title: Diversity of the basic defect of homozygous CFTR mutation genotypes in humans.
abstract: BACKGROUND
  Knowledge of how CFTR mutations other than F508del translate into the basic defect in cystic fibrosis (CF) is scarce due to the low incidence of homozygous index cases.
  
  
  METHODS
  17 individuals who are homozygous for deletions, missense, stop or splice site mutations in the CFTR gene were investigated for clinical symptoms of CF and assessed in CFTR function by sweat test, nasal potential difference and intestinal current measurement.
  
  
  RESULTS
  CFTR activity in sweat gland, upper airways and distal intestine was normal for homozygous carriers of G314E or L997F and in the range of F508del homozygotes for homozygous carriers of E92K, W1098L, R553X, R1162X, CFTRdele2(ins186) or CFTRdele2,3(21 kb). Homozygotes for M1101K, 1898+3 A-G or 3849+10 kb C-T were not consistent CF or non-CF in the three bioassays. 14 individuals exhibited some chloride conductance in the airways and/or in the intestine which was identified by the differential response to cAMP and DIDS as being caused by CFTR or at least two other chloride conductances.
  
  
  CONCLUSIONS
  CFTR mutations may lead to unusual electrophysiological or clinical manifestations. In vivo and ex vivo functional assessment of CFTR function and in-depth clinical examination of the index cases are indicated to classify yet uncharacterised CFTR mutations as either disease-causing lesions, risk factors, modifiers or neutral variants.
authors.affiliation: Klinische Forschergruppe, OE 6710, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Stanke
authors.forename: M
authors.initials: M
authors.lastname: Ballmann
authors.forename: I
authors.initials: I
authors.lastname: Bronsveld
authors.forename: T
authors.initials: T
authors.lastname: Dörk
authors.forename: S
authors.initials: S
authors.lastname: Gallati
authors.forename: U
authors.initials: U
authors.lastname: Laabs
authors.forename: N
authors.initials: N
authors.lastname: Derichs
authors.forename: M
authors.initials: M
authors.lastname: Ritzka
authors.forename: H-G
authors.initials: HG
authors.lastname: Posselt
authors.forename: H K
authors.initials: HK
authors.lastname: Harms
authors.forename: M
authors.initials: M
authors.lastname: Griese
authors.forename: H
authors.initials: H
authors.lastname: Blau
authors.forename: G
authors.initials: G
authors.lastname: Mastella
authors.forename: J
authors.initials: J
authors.lastname: Bijman
authors.forename: H
authors.initials: H
authors.lastname: Veeze
authors.forename: B
authors.initials: B
authors.lastname: Tümmler
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002712:Chlorides / Q000032:analysis / Q000378:metabolism; D003550:Cystic Fibrosis / Q000235:genetics* / Q000503:physiopathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D009154:Mutation; D009297:Nasal Mucosa / Q000378:metabolism; D013542:Sweat / Q000737:chemistry; D013545:Sweat Glands / Q000378:metabolism
chemical_list: C505032:CFTR protein, human; D002712:Chlorides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator