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J Biol Chem, Vol. 275, Issue 5, 3561-3567, February 4, 2000

A Naturally Occurring Sequence Variation That Creates a YY1 Element Is Associated with Increased Cystic Fibrosis Transmembrane Conductance Regulator Gene Expression^*

Marie-Catherine Romey^§¶, Nathalie Pallares-Ruiz^§¶, Alain Mange^¶, Clément Mettling^¶**, Régis Peytavi^§, Jacques Demaille^§¶, and Mireille Claustres^§¶§§

From the  Laboratoire de Génétique Moléculaire, Centre Spitalier Universitaire, and the  Laboratoire de Virologie Moléculaire, ^§ Institut de Biologie, 34060 Montpellier and the  Laboratoire de Biologie des Encéphalopathies Spongiformes Transmissibles and the ^** Laboratoire de Virologie Moléculaire et Transfert de Gènes, ^¶ CNRS Institut de Génétique Humaine Unité Propre de Recherche 1142, 34396 Montpellier Cedex 5, France

We have identified previously a novel complex mutant allele in the cystic fibrosis transmembrane conductance regulator (CFTR) gene in a patient affected with cystic fibrosis (CF). This allele contained a mutation in CFTR exon 11 known to cause CF (S549R(T>G)), associated with the first alteration described so far in the minimal CFTR promoter region (102T>A). Studies on genotype-phenotype correlations revealed striking differences between patients carrying mutation (S549R(T>G)) alone, who had a severe disease, and patients carrying the complex allele (102(T>A)+S549R(T>G)), who exhibited milder forms of CF. We thus postulated that the sequence change (102T>A) may attenuate the effects of the severe (S549R(T>G)) mutation through regulation of CFTR expression. Analysis of transiently transfected cell lines with wild-type and 102A variant human CFTR-directed luciferase reporter genes demonstrates that constructs containing the 102A variant (which creates a Yin Yang 1 (YY1) core element) increases CFTR expression significantly. Electrophoretic mobility shift assays indicate that the 102 site is located in a region of multiple DNA-protein interactions and that the 102A allele recruits specifically an additional nuclear protein related to YY1. The finding that the YY1-binding allele causes a significant increase in CFTR expression in vitro may allow a better understanding of the milder phenotype observed in patients who carry a severe CF mutation within the same gene.

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^* This work was supported in part by Association Française de Lutte contre la Mucoviscidose Grant R98043.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^§§ To whom correspondence should be addressed: Laboratoire de Génétique Moléculaire, Institut de Biologie, 34060 Montpellier Cedex, France. Tel.: 33-4-6760-9506; Fax: 33-4-6760-1181; E-mail: Mireille.Claustres@igh.cnrs.fr.

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Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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