Communicated by Garry R. Cutting
CFTR mutation combinations producing frequent complex alleles with different clinical and functional outcomes†
Article first published online: 2 JUL 2012
© 2012 Wiley Periodicals, Inc.
Volume 33, Issue 11, pages 1557–1565, November 2012
How to Cite
El-Seedy, A., Girodon, E., Norez, C., Pajaud, J., Pasquet, M.-C., de Becdelièvre, A., Bienvenu, T., des Georges, M., Cabet, F., Lalau, G., Bieth, E., Blayau, M., Becq, F., Kitzis, A., Fanen, P. and Ladeveze, V. (2012), CFTR mutation combinations producing frequent complex alleles with different clinical and functional outcomes. Hum. Mutat., 33: 1557–1565. doi: 10.1002/humu.22129
- Issue published online: 11 OCT 2012
- Article first published online: 2 JUL 2012
- Accepted manuscript online: 7 JUN 2012 04:35PM EST
- Manuscript Accepted: 21 MAY 2012
- Manuscript Received: 13 FEB 2012
- Association mucoviscidose: ABCF2; the French association Vaincre la Mucoviscidose (to C.N. and F.B.)
- cystic fibrosis;
- complex allele;
Genotype–phenotype correlations in cystic fibrosis (CF) may be difficult to establish because of phenotype variability, which is associated with certain CF transmembrane conductance regulator (CFTR) gene mutations and the existence of complex alleles. To elucidate the clinical significance of complex alleles involving p.Gly149Arg, p.Asp443Tyr, p.Gly576Ala, and p.Arg668Cys, we performed a collaborative genotype–phenotype correlation study, collected epidemiological data, and investigated structure–function relationships for single and natural complex mutants, p.[Gly576Ala;Arg668Cys], p.[Gly149Arg;Gly576Ala;Arg668Cys], and p.[Asp443Tyr;Gly576Ala;Arg668Cys]. Among 153 patients carrying at least one of these mutations, only three had classical CF and all carried p.Gly149Arg in the triple mutant. Sixty-four had isolated infertility and seven were healthy individuals with a severe mutation in trans, but none had p.Gly149Arg. Functional studies performed on all single and natural complex mutants showed that (1) p.Gly149Arg results in a severe misprocessing defect; (2) p.Asp443Tyr moderately alters CFTR maturation; and (3) p.Gly576Ala, a known splicing mutant, and p.Arg668Cys mildly alter CFTR chloride conductance. Overall, the results consistently show the contribution of p.Gly149Arg to the CF phenotype, and suggest that p.[Arg668Cys], p.[Gly576Ala;Arg668Cys], and p.[Asp443Tyr;Gly576Ala;Arg668Cys] are associated with CFTR-related disorders. The present study emphasizes the importance of comprehensive genotype–phenotype and functional studies in elucidating the impact of mutations on clinical phenotype. Hum Mutat 33:1557–1565, 2012. © 2012 Wiley Periodicals, Inc.