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13. Variation in a repeat sequence determines whether a common variant of the cystic fibrosis transmembrane conductance regulator gene is pathogenic or benign

Author

Groman, JD Hefferon, TW Casals, T Bassas, LS Estivill, X and Des Georges, M Guittard, C Koudova, M Fallin, MD and Nemeth, K Fekete, G Kadasi, L Friedman, K Schwarz, M and Bombieri, C Pignatti, PF Kanavakis, E Tzetis, M and Schwartz, M Novelli, G D'Apice, MR Sobczynska-Tomaszewska, A and Bal, J Stuhrmann, M Macek, M Claustres, M Cutting, GR

Abstract

An abbreviated tract of five thymidines (5T) in intron 8 of the cystic fibrosis transmembrane conductance regulator ( CFTR) gene is found in similar to 10% of individuals in the general population. When found in trans with a severe CFTR mutation, 5T can result in male infertility, nonclassic cystic fibrosis, or a normal phenotype. To test whether the number of TG repeats adjacent to 5T influences disease penetrance, we determined TG repeat number in 98 patients with male infertility due to congenital absence of the vas deferens, 9 patients with nonclassic CF, and 27 unaffected individuals ( fertile men). Each of the individuals in this study had a severe CFTR mutation on one CFTR gene and 5T on the other. Of the unaffected individuals, 78% ( 21 of 27) had 5T adjacent to 11 TG repeats, compared with 9% ( 10 of 107) of affected individuals. Conversely, 91% ( 97 of 107) of affected individuals had 12 or 13 TG repeats, versus only 22% ( 6 of 27) of unaffected individuals (P < .00001). Those individuals with 5T adjacent to either 12 or 13 TG repeats were substantially more likely to exhibit an abnormal phenotype than those with 5T adjacent to 11 TG repeats ( odds ratio 34.0, 95% CI 11.1 - 103.7, P < .00001). Thus, determination of TG repeat number will allow for more accurate prediction of benign versus pathogenic 5T alleles.

Published
2004

14. 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

Author

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

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 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.

Published
2000

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

Author

Doerk, T., Macek, M., Mekus, F., Tuemmler, B., Tzountzouris, J., Casals, T., Krebsova, A., Koudova, M., Sakmaryova, I., Vavrova, V., Zemkova, D., Ginter, E., Petrova, N.V., Ivaschenko, T., Baranov, V., Witt, M., Pogorzelski, A., Bal, J., Zekanowsky, C., Wagner, K., Stuhrmann, M., Bauer, I., Seydewitz, H.H., Neumann, T., Jakubiczka, S., and Sertić, Jadranka

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 deltaF508/CFTRdele2, 3(21 kb) with pairwise-matched deltaF508 homozygotes indicate that this deleton 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.

Published
2000

16. Keratin 8 sequence variants in patients with pancreatitis and pancreatic cancer.

Author

Treiber, M., Schulz, H.U., Landt, O., Drenth, J.P.H., Castellani, C., Real, F.X., Akar, N., Ammann, R.W., Bargetzi, M., Bhatia, E., Demaine, A.G., Battagia, C., Kingsnorth, A., O'reilly, D., Truninger, K., Koudova, M., Spicak, J., Cerny, M., Menzel, H.J., Moral, P., Pignatti, P.F., Romanelli, M.G., Rickards, O, Stefano, G.F. De, Zarnescu, N.O., Choudhuri, G., Sikora, S.S., Jansen, J.B.M.J., Weiss, F.U., Pietschmann, M., Teich, N., Gress, T.M., Ockenga, J., Schmidt, H., Kage, A., Halangk, J., Rosendahl, J., Groneberg, D.A., Nickel, R., Witt, H., Treiber, M., Schulz, H.U., Landt, O., Drenth, J.P.H., Castellani, C., Real, F.X., Akar, N., Ammann, R.W., Bargetzi, M., Bhatia, E., Demaine, A.G., Battagia, C., Kingsnorth, A., O'reilly, D., Truninger, K., Koudova, M., Spicak, J., Cerny, M., Menzel, H.J., Moral, P., Pignatti, P.F., Romanelli, M.G., Rickards, O, Stefano, G.F. De, Zarnescu, N.O., Choudhuri, G., Sikora, S.S., Jansen, J.B.M.J., Weiss, F.U., Pietschmann, M., Teich, N., Gress, T.M., Ockenga, J., Schmidt, H., Kage, A., Halangk, J., Rosendahl, J., Groneberg, D.A., Nickel, R., and Witt, H.

Abstract

Contains fulltext : 50765.pdf (publisher's version ) (Closed access), Keratin 8 (KRT8) is one of the major intermediate filament proteins expressed in single-layered epithelia of the gastrointestinal tract. Transgenic mice over-expressing human KRT8 display pancreatic mononuclear infiltration, interstitial fibrosis and dysplasia of acinar cells resulting in exocrine pancreatic insufficiency. These experimental data are in accordance with a recent report describing an association between KRT8 variations and chronic pancreatitis. This prompted us to investigate KRT8 polymorphisms in patients with pancreatic disorders. The KRT8 Y54H and G62C polymorphisms were assessed in a cohort of patients with acute and chronic pancreatitis of various aetiologies or pancreatic cancer originating from Austria (n=16), the Czech Republic (n=90), Germany (n=1698), Great Britain (n=36), India (n=60), Italy (n=143), the Netherlands (n=128), Romania (n=3), Spain (n=133), and Switzerland (n=129). We also studied 4,234 control subjects from these countries and 1,492 control subjects originating from Benin, Cameroon, Ethiopia, Ecuador, and Turkey. Polymorphisms were analysed by melting curve analysis with fluorescence resonance energy transfer probes. The frequency of G62C did not differ between patients with acute or chronic pancreatitis, pancreatic adenocarcinoma and control individuals. The frequency of G62C varied in European populations from 0.4 to 3.8%, showing a northwest to southeast decline. The Y54H alteration was not detected in any of the 2,436 patients. Only 3/4,580 (0.07%) European, Turkish and Indian control subjects were heterozygous for Y54H in contrast to 34/951 (3.6%) control subjects of African descent. Our data suggest that the KRT8 alterations, Y54H and G62C, do not predispose patients to the development of pancreatitis or pancreatic cancer.

Published
2006

17. A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis.

Author

Witt, H., Sahin-Toth, M., Landt, O., Chen, J.M., Kahne, T., Drenth, J.P.H., Kukor, Z., Szepessy, E., Halangk, W., Dahm, S., Rohde, K., Schulz, H.U., Marechal, C. Le, Akar, N., Ammann, R.W., Truninger, K., Bargetzi, M., Bhatia, E., Castellani, C., Cavestro, G.M., Cerny, M., Destro-Bisol, G., Spedini, G., Eiberg, H., Jansen, J.B.M.J., Koudova, M., Rausova, E., Macek Jr, M., Malats, N., Real, F.X., Menzel, H.J., Moral, P., Galavotti, R., Pignatti, P.F., Rickards, O, Spicak, J., Zarnescu, N.O., Bock, W., Gress, T.M., Friess, H., Ockenga, J., Schmidt, H., Pfutzer, R., Lohr, M., Simon, P., Weiss, F.U., Lerch, M.M., Teich, N., Keim, V., Berg, T. van den, Wiedenmann, B., Luck, W., Groneberg, D.A., Becker, M., Keil, T., Kage, A., Bernardova, J., Braun, M., Guldner, C., Halangk, J., Rosendahl, J., Witt, U., Treiber, M., Nickel, R., Ferec, C., Witt, H., Sahin-Toth, M., Landt, O., Chen, J.M., Kahne, T., Drenth, J.P.H., Kukor, Z., Szepessy, E., Halangk, W., Dahm, S., Rohde, K., Schulz, H.U., Marechal, C. Le, Akar, N., Ammann, R.W., Truninger, K., Bargetzi, M., Bhatia, E., Castellani, C., Cavestro, G.M., Cerny, M., Destro-Bisol, G., Spedini, G., Eiberg, H., Jansen, J.B.M.J., Koudova, M., Rausova, E., Macek Jr, M., Malats, N., Real, F.X., Menzel, H.J., Moral, P., Galavotti, R., Pignatti, P.F., Rickards, O, Spicak, J., Zarnescu, N.O., Bock, W., Gress, T.M., Friess, H., Ockenga, J., Schmidt, H., Pfutzer, R., Lohr, M., Simon, P., Weiss, F.U., Lerch, M.M., Teich, N., Keim, V., Berg, T. van den, Wiedenmann, B., Luck, W., Groneberg, D.A., Becker, M., Keil, T., Kage, A., Bernardova, J., Braun, M., Guldner, C., Halangk, J., Rosendahl, J., Witt, U., Treiber, M., Nickel, R., and Ferec, C.

Abstract

Contains fulltext : 51133.pdf (publisher's version ) (Closed access), Chronic pancreatitis is a common inflammatory disease of the pancreas. Mutations in the genes encoding cationic trypsinogen (PRSS1) and the pancreatic secretory trypsin inhibitor (SPINK1) are associated with chronic pancreatitis. Because increased proteolytic activity owing to mutated PRSS1 enhances the risk for chronic pancreatitis, mutations in the gene encoding anionic trypsinogen (PRSS2) may also predispose to disease. Here we analyzed PRSS2 in individuals with chronic pancreatitis and controls and found, to our surprise, that a variant of codon 191 (G191R) is overrepresented in control subjects: G191R was present in 220/6,459 (3.4%) controls but in only 32/2,466 (1.3%) affected individuals (odds ratio 0.37; P = 1.1 x 10(-8)). Upon activation by enterokinase or trypsin, purified recombinant G191R protein showed a complete loss of trypsin activity owing to the introduction of a new tryptic cleavage site that renders the enzyme hypersensitive to autocatalytic proteolysis. In conclusion, the G191R variant of PRSS2 mitigates intrapancreatic trypsin activity and thereby protects against chronic pancreatitis.

Published
2006

19. Polymorphisms of UDP-glucuronosyltransferase 1A7 are not involved in pancreatic diseases.

Author

Verlaan, M., Drenth, J.P.H., Truninger, K., Koudova, M., Schulz, H.U., Bargetzi, M., Kunzli, B., Friess, H., Cerny, M., Kage, A., Landt, O., Morsche, R.H.M. te, Rosendahl, J., Luck, W., Nickel, R., Halangk, J., Macek Jr, M., Jansen, J.B.M.J., Witt, H., Verlaan, M., Drenth, J.P.H., Truninger, K., Koudova, M., Schulz, H.U., Bargetzi, M., Kunzli, B., Friess, H., Cerny, M., Kage, A., Landt, O., Morsche, R.H.M. te, Rosendahl, J., Luck, W., Nickel, R., Halangk, J., Macek Jr, M., Jansen, J.B.M.J., and Witt, H.

Abstract

Contains fulltext : 49189.pdf (publisher's version ) (Closed access), BACKGROUND: Xenobiotic mediated cellular injury is thought to play a major role in the pathogenesis of pancreatic diseases. Genetic variations that reduce the expression or activity of detoxifying phase II biotransformation enzymes such as the UDP-glucuronosyltransferases might be important in this respect. Recently, a UGT1A7 low detoxification activity allele, UGT1A7*3, has been linked to pancreatic cancer and alcoholic chronic pancreatitis. OBJECTIVE: To investigate whether UGT1A7 polymorphisms contribute to the risk of pancreatitis and pancreatic cancer. METHODS: Genetic polymorphisms in the UGT1A7 gene were assessed in a large cohort of patients with different types of pancreatitis and pancreatic cancer originating from the Czech Republic (n = 93), Germany (n = 638), Netherlands (n = 136), and Switzerland (n = 106), and in healthy (n = 1409) and alcoholic (n = 123) controls from the same populations. Polymorphisms were determined by melting curve analysis using fluorescence resonance energy transfer probes. In addition, 229 Dutch subjects were analysed by restriction fragment length polymorphism. RESULTS: The frequencies of UGT1A7 genotypes did not differ between patients with acute or chronic pancreatitis or pancreatic adenocarcinoma and alcoholic and healthy controls. CONCLUSIONS: The data suggest that, in contrast to earlier studies, UGT1A7 polymorphisms do not predispose patients to the development of pancreatic cancer and pancreatitis.

Published
2005

20. 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

Author

Dork, T, Macek, M, Mekus, F, Tummler, B, Tzountzouris, J, Casals, T, Krebsova, A, Koudova, M, Sakmaryova, I, Vavrova, V, Zemkova, D, Ginter, E, Petrova, NV, Ivaschenko, T, Baranov, V, Witt, M, Pogorzelski, A, Bal, J, Zekanowsky, 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, Kadasi, L, Ravnik-Glavac, M, Glavac, D, Komel, R, Vouk, K, Kucinskas, V, Krumina, A, Teder, M, Kocheva, S, Efremov, GD, Onay, T, Kirdar, B, Malone, G, Schwarz, M, Zhou, ZQ, Friedman, KJ, Carles, S, Claustres, M, Bozon, D, Verlingue, C, Ferec, C, Tzetis, M, Kanavakis, E, Cuppens, H, Bombieri, C, Pignatti, PF, Sangiuolo, F, Jordanova, A, Kušić-Tišma, Jelena, Radojković, Dragica, 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, Dork, T, Macek, M, Mekus, F, Tummler, B, Tzountzouris, J, Casals, T, Krebsova, A, Koudova, M, Sakmaryova, I, Vavrova, V, Zemkova, D, Ginter, E, Petrova, NV, Ivaschenko, T, Baranov, V, Witt, M, Pogorzelski, A, Bal, J, Zekanowsky, 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, Kadasi, L, Ravnik-Glavac, M, Glavac, D, Komel, R, Vouk, K, Kucinskas, V, Krumina, A, Teder, M, Kocheva, S, Efremov, GD, Onay, T, Kirdar, B, Malone, G, Schwarz, M, Zhou, ZQ, Friedman, KJ, Carles, S, Claustres, M, Bozon, D, Verlingue, C, Ferec, C, Tzetis, M, Kanavakis, E, Cuppens, H, Bombieri, C, Pignatti, PF, Sangiuolo, F, Jordanova, A, Kušić-Tišma, Jelena, Radojković, Dragica, 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, and Zielenski, J

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 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

Published
2000

22. A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis

Author

Heiko, Witt, Miklos Sahin Toth, Olfert, Landt, Jian Min Chen, Thilo, Kahne, Drenth, Joost P. H., Zoltan, Kukor, Edit, Szepessy, Walter, Halangk, Stefan, Dahm, Klaus, Rohde, Hans Ulrich Schulz, Cedric Le Marechal, Nejat, Akar, Ammann, Rudolf W., Kaspar, Truninger, Mario, Bargetzi, Eesh, Bhatia, Carlo, Castellani, Giulia Martina Cavestro, Milos, Cerny, DESTRO-BISOL, Giovanni, Spedini, Gabriella, Hans, Eiberg, Jansen, Jan B. M. J., Monika, Koudova, Eva, Rausova, Milan, Macek, Macek Jr, M., Nuria, Malats, Real, Francisco X., Hans Jurgen Menzel, Pedro, Moral, Roberta, Galavotti, Pier Franco Pignatti, Olga, Rickards, Julius, Spicak, Narcis Octavian Zarnescu, Wolfgang, Bock, Gress, Thomas M., Helmut, Friess, Johann, Ockenga, Hartmut, Schmidt, Roland, Pfutzer, Matthias, Lohr, Peter, Simon, Frank Ulrich Weiss, Lerch, Markus M., Niels, Teich, Volker, Keim, Thomas, Berg, Bertram, Wiedenmann, Werner, Luck, David Alexander Groneberg, Michael, Becker, Thomas, Keil, Andreas, Kage, Jana, Bernardova, Markus, Braun, Claudia, Guldner, Juliane, Halangk, Jonas, Rosendahl, Ulrike, Witt, Matthias, Treiber, Renate, Nickel, Claude, Ferec, Witt, H, SAHIN TOTH, M, Landt, O, Chen, Jm, Kahne, T, Drenth, Jp, Kukor, Z, Szepessy, E, Halangk, W, Dahm, S, Rohde, K, Schulz, Hu, LE MARECHAL, C, Akar, N, Ammann, Rw, Truninger, K, Bargetzi, M, Bhatia, E, Castellani, C, Cavestro, GIULIA MARTINA, Cerny, M, DESTRO BISOL, G, Spedini, G, Eiberg, H, Jansen, Jb, Koudova, M, Rausova, E, MACEK M., Jr, Malats, N, Real, Fx, Menzel, Hj, Moral, P, Galavotti, R, Pignatti, Pf, Rickards, O, Spicak, J, Zarnescu, No, Bock, W, Gress, Tm, Friess, H, Ockenga, J, Schmidt, H, Pfutzer, R, Lohr, M, Simon, P, Weiss, Fu, Lerch, Mm, Teich, N, Keim, V, Berg, T, Wiedenmann, B, Luck, W, Groneberg, Da, Becker, M, Keil, T, Kage, A, Bernardova, J, Braun, M, Guldner, C, Halangk, J, Rosendahl, J, Witt, U, Treiber, M, Nickel, R, and Ferec, C.

Subjects
trypsin inhibitor, Models, Molecular, Enteropeptidase, Pancreatic disease, Membrane transport and intracellular motility [NCMLS 5], arginine, genetic risk, chemistry.chemical_compound, Models, proteinosis, Trypsin, Pancreatic Secretory Trypsin Inhibitor, PRSS1 gene, enteropeptidase, medicine.diagnostic_test, adult, Hydrolysis, cationic trypsinogen, protection, unclassified drug, enzyme activity, female, priority journal, risk factor, CHRONIC PANCREATITIS, protein degradation, Trypsinogen, medicine.drug, medicine.medical_specialty, anionic trypsinogen, Proteolysis, Biology, Article, male, Internal medicine, Genetics, medicine, Matrix-Assisted Laser Desorption-Ionization, Humans, PRSS2, controlled study, human, Molecular gastro-enterology and hepatology [IGMD 2], gene, DNA Primers, Genetic polymorphism, catalysis, Base Sequence, Spectrometry, disease predisposition, Molecular, cationic trypsinogen prss1, glycine, pancreatic secretory trypsin inhibitor spink1, trypsin, trypsinogen, article, chronic pancreatitis, codon, genetic susceptibility, major clinical study, nucleotide sequence, Chronic Disease, Haplotypes, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Mass, medicine.disease, Tripsinogen, Tripsina, Settore BIO/18 - Genetica, Endocrinology, Genetic defects of metabolism [UMCN 5.1], Pancreatitis, chemistry, Genètica
Abstract

Chronic pancreatitis is a common inflammatory disease of the pancreas. Mutations in the genes encoding cationic trypsinogen (PRSS1) and the pancreatic secretory trypsin inhibitor (SPINK1) are associated with chronic pancreatitis. Because increased proteolytic activity owing to mutated PRSS1 enhances the risk for chronic pancreatitis, mutations in the gene encoding anionic trypsinogen (PRSS2) may also predispose to disease. Here we analyzed PRSS2 in individuals with chronic pancreatitis and controls and found, to our surprise, that a variant of codon 191 (G191R) is overrepresented in control subjects: G191R was present in 220/6,459 (3.4%) controls but in only 32/2,466 (1.3%) affected individuals (odds ratio 0.37; P = 1.1 x 10(-8)). Upon activation by enterokinase or trypsin, purified recombinant G191R protein showed a complete loss of trypsin activity owing to the introduction of a new tryptic cleavage site that renders the enzyme hypersensitive to autocatalytic proteolysis. In conclusion, the G191R variant of PRSS2 mitigates intrapancreatic trypsin activity and thereby protects against chronic pancreatitis. The initial experiments were supported by the DFG (Wi 2036/1-1). This work was supported by the Sonnenfeld-Stiftung, Berlin, Germany (to H.W.), the US National Institutes of Health (NIH) (grant DK058088 to M.S.-T.), INSERM (Institut National de la Santé et de la Recherche Médicale) and the Programme Hospitalier de Recherche Clinique (grant PHRC R 08-04 to C.F.)

Published
2006
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23. A comprehensive study evaluating germline FANCG variants in predisposition to breast and ovarian cancer.

Author

Soukupova J, Stastna B, Kanwal M, Hojny J, Zemankova P, Borecka M, Cerna L, Cerna M, Cerna M, Curtisova V, Dolezalova T, Duskova P, Foretova L, Havranek O, Horackova K, Hovhannisyan M, Hruskova L, Chvojka S, Janatova M, Janikova M, Jelinkova S, Just P, Kalousova M, Kleiblova P, Kosarova M, Koudova M, Kral J, Krausova M, Krutilkova V, Machackova E, Matejkova K, Michalovska R, Nehasil P, Nemcova B, Novotny J, Palek M, Pesek P, Safarikova M, Scheinost O, Springer D, Stolarova L, Stranecky V, Subrt I, Tavandzis S, Tureckova E, Vesela K, Vlckova Z, Vocka M, Zima T, Macurek L, and Kleibl Z

Subjects
Humans, Female, Middle Aged, Adult, DNA Repair genetics, Case-Control Studies, Aged, Germ-Line Mutation, Genetic Predisposition to Disease, Breast Neoplasms genetics, Ovarian Neoplasms genetics, Fanconi Anemia Complementation Group G Protein genetics
Abstract

Background: Monoallelic germline pathogenic variants (GPVs) in five Fanconi anemia (FA) genes (BRCA1/FANCS, BRCA2/FANCD1, PALB2/FANCN, BRIP1/FANCJ, and RAD51C/FANCO) confer an increased risk of breast (BC) and/or ovarian (OC) cancer, but the role of GPVs in 17 other FA genes remains unclear., Methods: Here, we investigated the association of germline variants in FANCG/XRCC9 with BC and OC risk., Results: The frequency of truncating GPVs in FANCG did not differ between BC (20/10,204; 0.20%) and OC (8/2966; 0.27%) patients compared to controls (6/3250; 0.18%). In addition, only one out of five tumor samples showed loss-of-heterozygosity of the wild-type FANCG allele. Finally, none of the nine functionally tested rare recurrent missense FANCG variants impaired DNA repair activities (FANCD2 monoubiquitination and FANCD2 foci formation) upon DNA damage, in contrast to all tested FANCG truncations., Conclusion: Our study suggests that heterozygous germline FANCG variants are unlikely to contribute to the development of BC or OC., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Published
2024
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24. A comprehensive analysis of germline predisposition to early-onset ovarian cancer.

Author

Horackova K, Zemankova P, Nehasil P, Vocka M, Hovhannisyan M, Matejkova K, Janatova M, Cerna M, Kleiblova P, Jelinkova S, Stastna B, Just P, Dolezalova T, Nemcova B, Urbanova M, Koudova M, Hazova J, Machackova E, Foretova L, Stranecky V, Zikan M, Kleibl Z, and Soukupova J

Subjects
Humans, Female, Adult, Middle Aged, Case-Control Studies, Young Adult, Checkpoint Kinase 2 genetics, Genetic Predisposition to Disease, Germ-Line Mutation, Ovarian Neoplasms genetics, Age of Onset
Abstract

The subset of ovarian cancer (OC) diagnosed ≤ 30yo represents a distinct subgroup exhibiting disparities from late-onset OC in many aspects, including indefinite germline cancer predisposition. We performed DNA/RNA-WES with HLA-typing, PRS assessment and survival analysis in 123 early-onset OC-patients compared to histology/stage-matched late-onset and unselected OC-patients, and population-matched controls. Only 6/123(4.9%) early-onset OC-patients carried a germline pathogenic variant (GPV) in high-penetrance OC-predisposition genes. Nevertheless, our comprehensive germline analysis of early-onset OC-patients revealed two divergent trajectories of potential germline susceptibility. Firstly, overrepresentation analysis highlighted a connection to breast cancer (BC) that was supported by the CHEK2 GPV enrichment in early-onset OC(p = 1.2 × 10 -4 ), and the presumably BC-specific PRS 313 , which successfully stratified early-onset OC-patients from controls(p = 0.03). The second avenue pointed towards the impaired immune response, indicated by LY75-CD302 GPV(p = 8.3 × 10 -4 ) and diminished HLA diversity compared with controls(p = 3 × 10 -7 ). Furthermore, we found a significantly higher overall GPV burden in early-onset OC-patients compared to controls(p = 3.8 × 10 -4 ). The genetic predisposition to early-onset OC appears to be a heterogeneous and complex process that goes beyond the traditional Mendelian monogenic understanding of hereditary cancer predisposition, with a significant role of the immune system. We speculate that rather a cumulative overall GPV burden than specific GPV may potentially increase OC risk, concomitantly with reduced HLA diversity., (© 2024. The Author(s).)

Published
2024
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25. A deep intronic recurrent CHEK2 variant c.1009-118&#95;1009-87delinsC affects pre-mRNA splicing and contributes to hereditary breast cancer predisposition.

Author

Zemankova P, Cerna M, Horackova K, Ernst C, Soukupova J, Borecka M, Blümcke B, Cerna L, Cerna M, Curtisova V, Dolezalova T, Duskova P, Dvorakova L, Foretova L, Havranek O, Hauke J, Hahnen E, Hodulova M, Hovhannisyan M, Hruskova L, Janatova M, Janikova M, Jelinkova S, Just P, Kosarova M, Koudova M, Krutilkova V, Machackova E, Matejkova K, Michalovska R, Misove A, Nehasil P, Nemcova B, Novotny J, Panczak A, Pesek P, Scheinost O, Springer D, Stastna B, Stranecky V, Subrt I, Tavandzis S, Tureckova E, Vesela K, Vlckova Z, Vocka M, Wappenschmidt B, Zima T, Kleibl Z, and Kleiblova P

Subjects
Humans, Female, Czech Republic, Adult, Middle Aged, RNA Precursors genetics, Germany, Ovarian Neoplasms genetics, Checkpoint Kinase 2 genetics, Breast Neoplasms genetics, Genetic Predisposition to Disease genetics, Germ-Line Mutation, Introns genetics, RNA Splicing genetics
Abstract

Germline CHEK2 pathogenic variants confer an increased risk of female breast cancer (FBC). Here we describe a recurrent germline intronic variant c.1009-118&#95;1009-87delinsC, which showed a splice acceptor shift in RNA analysis, introducing a premature stop codon (p.Tyr337PhefsTer37). The variant was found in 21/10,204 (0.21%) Czech FBC patients compared to 1/3250 (0.03%) controls (p = 0.04) and in 4/3639 (0.11%) FBC patients from an independent German dataset. In addition, we found this variant in 5/2966 (0.17%) Czech (but none of the 443 German) ovarian cancer patients, three of whom developed early-onset tumors. Based on these observations, we classified this variant as likely pathogenic., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Published
2024
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26. Germline multigene panel testing of patients with endometrial cancer.

Author

Kral J, Jelinkova S, Zemankova P, Vocka M, Borecka M, Cerna L, Cerna M, Dostalek L, Duskova P, Foretova L, Havranek O, Horackova K, Hovhannisyan M, Chvojka S, Kalousova M, Kosarova M, Koudova M, Krutilkova V, Machackova E, Nehasil P, Novotny J, Otahalova B, Puchmajerova A, Safarikova M, Slama J, Stranecky V, Subrt I, Tavandzis S, Zikan M, Zima T, Soukupova J, Kleiblova P, Kleibl Z, and Janatova M

Abstract

Endometrial cancer (EC) is the most common gynecological malignancy in developed countries. The present study aimed to determine the frequency of germline pathogenic variants (PV) in patients with EC. In this multicenter retrospective cohort study, germline genetic testing (GGT) was performed in 527 patients with EC using a next generation sequencing panel targeting 226 genes, including 5 Lynch syndrome (LS) and 14 hereditary breast and ovarian cancer (HBOC) predisposition genes, and 207 candidate predisposition genes. Gene-level risks were calculated using 1,662 population-matched controls (PMCs). Patients were sub-categorized to fulfill GGT criteria for LS, HBOC, both or none. A total of 60 patients (11.4%) carried PV in LS (5.1%) and HBOC (6.6%) predisposition genes, including two carriers of double PV. PV in LS genes conferred a significantly higher EC risk [odds ratio (OR), 22.4; 95% CI, 7.8-64.3; P=1.8×10 -17 ] than the most frequently altered HBOC genes BRCA1 (OR, 3.9; 95% CI, 1.6-9.5; P=0.001), BRCA2 (OR, 7.4; 95% CI, 1.9-28.9; P=0.002) and CHEK2 (OR, 3.2; 95% CI, 1.0-9.9; P=0.04). Furthermore, >6% of patients with EC not fulfilling LS or HBOC GGT indication criteria carried a PV in a clinically relevant gene. Carriers of PV in LS genes had a significantly lower age of EC onset than non-carriers (P=0.01). Another 11.0% of patients carried PV in a candidate gene (the most frequent were FANCA and MUTYH ); however, their individual frequencies did not differ from PMCs (except for aggregated frequency of loss-of-function variants in POLE / POLD1 ; OR, 10.44; 95% CI, 1.1-100.5; P=0.012). The present study demonstrated the importance of GGT in patients with EC. The increased risk of EC of PV carriers in HBOC genes suggests that the diagnosis of EC should be included in the HBOC GGT criteria., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Kral et al.)

Published
2023
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27. Multigene Panel Germline Testing of 1333 Czech Patients with Ovarian Cancer.

Author

Lhotova K, Stolarova L, Zemankova P, Vocka M, Janatova M, Borecka M, Cerna M, Jelinkova S, Kral J, Volkova Z, Urbanova M, Kleiblova P, Machackova E, Foretova L, Hazova J, Vasickova P, Lhota F, Koudova M, Cerna L, Tavandzis S, Indrakova J, Hruskova L, Kosarova M, Vrtel R, Stranecky V, Kmoch S, Zikan M, Macurek L, Kleibl Z, and Soukupova J

Abstract

Ovarian cancer (OC) is the deadliest gynecologic malignancy with a substantial proportion of hereditary cases and a frequent association with breast cancer (BC). Genetic testing facilitates treatment and preventive strategies reducing OC mortality in mutation carriers. However, the prevalence of germline mutations varies among populations and many rarely mutated OC predisposition genes remain to be identified. We aimed to analyze 219 genes in 1333 Czech OC patients and 2278 population-matched controls using next-generation sequencing. We revealed germline mutations in 18 OC/BC predisposition genes in 32.0% of patients and in 2.5% of controls. Mutations in BRCA1/BRCA2 , RAD51C/RAD51D , BARD1 , and mismatch repair genes conferred high OC risk (OR > 5). Mutations in BRIP1 and NBN were associated with moderate risk (both OR = 3.5). BRCA1/2 mutations dominated in almost all clinicopathological subgroups including sporadic borderline tumors of ovary (BTO). Analysis of remaining 201 genes revealed somatic mosaics in PPM1D and germline mutations in SHPRH and NAT1 associating with a high/moderate OC risk significantly; however, further studies are warranted to delineate their contribution to OC development in other populations. Our findings demonstrate the high proportion of patients with hereditary OC in Slavic population justifying genetic testing in all patients with OC, including BTO.

Published
2020
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28. Monozygotic twins with 17q21.31 microdeletion syndrome.

Author

Vlckova M, Hancarova M, Drabova J, Slamova Z, Koudova M, Alanova R, Mannik K, Kurg A, and Sedlacek Z

Subjects
Adult, Chromosome Deletion, Chromosomes, Human, Pair 17 genetics, Female, Humans, Intellectual Disability pathology, Male, Smith-Magenis Syndrome, Haplotypes, Intellectual Disability genetics, Polymorphism, Single Nucleotide, Twins, Monozygotic genetics
Abstract

Chromosome 17q21.31 microdeletion syndrome is a genomic disorder caused by a recurrent 600 kb long deletion. The deletion affects the region of a common inversion present in about 20% of Europeans. The inversion is associated with the H2 haplotype carrying additional low-copy repeats susceptible to non-allelic homologous recombination, and this haplotype is prone to deletion. No instances of 17q21.31 deletions inherited from an affected parent have been reported, and the deletions always affected a parental chromosome with the H2 haplotype. The syndrome is characterized clinically by intellectual disability, hypotonia, friendly behavior and specific facial dysmorphism with long face, large tubular or pear-shaped nose and bulbous nasal tip. We present monozygotic twin sisters showing the typical clinical picture of the syndrome. The phenotype of the sisters was very similar, with a slightly more severe presentation in Twin B. The 17q21.31 microdeletion was confirmed in both patients but in neither of their parents. Potential copy number differences between the genomes of the twins were subsequently searched using high-resolution single nucleotide polymorphism (SNP) and comparative genome hybridisation (CGH) arrays. However, these analyses identified no additional aberrations or genomic differences that could potentially be responsible for the subtle phenotypic differences. These could possibly be related to the more severe perinatal history of Twin B, or to the variable expressivity of the disorder. In accord with the expectations, one of the parents (the mother) was shown to carry the H2 haplotype, and the maternal allele of chromosome 17q21.31 was missing in the twins.

Published
2014
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30. Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens.

Author

Steiner B, Rosendahl J, Witt H, Teich N, Keim V, Schulz HU, Pfützer R, Löhr M, Gress TM, Nickel R, Landt O, Koudova M, Macek M Jr, Farre A, Casals T, Desax MC, Gallati S, Gomez-Lira M, Audrezet MP, Férec C, des Georges M, Claustres M, and Truninger K

Subjects
Adolescent, Adult, Carrier Proteins genetics, Child, Epistasis, Genetic, Humans, Infertility, Male genetics, Male, Middle Aged, Mutation genetics, Trypsin Inhibitor, Kazal Pancreatic, Vas Deferens abnormalities, Young Adult, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Genetic Predisposition to Disease genetics, Haplotypes, Male Urogenital Diseases genetics, Pancreatitis, Chronic genetics
Abstract

CFTR mutations enhance susceptibility for idiopathic chronic pancreatitis (ICP) and congenital bilateral absence of the vas deferens (CBAVD); however, it is unknown why CFTR heterozygotes are at increased disease risk. We recently showed that common CFTR variants are associated with aberrantly spliced transcripts. Here, we genotyped for common CFTR variants and tested for associations in two ICP (ICP-A: 126 patients, 319 controls; ICP-B: 666 patients, 1,181 controls) and a CBAVD population (305 patients, 319 controls). Haplotype H10 (TG11-T7-470V) conferred protection (ICP-A: OR 0.19, P<0.0001; ICP-B: OR 0.78, P = 0.06; CBAVD OR 0.08, P<0.001), whereas haplotype H3 (TG10-T7-470M) increased disease risk (ICP-A: OR 8.34, P = 0.003; ICP-B: OR 1.88, P = 0.007; CBAVD: OR 5.67, P = 0.01). The risk of heterozygous CFTR mutations carriers for ICP (OR 2.44, P<0.001) and CBAVD (OR 14.73, P<0.001) was fully abrogated by the H10/H10 genotype. Similarly, ICP risk of heterozygous p.Asn34Ser SPINK1 mutation carriers (OR 10.34, P<0.001) was compensated by H10/H10. Thus, common CFTR haplotypes modulate ICP and CBAVD susceptibility alone and in heterozygous CFTR and p.Asn34Ser mutation carriers. Determination of these haplotypes helps to stratify carriers into high- and low-risk subjects, providing helpful information for genetic counseling., (© 2011 Wiley-Liss, Inc.)

Published
2011
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31. Novel BRAF mutation in a patient with LEOPARD syndrome and normal intelligence.

Author

Koudova M, Seemanova E, and Zenker M

Subjects
Adolescent, Amino Acid Sequence, Amino Acid Substitution, Conserved Sequence, DNA genetics, DNA isolation & purification, DNA Mutational Analysis, Facies, Humans, Leucine metabolism, Male, Molecular Sequence Data, Noonan Syndrome genetics, Sequence Homology, Amino Acid, Abnormalities, Multiple genetics, Heart Defects, Congenital genetics, LEOPARD Syndrome genetics, Mutation, Proto-Oncogene Proteins B-raf genetics
Abstract

Noonan syndrome (NS) and related disorders are caused by mutations in various genes encoding molecules involved in the RAS-MAPK signalling cascade. There are strong genotype-phenotype correlations. BRAF is the major gene for cardio-facio-cutaneous syndrome (CFCS), and usually patients with a BRAF mutation have significant cognitive impairment. We report on a patient with LEOPARD syndrome and normal intelligence who was found to carry a novel sequence change in BRAF. The mutation p.L245F was demonstrated to be de novo with no evidence of somatic mosaicism. This observation illustrates that the phenotypic spectrum caused by BRAF mutations is broader than previously assumed and that mental retardation is not necessarily associated. We speculate that the impact of p.L245F on BRAF protein function differs either qualitatively or quantitatively from those mutations associated with CFCS.

Published
2009
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32. Keratin 8 sequence variants in patients with pancreatitis and pancreatic cancer.

Author

Treiber M, Schulz HU, Landt O, Drenth JP, Castellani C, Real FX, Akar N, Ammann RW, Bargetzi M, Bhatia E, Demaine AG, Battagia C, Kingsnorth A, O'Reilly D, Truninger K, Koudova M, Spicak J, Cerny M, Menzel HJ, Moral P, Pignatti PF, Romanelli MG, Rickards O, De Stefano GF, Zarnescu NO, Choudhuri G, Sikora SS, Jansen JB, Weiss FU, Pietschmann M, Teich N, Gress TM, Ockenga J, Schmidt H, Kage A, Halangk J, Rosendahl J, Groneberg DA, Nickel R, and Witt H

Subjects
Acute Disease, Adenocarcinoma genetics, Adenocarcinoma pathology, Adult, Aged, Alleles, Asian People genetics, Black People genetics, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal pathology, Case-Control Studies, Chronic Disease, Cohort Studies, Female, Gene Frequency, Geography, Heterozygote, Humans, Male, Middle Aged, Pancreatic Neoplasms pathology, Pancreatitis pathology, Pancreatitis, Alcoholic pathology, Polymorphism, Genetic, Retrospective Studies, White People genetics, Genetic Variation, Keratin-8 genetics, Pancreatic Neoplasms genetics, Pancreatitis genetics, Pancreatitis, Alcoholic genetics
Abstract

Keratin 8 (KRT8) is one of the major intermediate filament proteins expressed in single-layered epithelia of the gastrointestinal tract. Transgenic mice over-expressing human KRT8 display pancreatic mononuclear infiltration, interstitial fibrosis and dysplasia of acinar cells resulting in exocrine pancreatic insufficiency. These experimental data are in accordance with a recent report describing an association between KRT8 variations and chronic pancreatitis. This prompted us to investigate KRT8 polymorphisms in patients with pancreatic disorders. The KRT8 Y54H and G62C polymorphisms were assessed in a cohort of patients with acute and chronic pancreatitis of various aetiologies or pancreatic cancer originating from Austria (n=16), the Czech Republic (n=90), Germany (n=1698), Great Britain (n=36), India (n=60), Italy (n=143), the Netherlands (n=128), Romania (n=3), Spain (n=133), and Switzerland (n=129). We also studied 4,234 control subjects from these countries and 1,492 control subjects originating from Benin, Cameroon, Ethiopia, Ecuador, and Turkey. Polymorphisms were analysed by melting curve analysis with fluorescence resonance energy transfer probes. The frequency of G62C did not differ between patients with acute or chronic pancreatitis, pancreatic adenocarcinoma and control individuals. The frequency of G62C varied in European populations from 0.4 to 3.8%, showing a northwest to southeast decline. The Y54H alteration was not detected in any of the 2,436 patients. Only 3/4,580 (0.07%) European, Turkish and Indian control subjects were heterozygous for Y54H in contrast to 34/951 (3.6%) control subjects of African descent. Our data suggest that the KRT8 alterations, Y54H and G62C, do not predispose patients to the development of pancreatitis or pancreatic cancer.

Published
2006
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33. Haplotype block structure study of the CFTR gene. Most variants are associated with the M470 allele in several European populations.

Author

Pompei F, Ciminelli BM, Bombieri C, Ciccacci C, Koudova M, Giorgi S, Belpinati F, Begnini A, Cerny M, Des Georges M, Claustres M, Ferec C, Macek M Jr, Modiano G, and Pignatti PF

Subjects
Gene Frequency, Humans, Linkage Disequilibrium, Mutation, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Genetic Variation, Haplotypes genetics, White People genetics
Abstract

An average of about 1700 CFTR (cystic fibrosis transmembrane conductance regulator) alleles from normal individuals from different European populations were extensively screened for DNA sequence variation. A total of 80 variants were observed: 61 coding SNSs (results already published), 13 noncoding SNSs, three STRs, two short deletions, and one nucleotide insertion. Eight DNA variants were classified as non-CF causing due to their high frequency of occurrence. Through this survey the CFTR has become the most exhaustively studied gene for its coding sequence variability and, though to a lesser extent, for its noncoding sequence variability as well. Interestingly, most variation was associated with the M470 allele, while the V470 allele showed an 'extended haplotype homozygosity' (EHH). These findings make us suggest a role for selection acting either on the M470V itself or through an hitchhiking mechanism involving a second site. The possible ancient origin of the V allele in an 'out of Africa' time frame is discussed.

Published
2006
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34. Variation in a repeat sequence determines whether a common variant of the cystic fibrosis transmembrane conductance regulator gene is pathogenic or benign.

Author

Groman JD, Hefferon TW, Casals T, Bassas L, Estivill X, Des Georges M, Guittard C, Koudova M, Fallin MD, Nemeth K, Fekete G, Kadasi L, Friedman K, Schwarz M, Bombieri C, Pignatti PF, Kanavakis E, Tzetis M, Schwartz M, Novelli G, D'Apice MR, Sobczynska-Tomaszewska A, Bal J, Stuhrmann M, Macek M Jr, Claustres M, and Cutting GR

Subjects
Base Sequence, Cystic Fibrosis genetics, Dinucleotide Repeats genetics, Genotype, Humans, Male, Phenotype, Reference Values, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Genetic Variation genetics, Mutation genetics
Abstract

An abbreviated tract of five thymidines (5T) in intron 8 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene is found in approximately 10% of individuals in the general population. When found in trans with a severe CFTR mutation, 5T can result in male infertility, nonclassic cystic fibrosis, or a normal phenotype. To test whether the number of TG repeats adjacent to 5T influences disease penetrance, we determined TG repeat number in 98 patients with male infertility due to congenital absence of the vas deferens, 9 patients with nonclassic CF, and 27 unaffected individuals (fertile men). Each of the individuals in this study had a severe CFTR mutation on one CFTR gene and 5T on the other. Of the unaffected individuals, 78% (21 of 27) had 5T adjacent to 11 TG repeats, compared with 9% (10 of 107) of affected individuals. Conversely, 91% (97 of 107) of affected individuals had 12 or 13 TG repeats, versus only 22% (6 of 27) of unaffected individuals (P<.00001). Those individuals with 5T adjacent to either 12 or 13 TG repeats were substantially more likely to exhibit an abnormal phenotype than those with 5T adjacent to 11 TG repeats (odds ratio 34.0, 95% CI 11.1-103.7, P<.00001). Thus, determination of TG repeat number will allow for more accurate prediction of benign versus pathogenic 5T alleles.

Published
2004
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