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

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.