Characterization of a novel 21-kb deletion, CFTRdele2,3(21 kb), in the CFTR gene: A cystic fibrosis mutation of Slavic origin common in Central and East Europe

Thilo Dörk, Milan Macek, Frauke Mekus, Burkhard Tümmler, John Tzountzouris, Teresa Casals, Alice Krebsová, Monika Koudová, Iva Sakmaryová, Věra Vávrová, Dana Zemková, Evgeny Ginter, Nica V. Petrova, Tatiana Ivaschenko, Vladislav Baranov, Michal Witt, Andrzej Pogorzelski, Jerzy Bal, Cesary Zékanowsky, Klaus WagnerManfred Stuhrmann, Ingrid Bauer, Hans H. Seydewitz, Thomas Neumann, Sibylle Jakubiczka, Cornelia Kraus, Barbara Thamm, Marina Nechiporenko, Ludmila Livshits, Natalia Mosse, Gennady Tsukerman, Ludovít Kadási, Metka Ravnik-Glavač, Damjan Glavač, Radovan Komel, Katja Vouk, Vaidutis Kučinskas, Astrida Krumina, Maris Teder, Svetlana Kocheva, Georgi D. Efremov, Tuncer Onay, Betul Kirdar, Geraldine Malone, Martin Schwarz, Zhaoqing Zhou, Kenneth J. Friedman, Soukeyna Carles, Mireille Claustres, Dominique Bozon, Claudine Verlingue, Claude Férec, Maria Tzetis, Emmanuel Kanavakis, Harry Cuppens, Christina Bombieri, Pier Franco Pignatti, Federica Sangiuolo, Albena Jordanova, Jelena Kusic, Dragica Radojkovič, Jadranka Sertić, Darko Richter, Ana Stavljenić Rukavina, Eva Bjorck, Birgitta Strandvik, Horacio Cardoso, Mark Montgomery, Barbara Nakielna, Daniel Hughes, Xavier P. Estivill, Isabel Aznarez, Elizabeth Tullis, Lap Chee Tsui, Julian Zielenski

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Abstract

We report a large genomic deletion of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, viz., a deletion that is frequently observed in Central and Eastern Europe. The mutation, termed CFTRdele2,3(21 kb), deletes 21,080 bp spanning introns 1-3 of the CFTR gene. Transcript analyses have revealed that this deletion results in the loss of exons 2 and 3 in epithelial CFTR mRNA, thereby producing a premature termination signal within exon 4. In order to develop a simple polymerase chain reaction assay for this allele, we defined the end-points of the deletion at the DNA sequence level. We next screened for this mutation in a representative set of European and European-derived populations. Some 197 CF patients, including seven homozygotes, bearing this mutation have been identified during the course of our study. Clinical evaluation of CFTRdele2,3(21 kb) homozygotes and a comparison of compound heterozygotes for ΔF508/CFTRdele2,3(21 kb) with pairwise-matched ΔF508 homozygotes indicate that this deletion represents a severe mutation associated with pancreatic insufficiency and early age at diagnosis. Current data show that the mutation is particularly common in Czech (6.4% of all CF chromosomes), Russian (5.2%), Belorussian (3.3%), Austrian (2.6%), German (1.5%), Polish (1.5%), Slovenian (1.5%), Ukrainian (1.2%), and Slovak patients (1.1%). It has also been found in Lithuania, Latvia, Macedonia and Greece and has sporadically been observed in Canada, USA, France, Spain, Turkey, and UK, but not in CF patients from Bulgaria, Croatia, Romania or Serbia. Haplotype analysis has identified the same extragenic CF-haplotype XV-2c/KM. 19 'A' and the same infrequent intragenic microsatellite haplotype 16-33-13 (IVS8CA-IVS17bTA-IVS17bCA) in all examined CFTRdele2,3(21 kb) chromosomes, suggesting a common origin for this deletion. We conclude that the 21-kb deletion is a frequent and severe CF mutation in populations of Eastern- and Western-Slavic descent.

Original languageEnglish
Pages (from-to)259-268
Number of pages10
JournalHuman Genetics
Volume106
Issue number3
DOIs
Publication statusPublished - 2000
Externally publishedYes

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ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Dörk, T., Macek, M., Mekus, F., Tümmler, B., Tzountzouris, J., Casals, T., Krebsová, A., Koudová, M., Sakmaryová, I., Vávrová, V., Zemková, D., Ginter, E., Petrova, N. V., Ivaschenko, T., Baranov, V., Witt, M., Pogorzelski, A., Bal, J., Zékanowsky, C., ... Zielenski, J. (2000). Characterization of a novel 21-kb deletion, CFTRdele2,3(21 kb), in the CFTR gene: A cystic fibrosis mutation of Slavic origin common in Central and East Europe. Human Genetics, 106(3), 259-268. https://doi.org/10.1007/s004390000246