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CFTR mutation combinations producing frequent complex alleles with different clinical and functional outcomes
Human mutation, 2012-11, Vol.33 (11), p.1557-1565
El-Seedy, Ayman
Girodon, Emmanuelle
Norez, Caroline
Pajaud, Julie
Pasquet, Marie-Claude
de Becdelièvre, Alix
Bienvenu, Thierry
des Georges, Marie
Cabet, Faïza
Lalau, Guy
Bieth, Eric
Blayau, Martine
Becq, Frédéric
Kitzis, Alain
Fanen, Pascale
Ladeveze, Véronique
2012
Volltextzugriff (PDF)
Details
Autor(en) / Beteiligte
El-Seedy, Ayman
Girodon, Emmanuelle
Norez, Caroline
Pajaud, Julie
Pasquet, Marie-Claude
de Becdelièvre, Alix
Bienvenu, Thierry
des Georges, Marie
Cabet, Faïza
Lalau, Guy
Bieth, Eric
Blayau, Martine
Becq, Frédéric
Kitzis, Alain
Fanen, Pascale
Ladeveze, Véronique
Titel
CFTR mutation combinations producing frequent complex alleles with different clinical and functional outcomes
Ist Teil von
Human mutation, 2012-11, Vol.33 (11), p.1557-1565
Ort / Verlag
Hoboken: Wiley Subscription Services, Inc., A Wiley Company
Erscheinungsjahr
2012
Quelle
MEDLINE
Beschreibungen/Notizen
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.
Sprache
Englisch
Identifikatoren
ISSN: 1059-7794
eISSN: 1098-1004
DOI: 10.1002/humu.22129
Titel-ID: cdi_hal_primary_oai_HAL_hal_02446189v1
Format
–
Schlagworte
Alleles
,
Amino Acid Substitution
,
CFTR
,
complex allele
,
cystic fibrosis
,
Cystic Fibrosis - genetics
,
Cystic Fibrosis - physiopathology
,
Cystic Fibrosis Transmembrane Conductance Regulator - chemistry
,
Cystic Fibrosis Transmembrane Conductance Regulator - genetics
,
Cystic Fibrosis Transmembrane Conductance Regulator - physiology
,
France
,
function
,
Gene Frequency
,
Genetic Association Studies
,
HeLa Cells
,
Heterozygote
,
Humans
,
Life Sciences
,
Mutant Proteins - chemistry
,
Mutant Proteins - genetics
,
Mutant Proteins - physiology
,
Mutation
,
Mutation, Missense
,
Protein Structure, Tertiary
,
Recombinant Proteins - genetics
,
Recombinant Proteins - metabolism
,
structure
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