Advertisement

Human Genetics

, Volume 106, Issue 3, pp 259–268 | Cite as

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

  • T. Dörk
  • M. Macek Jr
  • F. Mekus
  • B. Tümmler
  • J. Tzountzouris
  • T. Casals
  • A. Krebsová
  • M. Koudová
  • I. Sakmaryová
  • M. Macek Sr
  • V. Vávrová
  • D. Zemková
  • E. Ginter
  • N.V. Petrova
  • T. Ivaschenko
  • V. Baranov
  • M. Witt
  • A. Pogorzelski
  • J. Bal
  • C. Zékanowsky
  • K. Wagner
  • M. Stuhrmann
  • I. Bauer
  • H.H. Seydewitz
  • T. Neumann
  • S. Jakubiczka
  • C. Kraus
  • B. Thamm
  • M. Nechiporenko
  • L. Livshits
  • N. Mosse
  • G. Tsukerman
  • L. Kadási
  • M. Ravnik-Glavač
  • D. Glavač
  • R. Komel
  • K. Vouk
  • V. Kučinskas
  • A. Krumina
  • M. Teder
  • S. Kocheva
  • G.D. Efremov
  • T. Onay
  • B. Kirdar
  • G. Malone
  • M. Schwarz
  • Z. Zhou
  • K.J. Friedman
  • S. Carles
  • M. Claustres
  • D. Bozon
  • C. Verlingue
  • C. Férec
  • M. Tzetis
  • E. Kanavakis
  • H. Cuppens
  • C. Bombieri
  • P.F. Pignatti
  • F. Sangiuolo
  • A. Jordanova
  • J. Kusic
  • D. Radojkovič
  • J. Sertić
  • D. Richter
  • A. Stavljenić Rukavina
  • E. Bjorck
  • B. Strandvik
  • H. Cardoso
  • M. Montgomery
  • B. Nakielna
  • D. Hughes
  • X. Estivill
  • I. Aznarez
  • E. Tullis
  • L.-C. Tsui
  • J. Zielenski
Original Investigation

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.

Keywords

Cystic Fibrosis Transmembrane Conductance Regulator Cystic Fibrosis Transmembrane Conductance Regulator Gene Cystic Fibrosis Mutation Large Genomic Deletion Microsatellite Haplotype 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Copyright information

© Springer-Verlag 2000

Authors and Affiliations

  • T. Dörk
    • 1
  • M. Macek Jr
    • 3
  • F. Mekus
    • 2
  • B. Tümmler
    • 2
  • J. Tzountzouris
    • 4
  • T. Casals
    • 5
  • A. Krebsová
    • 3
  • M. Koudová
    • 3
  • I. Sakmaryová
    • 3
  • M. Macek Sr
    • 3
  • V. Vávrová
    • 3
  • D. Zemková
    • 3
  • E. Ginter
    • 6
  • N.V. Petrova
    • 6
  • T. Ivaschenko
    • 7
  • V. Baranov
    • 7
  • M. Witt
    • 8
  • A. Pogorzelski
    • 9
  • J. Bal
    • 10
  • C. Zékanowsky
    • 10
  • K. Wagner
    • 11
  • M. Stuhrmann
    • 1
  • I. Bauer
    • 12
  • H.H. Seydewitz
    • 13
  • T. Neumann
    • 14
  • S. Jakubiczka
    • 15
  • C. Kraus
    • 16
  • B. Thamm
    • 17
  • M. Nechiporenko
    • 18
  • L. Livshits
    • 18
  • N. Mosse
    • 19
  • G. Tsukerman
    • 19
  • L. Kadási
    • 20
  • M. Ravnik-Glavač
    • 21
  • D. Glavač
    • 21
  • R. Komel
    • 22
  • K. Vouk
    • 22
  • V. Kučinskas
    • 23
  • A. Krumina
    • 24
  • M. Teder
    • 25
  • S. Kocheva
    • 26
  • G.D. Efremov
    • 26
  • T. Onay
    • 27
  • B. Kirdar
    • 27
  • G. Malone
    • 28
  • M. Schwarz
    • 28
  • Z. Zhou
    • 29
  • K.J. Friedman
    • 29
  • S. Carles
    • 30
  • M. Claustres
    • 30
  • D. Bozon
    • 31
  • C. Verlingue
    • 32
  • C. Férec
    • 32
  • M. Tzetis
    • 33
  • E. Kanavakis
    • 33
  • H. Cuppens
    • 34
  • C. Bombieri
    • 35
  • P.F. Pignatti
    • 35
  • F. Sangiuolo
    • 36
  • A. Jordanova
    • 37
  • J. Kusic
    • 38
  • D. Radojkovič
    • 38
  • J. Sertić
    • 39
  • D. Richter
    • 39
  • A. Stavljenić Rukavina
    • 39
  • E. Bjorck
    • 40
  • B. Strandvik
    • 40
  • H. Cardoso
    • 41
  • M. Montgomery
    • 42
  • B. Nakielna
    • 43
  • D. Hughes
    • 44
  • X. Estivill
    • 5
  • I. Aznarez
    • 4
  • E. Tullis
    • 45
  • L.-C. Tsui
    • 4
  • J. Zielenski
    • 4
  1. 1.Institute of Human Genetics, Medical School Hannover, D-30625 Hannover, Germany
  2. 2.Department of Pediatric Pulmonology, Medical School Hannover, D-30625 Hannover, Germany
  3. 3.Institute of Biology and Medical Genetics, Charles-University Prague-Motol, Prague, Czech Republic
  4. 4.Department of Genetics and Genomic Biology, Hospital for Sick Children, Toronto, Canada
  5. 5.Genetics Department IRO, Hospital DYR, Barcelona, Spain
  6. 6.Research Center for Medical Genetics, Russian Academy of Sciences, Moscow, Russia
  7. 7.Institute of Obstetrics and Gynecology, St. Petersburg, Russia
  8. 8.Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland
  9. 9.Institute for Tuberculosis and Lung Diseases, Rabka, Poland
  10. 10.Department of Genetics, National Research Institute of Mother and Child, Warsaw, Poland
  11. 11.Department of Human Genetics, Graz, Austria
  12. 12.Department of Medical Genetics, Rostock, Germany
  13. 13.Children's Hospital, University Clinics, Freiburg, Germany
  14. 14.Institute of Human Genetics, Westf. Wilhelm's University, Münster, Germany
  15. 15.Institute of Human Genetics, Otto-von-Guericke University, Magdeburg, Germany
  16. 16.Institute of Human Genetics, University Nürnberg-Erlangen, Erlangen, Germany
  17. 17.Institute of Human Genetics, Leipzig, Germany
  18. 18.Institute of Molecular Biology and Genetics, Kiev, Ukraine
  19. 19.Institute for Hereditary Disorders, Oblovskaya 66, Minsk, Belarus
  20. 20.Institute of Molecular Physiology and Genetics, Comenius University, Bratislava, Slovakia
  21. 21.Laboratory of Molecular Genetics, Institute of Pathology, Medical Faculty, Ljubljana, Slovenia
  22. 22.Medical Center for Molecular Biology, Ljubljana, Slovenia
  23. 23.Human Genetics Center, University Hospital, Vilnius, Lithuania
  24. 24.Department of Medical Biology and Genetics, Medical Academy, Riga, Latvia
  25. 25.Center for Medical Genetics, University of Tartu, Tartu, Estonia
  26. 26.Macedonian Academy of Sciences and Arts, Skopje, Macedonia
  27. 27.Department of Chemical Engineering and Medical Biology and Genetics, Bogazici University, Bebek-Instanbul, Turkey
  28. 28.Royal Manchester Children's Hospital, Manchester, UK
  29. 29.Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, USA
  30. 30.Centre Hospitalier Universitaire, Montpellier, France
  31. 31.Hopital Debrousse, Lyon, France
  32. 32.Centre de Transfusion Consanguine, Brest, France
  33. 33.First Department of Pediatrics, Athens University, Athens, Greece
  34. 34.Center for Human Genetics, Leuven, Belgium
  35. 35.Section of Biology and Genetics, DMIBG, University of Verona, Verona, Italy
  36. 36.Cattedra di Genetica Umana, Tor Vergata University and CSS Mendel, Roma, Italy
  37. 37.Laboratory of Molecular Pathology, University Hospital of Obstetrics and Gynecology, Sofia, Bulgaria
  38. 38.Institute of Molecular Genetics and Genetic Engineering, Belgrade, Yugoslavia
  39. 39.Clinical Institute of Laboratory Diagnosis, University School of Medicine, Zagreb, Croatia
  40. 40.Department of Clinical Genetics and Pediatrics, Sahlgrenska University Hospital/East Gothenborg University, Gothenborg, Sweden
  41. 41.IIBCE, Montevideo, Uruguay
  42. 42.Alberta Children Hospital, Calgary, Alberta, Canada
  43. 43.CF Adult Clinic, St. Paul's Hospital, Vancouver, Canada
  44. 44.IWK Grace Health Centre, Halifax, Nova Scotia, Canada
  45. 45.CF Adult Clinic, St. Michael's Hospital, Wellesley Site, Toronto, Canada

Personalised recommendations