Περίληψη:
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 Delta
F508/CFTRdele2,3(21 kb) with pairwise-matched Delta F508 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-IVSI7bCA) 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.
Συγγραφείς:
Dork, T
Macek, M
Mekus, F
Tummler, B
Tzountzouris, J and
Casals, T
Krebsova, A
Koudova, M
Sakmaryova, I
Macek, M
and Vavrova, V
Zemkova, D
Ginter, E
Petrova, NV and
Ivaschenko, T
Baranov, V
Witt, M
Pogorzelski, A
Bal, J
and Zekanowsky, C
Wagner, K
Stuhrmann, M
Bauer, I and
Seydewitz, HH
Neumann, T
Jakubiczka, S
Kraus, C
Thamm, B
and Nechiporenko, M
Livshits, L
Mosse, N
Tsukerman, G and
Kadasi, L
Ravnik-Glavac, M
Glavac, D
Komel, R
Vouk, K
and Kucinskas, V
Krumina, A
Teder, M
Kocheva, S
Efremov,
GD
Onay, T
Kirdar, B
Malone, G
Schwarz, M
Zhou, ZQ
and Friedman, KJ
Carles, S
Claustres, M
Bozon, D and
Verlingue, C
Ferec, C
Tzetis, M
Kanavakis, E
Cuppens, H
and Bombieri, C
Pignatti, PF
Sangiuolo, F
Jordanova, A and
Kusic, J
Radojkovic, D
Sertic, J
Richter, D
Rukavina, AS
and Bjorck, E
Strandvik, B
Cardoso, H
Montgomery, M and
Nakielna, B
Hughes, D
Estivill, X
Aznarez, I
Tullis, E
and Tsui, LC
Zielenski, J
