,8 PierGB, GroutM, MeluleniG, et al.Salmonella typhiuses CFTRto

enter intestinalepithelial cells.Nature1998;393:79±82. reduced chloridesecretion onto,and increasedsodium

9 DahlM, Tybjaer g-HansenA,LangeP,et al. Delta-F508heterozygosity

absorption from,the airwaylumen maylead toa sub-

10 CounahanR, MearnsM. Prevalenceof atopyand exercise-induced

optimal volumeof airwaysurface liquidand hence bronchial labilityin relativesof patientswith cystic®brosis. ArchDis impaired mucociliaryclearance, increasedbacterial col-

Child1975;50:477±81.

11W arnerJO,NormanAP ,Soothill JF. Cystic®brosisheterozygosityin

onisation, andrepeated infection.However ,other de- the pathogenesisof allergy .Lancet1976;i:990±1. fects inhost defencemay alsoplay apartÐfor example,

12 SchroederSA, GaughanDM, SwiftM. Protectionagainst bronchial

increased bacterialadherence, 33
reduced ingestionof asthma byCFTR deltaDF508 mutation:a heterozygoteadvantage in cystic®brosis. NatureMed 1995;1:703±5. bacteria byepithelial cells, 34
and impairedantibacterial

13 MennieM, Gil®llanA, BrockDJ, et al. Heterozygotesfor thedelta

activity ofsurface defensins. 35

Altered cytokinesecretion

D F508 cystic®brosis alleleare notprotected againstbronchial asthma.

NatureMed 1995;1:978±9.

has recentlybeen detectedin CFlungs andmight in

14 DavisP ,ByardP. Heterozygotesfor cystic®brosis:modelsfor studyof

part explainthe chronicin¯ammation seenin young airway andautonomic reactivity. J ApplPhysiol 1989;66:2124±8.

15 Rave-HarelN, KeremE, Nissin-Ra®niaM, et al.The molecularbasis

patients withCF inthe absenceof bacterialinfection. 36
of partialpenetrance ofsplicing mutationsin cystic®brosis. Am J

The ®ndingthat CFTRis likelyto beinvolved in

Hum Genet1997;60:87±94.

16 LissensW ,LiebaersI.The geneticsof maleinfertility inrelation to

the functioningof intracellularprocesses, particularly cystic ®brosis.Bailliere'sClinObstet Gynaecol1997;11:797±817. endocytosis andexocytosis, maybe animportant link

17 ChillonM, CasalsT ,Mercier B,et al.Mutations inthe cystic®brosis

with diseasecausation. Thus,if CFTRacts atan earlygene inpatients withcongenital absenceof thevas deferens.N Engl

J Med1995;332:1475±80.

stage inthe processingof proteins,a widespectrum of

18 ColinAA, SawyerSM, MickieJE, et al.Pulmonary functionand clinical

abnormalities couldbe produced.It iseven lesswell observations inmen withcongenital bilateralabsence ofthe vas deferens.Chest1996;110:440±5. understood howthe absenceof functionalCFTRleads

19 PradalU, CastellaniC, DelmarcoA, et al. Nasalpotential diVerence

to manifestationof theCF phenotypein theother in congenitalbilateral absenceof thevas deferens.Am JRespir Crit

CareMed 1998;158:896±901.

a V ected organs,butdehydration andmucus ac-

20 SharerN, SchwarzM, MaloneG, et al.Mutations ofthe cystic®brosis

cumulation appearto becentral tothe disease.In gene inpatients withchronic pancreatitis.N EnglJ Med1998;339: addition, impairedCFTRmediated bicarbonate645±52.

21 CohnJA, FriedmanKJ, NoonePG, et al.Relation betweenmutations

(HCO 3- ) secretionhas beenimplicated incausing pan- of thecystic ®brosisgene andidiopathic pancreatitis.N EnglJ Med creatic insu Y ciency inCF .Itisgenerally assumedthat 1998;
339
:653±8.

22 SharerNM, SchwartzMJ. Correction:Mutations ofthe cystic®brosis

heterozygote carriersof CFTRmutations haveabout gene inpatients withchronic pancreatitis.N EnglJ Med1999;340:

50% ofnormal function,which issu Ycient toremain

1592±3.

23 vander Ven K,MesserL,van derV enH, et al.Cystic ®brosismutation

free ofdisease. However, afurtherreductionin CFTR screening inhealthy menwith reducedsperm quality. Hum Reprod function due,for example,to thepresence ofthe 5T 1996;

11:513±7.

24 SemczukM, KostuchM, KrzyzanowskiA, et al.The detectionof CFTR

variant inintron 8or certainas yetunidenti®ed CFTR gene mutationin patientswith azoospermia.Ginekologia Polska1998; modi®er genesprobably causesmanifestation ofisolated 69
:506±11.

CF diseasefeatures suchas CBAVD, chronicpan- 25 TuerlingsJH,Mol B,Kremer JA,et al.Mutation frequencyof cystic

®brosis transmembraneregulator isnot increasedin oligozoospermic creatitis, andperhaps asthma.The degreeof disease manifestation dependspartly onthe genotypeand, in 69
:899±903.

26 MillerPW ,HamoshA,Macek MJr ,et al.Cystic ®brosistransmembrane

addition, thereappears tobe atissue speci®cminimal conductance regulator(CFTR) genemutations inaller gicbron- requirement fornormal CFTRfunction (®g1). Mild chopulmonary aspergillosis.Am JHum Genet1996;59:45±51.

27 BrihayeP ,JorissenM,Clement PA. Chronicrhinosinusitis incystic

mutations andthe 5Tvariant thatresult inreduction ®brosis (mucoviscidosis).Acta Oto-Rhino-LaryngolBelg 1997;51:323± ofCFTRfunction toabout 10%lead toCBA VD;mut- 7.

ations thatreduce theamount ofnormal CFTRto about28 IrvingRM, McMahonR, ClarkR, et al. Cystic®brosis transmembrane

conductance regulatorgene mutationsin severenasal polyposis.Clin

5% causelung andsweat glandabnormalities, andthe

Otolaryngol AlliedSci 1997;22:519±21.

most severemutations (lessthan 1%of normalCFTR)

29 GirodonE, CazeneuveC, Lebargy F, et al.CFTR genemutations in

adults withdisseminated bronchiectasis.Eur JHum Genet1997;5: also leadto thepancreatic insuYciency characteristic

149±55.

of CF.

30 PignattiPF ,BombieriC,Mar gioC, et al.Increased incidenceof cystic

®brosis genemutations inadults withdisseminated bronchiectasis.

Hum MolGenet 1995;4:635±9.1 WilschanskiM,Zielenski J,Markiewicz D,et al.Correlation ofsweat 31 EntzianP ,MullerE,Boyson A,et al.Frequency ofcommon cysticchloride concentrationwith classesof thecystic ®brosistrans- ®brosis genemutations inchronic bronchitispatients. Scand JClin membrane conductanceregulator genemutations. J Pediatr1995;127:705±10.Lab Invest1995;55:263±6.

on October 12, 2023 by guest. Protected by copyright.http://thorax.bmj.com/Thorax: first published as 10.1136/thx.54.2008.S19 on 1 August 1999. Dow

nloaded from The pathogenicconsequences ofa singlemutated CFTRgene S23

32 ArtlichA, BoysonA, BungeS, et al.Common CFTRmutations arehypersusceptibility ofcystic ®brosispatients tolung infections.Science1996;271:64±7.not likelyto predisposeto chronicbronchitis innorthern Germany. Hum Genet1995;95:226±8.35 SmithJJ, Travis SM,GreenbergEP ,et al. Cystic®brosis airwayepithelia fail tokill bacteriabecause ofabnormal airwaysurface ¯uid.Cell33 SaimanL, CacalanoG, GruenertD, et al. Comparisonof adherenceofPseudomonas aeruginosato respiratoryepithelial cellsfrom cystic1996;85:229±36.36 Bon®eldTL, PanuskaJR, KostanMW ,et al.In¯ammatory cytokines®brosis patientsand healthysubjects. Infect Immun1992;60:2808±14.34 PierGB, OlsenJC, JohnsonLG, et al.Role ofmutant CFTRin in cystic®brosis lungs.Am JRespir CritCar eMed 1995;152:2111±8.

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