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Diversity of the basic defect of homozygous CFTR mutation genotypes in humans

¹ Klinische Forschergruppe and Abteilungen für
² Pädiatrische Pneumologie und Neonatologie and
³ Gynäkologie und Geburtshilfe, Medizinische Hochschule Hannover, Hannover, Germany
⁴ Department of Pulmonology and Tuberculosis, Universitair Medisch Centrum Utrecht, Utrecht, The Netherlands
⁵ Abteilung für Humangenetik, Medizinische Universitätskinderklinik, Inselspital, Universität Bern, Bern, Switzerland
⁶ Universitäts-Kinderklinik, Johann-Wolfgang-Goethe Universität, Frankfurt/Main, Germany
⁷ Dr von Haunersches Kinderspital, Ludwig-Maximilians-Universität, Munich, Germany
⁸ Pulmonary and Cystic Fibrosis Unit, Schneider Children’s Medical Center of Israel, Petah-Tikva, and Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
⁹ Cystic Fibrosis Center, Ospedale Civile Maggiore, Piazzale Stefani, Verona, Italy
¹⁰ Erasmus University Rotterdam, Department of Neurosciences, Rotterdam, The Netherlands
¹¹ Stichting Diabeter, Rotterdam, The Netherlands

Correspondence to:
Dr Burkhard Tümmler, Klinische Forschergruppe, OE 6710, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany; tuemmler.burkhard{at}mh-hannover.de]

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.

Discussion: 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.