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 Wagner; Manfred 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 Estivill; Isabel Aznarez; Elizabeth Tullis; Lap Chee Tsui; Julian Zielenski

doi:10.1007/s004390000246

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 Estivill, Isabel Aznarez, Elizabeth Tullis, Lap Chee Tsui, Julian Zielenski

^*Corresponding author for this work

Pharmacology

Research output: Contribution to journal › Article › peer-review

123 Scopus citations

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 language	English (US)
Pages (from-to)	259-268
Number of pages	10
Journal	Human Genetics
Volume	106
Issue number	3
DOIs	https://doi.org/10.1007/s004390000246
State	Published - 2000

Funding

Acknowledgements We cordially thank all CF families who participated in this study. Particular thanks are due to Dr. Jürgen Gün-ther (Chemnitz), Dr. H. Rönitz (Frankfurt a.d. Oder), Dr. H. Rickers (Osnabrück), Dr. H. Schumacher (Kirchzarten), Dr. E. M. App (Freiburg), Dr. Hautz (Offenburg), Dr. Busch (Tübingen), Dr. K. Breuel (Rostock), Dr. K. Wilke (Münster), Dr. A. K. Webb (Manchester), Dr. M. Whiteford (Glasgow), Prof. G. Mastella (Verona), Dr. Algirdas Utkus (Vilnius), Drs. Petr Pohunek and Jana Bar-tosova (Prague), and Dr Liviu Pop (Timisoara) for providing clinical informations about their patients. We also thank Hildegard Frye and Andrea Korte (Hannover), Susann Körner (Magdeburg), Sayedha Waseem Yousouf (Münster), and Márina Machatková (Minsk) for their help in the mutation analysis. This study was supported by a grant from the Canadian Cystic Fibrosis Foundation (“Complete CFTR mutation characterization for CF patients: a multi-center Canada-wide study”) to J.Z. and L.-C.T., a grant from the State Committee for Scientific Research (4P05E06610) to J.B., a grant from ICGEB (no. CRP/YUG 96–05) to D.R., a grant from the Ministero della Sanita and Regione Lazio Fondo Sani-tario Nazionale per la Prevenzione e la Cura della Fibrosi Cistica (Legge 23 dicembre 1993, n 548) to F.S., a grant from the Italian CNR target project on Biotechnology to P.F.P, a grant from the Ministry of Science of Slovenia for project J1–8762–0381 and from the Slovenian Scientific Foundation for a fellowship to K.V., a grant FIS 99/0654 and ICS to T.C. and X.E., a grant from the Österreichische Nationalbank (no. 5139) to K.W., a grant from the State Committee for Scientific Research (KBN) 4P05B06010 to M.W., grants from Bogazici University Research Fund (95B0110 and 94B0142) to T.O. and B.K., a grant from the International Atomic Energy Agency (IAEA) to H.C., a grant from the Erica Lederhausen’s Foundation, Mdrta och Gunnar Bergendahls Foundation, to E.B. and B.S., a grant from the ICGEB-Trieste (CRP/MAC96–01) and a grant from Macedonian-American Joint Funds (no. 101) to G.D.E., grants from IGA MZCR (2899–5, 3526–3, 4124–3) and MSMT-OK192 a 11120003 to M.M.Jr., and the INCO Biomed grants BMH4-CT96–0462 (Biomed) and ERB IC20 CT96–0058 (INCO).

ASJC Scopus subject areas

Genetics(clinical)
Genetics

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10.1007/s004390000246

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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

@article{89b9591726944cd1a95acdf68ece20ad,

title = "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",

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.",

author = "Thilo D{\"o}rk and Milan Macek and Frauke Mekus and Burkhard T{\"u}mmler and John Tzountzouris and Teresa Casals and Alice Krebsov{\'a} and Monika Koudov{\'a} and Iva Sakmaryov{\'a} and V{\v e}ra V{\'a}vrov{\'a} and Dana Zemkov{\'a} and Evgeny Ginter and Petrova, {Nica V.} and Tatiana Ivaschenko and Vladislav Baranov and Michal Witt and Andrzej Pogorzelski and Jerzy Bal and Cesary Z{\'e}kanowsky and Klaus Wagner and Manfred Stuhrmann and Ingrid Bauer and Seydewitz, {Hans H.} and Thomas Neumann and Sibylle Jakubiczka and Cornelia Kraus and Barbara Thamm and Marina Nechiporenko and Ludmila Livshits and Natalia Mosse and Gennady Tsukerman and Ludov{\'i}t Kad{\'a}si and Metka Ravnik-Glava{\v c} and Damjan Glava{\v c} and Radovan Komel and Katja Vouk and Vaidutis Ku{\v c}inskas and Astrida Krumina and Maris Teder and Svetlana Kocheva and Efremov, {Georgi D.} and Tuncer Onay and Betul Kirdar and Geraldine Malone and Martin Schwarz and Zhaoqing Zhou and Friedman, {Kenneth J.} and Soukeyna Carles and Mireille Claustres and Dominique Bozon and Claudine Verlingue and Claude F{\'e}rec and Maria Tzetis and Emmanuel Kanavakis and Harry Cuppens and Christina Bombieri and Pignatti, {Pier Franco} and Federica Sangiuolo and Albena Jordanova and Jelena Kusic and Dragica Radojkovi{\v c} and Jadranka Serti{\'c} and Darko Richter and Rukavina, {Ana Stavljeni{\'c}} and Eva Bjorck and Birgitta Strandvik and Horacio Cardoso and Mark Montgomery and Barbara Nakielna and Daniel Hughes and Xavier Estivill and Isabel Aznarez and Elizabeth Tullis and Tsui, {Lap Chee} and Julian Zielenski",

note = "Funding Information: Acknowledgements We cordially thank all CF families who participated in this study. Particular thanks are due to Dr. J{\"u}rgen G{\"u}n-ther (Chemnitz), Dr. H. R{\"o}nitz (Frankfurt a.d. Oder), Dr. H. Rickers (Osnabr{\"u}ck), Dr. H. Schumacher (Kirchzarten), Dr. E. M. App (Freiburg), Dr. Hautz (Offenburg), Dr. Busch (T{\"u}bingen), Dr. K. Breuel (Rostock), Dr. K. Wilke (M{\"u}nster), Dr. A. K. Webb (Manchester), Dr. M. Whiteford (Glasgow), Prof. G. Mastella (Verona), Dr. Algirdas Utkus (Vilnius), Drs. Petr Pohunek and Jana Bar-tosova (Prague), and Dr Liviu Pop (Timisoara) for providing clinical informations about their patients. We also thank Hildegard Frye and Andrea Korte (Hannover), Susann K{\"o}rner (Magdeburg), Sayedha Waseem Yousouf (M{\"u}nster), and M{\'a}rina Machatkov{\'a} (Minsk) for their help in the mutation analysis. This study was supported by a grant from the Canadian Cystic Fibrosis Foundation (“Complete CFTR mutation characterization for CF patients: a multi-center Canada-wide study”) to J.Z. and L.-C.T., a grant from the State Committee for Scientific Research (4P05E06610) to J.B., a grant from ICGEB (no. CRP/YUG 96–05) to D.R., a grant from the Ministero della Sanita and Regione Lazio Fondo Sani-tario Nazionale per la Prevenzione e la Cura della Fibrosi Cistica (Legge 23 dicembre 1993, n 548) to F.S., a grant from the Italian CNR target project on Biotechnology to P.F.P, a grant from the Ministry of Science of Slovenia for project J1–8762–0381 and from the Slovenian Scientific Foundation for a fellowship to K.V., a grant FIS 99/0654 and ICS to T.C. and X.E., a grant from the {\"O}sterreichische Nationalbank (no. 5139) to K.W., a grant from the State Committee for Scientific Research (KBN) 4P05B06010 to M.W., grants from Bogazici University Research Fund (95B0110 and 94B0142) to T.O. and B.K., a grant from the International Atomic Energy Agency (IAEA) to H.C., a grant from the Erica Lederhausen{\textquoteright}s Foundation, Mdrta och Gunnar Bergendahls Foundation, to E.B. and B.S., a grant from the ICGEB-Trieste (CRP/MAC96–01) and a grant from Macedonian-American Joint Funds (no. 101) to G.D.E., grants from IGA MZCR (2899–5, 3526–3, 4124–3) and MSMT-OK192 a 11120003 to M.M.Jr., and the INCO Biomed grants BMH4-CT96–0462 (Biomed) and ERB IC20 CT96–0058 (INCO).",

year = "2000",

doi = "10.1007/s004390000246",

language = "English (US)",

volume = "106",

pages = "259--268",

journal = "Human Genetics",

issn = "0340-6717",

publisher = "Springer Verlag",

number = "3",

}

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, NV, Ivaschenko, T, Baranov, V, Witt, M, Pogorzelski, A, Bal, J, Zékanowsky, C, Wagner, K, Stuhrmann, M, Bauer, I, Seydewitz, HH, Neumann, T, Jakubiczka, S, Kraus, C, Thamm, B, Nechiporenko, M, Livshits, L, Mosse, N, Tsukerman, G, Kadási, L, Ravnik-Glavač, M, Glavač, D, Komel, R, Vouk, K, Kučinskas, V, Krumina, A, Teder, M, Kocheva, S, Efremov, GD, Onay, T, Kirdar, B, Malone, G, Schwarz, M, Zhou, Z, Friedman, KJ, Carles, S, Claustres, M, Bozon, D, Verlingue, C, Férec, C, Tzetis, M, Kanavakis, E, Cuppens, H, Bombieri, C, Pignatti, PF, Sangiuolo, F, Jordanova, A, Kusic, J, Radojkovič, D, Sertić, J, Richter, D, Rukavina, AS, Bjorck, E, Strandvik, B, Cardoso, H, Montgomery, M, Nakielna, B, Hughes, D, Estivill, X, Aznarez, I, Tullis, E, Tsui, LC & 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, vol. 106, no. 3, pp. 259-268. https://doi.org/10.1007/s004390000246

TY - JOUR

T1 - Characterization of a novel 21-kb deletion, CFTRdele2,3(21 kb), in the CFTR gene

T2 - A cystic fibrosis mutation of Slavic origin common in Central and East Europe

AU - Dörk, Thilo

AU - Macek, Milan

AU - Mekus, Frauke

AU - Tümmler, Burkhard

AU - Tzountzouris, John

AU - Casals, Teresa

AU - Krebsová, Alice

AU - Koudová, Monika

AU - Sakmaryová, Iva

AU - Vávrová, Věra

AU - Zemková, Dana

AU - Ginter, Evgeny

AU - Petrova, Nica V.

AU - Ivaschenko, Tatiana

AU - Baranov, Vladislav

AU - Witt, Michal

AU - Pogorzelski, Andrzej

AU - Bal, Jerzy

AU - Zékanowsky, Cesary

AU - Wagner, Klaus

AU - Stuhrmann, Manfred

AU - Bauer, Ingrid

AU - Seydewitz, Hans H.

AU - Neumann, Thomas

AU - Jakubiczka, Sibylle

AU - Kraus, Cornelia

AU - Thamm, Barbara

AU - Nechiporenko, Marina

AU - Livshits, Ludmila

AU - Mosse, Natalia

AU - Tsukerman, Gennady

AU - Kadási, Ludovít

AU - Ravnik-Glavač, Metka

AU - Glavač, Damjan

AU - Komel, Radovan

AU - Vouk, Katja

AU - Kučinskas, Vaidutis

AU - Krumina, Astrida

AU - Teder, Maris

AU - Kocheva, Svetlana

AU - Efremov, Georgi D.

AU - Onay, Tuncer

AU - Kirdar, Betul

AU - Malone, Geraldine

AU - Schwarz, Martin

AU - Zhou, Zhaoqing

AU - Friedman, Kenneth J.

AU - Carles, Soukeyna

AU - Claustres, Mireille

AU - Bozon, Dominique

AU - Verlingue, Claudine

AU - Férec, Claude

AU - Tzetis, Maria

AU - Kanavakis, Emmanuel

AU - Cuppens, Harry

AU - Bombieri, Christina

AU - Pignatti, Pier Franco

AU - Sangiuolo, Federica

AU - Jordanova, Albena

AU - Kusic, Jelena

AU - Radojkovič, Dragica

AU - Sertić, Jadranka

AU - Richter, Darko

AU - Rukavina, Ana Stavljenić

AU - Bjorck, Eva

AU - Strandvik, Birgitta

AU - Cardoso, Horacio

AU - Montgomery, Mark

AU - Nakielna, Barbara

AU - Hughes, Daniel

AU - Estivill, Xavier

AU - Aznarez, Isabel

AU - Tullis, Elizabeth

AU - Tsui, Lap Chee

AU - Zielenski, Julian

N1 - Funding Information: Acknowledgements We cordially thank all CF families who participated in this study. Particular thanks are due to Dr. Jürgen Gün-ther (Chemnitz), Dr. H. Rönitz (Frankfurt a.d. Oder), Dr. H. Rickers (Osnabrück), Dr. H. Schumacher (Kirchzarten), Dr. E. M. App (Freiburg), Dr. Hautz (Offenburg), Dr. Busch (Tübingen), Dr. K. Breuel (Rostock), Dr. K. Wilke (Münster), Dr. A. K. Webb (Manchester), Dr. M. Whiteford (Glasgow), Prof. G. Mastella (Verona), Dr. Algirdas Utkus (Vilnius), Drs. Petr Pohunek and Jana Bar-tosova (Prague), and Dr Liviu Pop (Timisoara) for providing clinical informations about their patients. We also thank Hildegard Frye and Andrea Korte (Hannover), Susann Körner (Magdeburg), Sayedha Waseem Yousouf (Münster), and Márina Machatková (Minsk) for their help in the mutation analysis. This study was supported by a grant from the Canadian Cystic Fibrosis Foundation (“Complete CFTR mutation characterization for CF patients: a multi-center Canada-wide study”) to J.Z. and L.-C.T., a grant from the State Committee for Scientific Research (4P05E06610) to J.B., a grant from ICGEB (no. CRP/YUG 96–05) to D.R., a grant from the Ministero della Sanita and Regione Lazio Fondo Sani-tario Nazionale per la Prevenzione e la Cura della Fibrosi Cistica (Legge 23 dicembre 1993, n 548) to F.S., a grant from the Italian CNR target project on Biotechnology to P.F.P, a grant from the Ministry of Science of Slovenia for project J1–8762–0381 and from the Slovenian Scientific Foundation for a fellowship to K.V., a grant FIS 99/0654 and ICS to T.C. and X.E., a grant from the Österreichische Nationalbank (no. 5139) to K.W., a grant from the State Committee for Scientific Research (KBN) 4P05B06010 to M.W., grants from Bogazici University Research Fund (95B0110 and 94B0142) to T.O. and B.K., a grant from the International Atomic Energy Agency (IAEA) to H.C., a grant from the Erica Lederhausen’s Foundation, Mdrta och Gunnar Bergendahls Foundation, to E.B. and B.S., a grant from the ICGEB-Trieste (CRP/MAC96–01) and a grant from Macedonian-American Joint Funds (no. 101) to G.D.E., grants from IGA MZCR (2899–5, 3526–3, 4124–3) and MSMT-OK192 a 11120003 to M.M.Jr., and the INCO Biomed grants BMH4-CT96–0462 (Biomed) and ERB IC20 CT96–0058 (INCO).

PY - 2000

Y1 - 2000

N2 - 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.

AB - 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.

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UR - http://www.scopus.com/inward/citedby.url?scp=0342657015&partnerID=8YFLogxK

U2 - 10.1007/s004390000246

DO - 10.1007/s004390000246

M3 - Article

C2 - 10798353

AN - SCOPUS:0342657015

SN - 0340-6717

VL - 106

SP - 259

EP - 268

JO - Human Genetics

JF - Human Genetics

IS - 3

ER -

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

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