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51. 3946Comparison of genetic signature of isolated left ventricular non-compaction cardiomyopathy and familial dilated cardiomyopathy as assessed by whole exome sequencing

Author

Kubanek, M., primary, Krebsova, A., additional, Piherova, L., additional, Stranecky, V., additional, Macek Jr, M., additional, Kockova, R., additional, Palecek, T., additional, Malek, F., additional, Melenovsky, V., additional, Kmoch, S., additional, and Kautzner, J., additional

Published
2017
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52. Candidate Gene Resequencing in a Large Bicuspid Aortic Valve-Associated Thoracic Aortic Aneurysm Cohort: SMAD6 as an Important Contributor

Author

Gillis, Elisabeth, primary, Kumar, Ajay A., additional, Luyckx, Ilse, additional, Preuss, Christoph, additional, Cannaerts, Elyssa, additional, van de Beek, Gerarda, additional, Wieschendorf, Björn, additional, Alaerts, Maaike, additional, Bolar, Nikhita, additional, Vandeweyer, Geert, additional, Meester, Josephina, additional, Wünnemann, Florian, additional, Gould, Russell A., additional, Zhurayev, Rustam, additional, Zerbino, Dmytro, additional, Mohamed, Salah A., additional, Mital, Seema, additional, Mertens, Luc, additional, Björck, Hanna M., additional, Franco-Cereceda, Anders, additional, McCallion, Andrew S., additional, Van Laer, Lut, additional, Verhagen, Judith M. A., additional, van de Laar, Ingrid M. B. H., additional, Wessels, Marja W., additional, Messas, Emmanuel, additional, Goudot, Guillaume, additional, Nemcikova, Michaela, additional, Krebsova, Alice, additional, Kempers, Marlies, additional, Salemink, Simone, additional, Duijnhouwer, Toon, additional, Jeunemaitre, Xavier, additional, Albuisson, Juliette, additional, Eriksson, Per, additional, Andelfinger, Gregor, additional, Dietz, Harry C., additional, Verstraeten, Aline, additional, and Loeys, Bart L., additional

Published
2017
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54. 1222Characteristics of an arrhythmogenic substrate and results of catheter ablation of ventricular arrhythmias in patients with desmoplakin mutation associated arrhythmogenic cardiomyopathy

Author

Peichl, P., primary, Krebsova, A., additional, Wichterle, D., additional, Kubanek, M., additional, Cihak, R., additional, Yamagata, K., additional, Aldhoon, B., additional, Piherova, L., additional, Norambuena, P., additional, Stranecky, V., additional, Kmoch, S., additional, Macek, M., additional, and Kautzner, J., additional

Published
2017
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55. Alu‐mediated Xq24 deletion encompassing CUL4B, LAMP2, ATP1B4, TMEM255A, and ZBTB33 genes causes Danon disease in a female patient.

Author

Majer, Filip, Kousal, Bohdan, Dusek, Petr, Piherova, Lenka, Reboun, Martin, Mihalova, Romana, Gurka, Jiri, Krebsova, Alice, Vlaskova, Hana, Dvorakova, Lenka, Krihova, Jana, Liskova, Petra, Kmoch, Stanislav, Kalina, Tomas, Kubanek, Milos, and Sikora, Jakub

Abstract

Cullin 4B (CUL4B), lysosomal‐associated membrane protein Type 2 (LAMP2), ATP1B4, TMEM255A, and ZBTB33 are neighboring genes on Xq24. Mutations in CUL4B result in Cabezas syndrome (CS). Male CS patients present with dysmorphic, neuropsychiatric, genitourinary, and endocrine abnormalities. Heterozygous CS females are clinically asymptomatic. LAMP2 mutations cause Danon disease (DD). Cardiomyopathy is a dominant feature of DD present in both males and heterozygous females. No monogenic phenotypes have been associated with mutations in ATP1B4, TMEM255A, and ZBTB33 genes. To facilitate diagnostics and counseling in CS and DD families, we present a female DD patient with a de novo Alu‐mediated Xq24 rearrangement causing a deletion encompassing CUL4B, LAMP2, and also the other three neighboring genes. Typical to females heterozygous for CUL4B mutations, the patient was CS asymptomatic, however, presented with extremely skewed X‐chromosome inactivation (XCI) ratios in peripheral white blood cells. As a result of the likely selection against CUL4B deficient clones, only minimal populations (~3%) of LAMP2 deficient leukocytes were identified by flow cytometry. On the contrary, myocardial LAMP2 protein expression suggested random XCI. We demonstrate that contiguous CUL4B and LAMP2 loss‐of‐function copy number variations occur and speculate that male patients carrying similar defects could present with features of both CS and DD. [ABSTRACT FROM AUTHOR]

Published
2020
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56. Candidate Gene Resequencing in a Large Bicuspid Aortic Valve-Associated Thoracic Aortic Aneurysm Cohort: SMAD6 as an Important Contributor

Author

Gillis, E., Kumar, A.A., Luyckx, I., Preuss, C., Cannaerts, E., Beek, G. van de, Wieschendorf, B., Alaerts, M., Bolar, N., Vandeweyer, G., Meester, J. de, Wunnemann, F., Gould, R.A., Zhurayev, R., Zerbino, D., Mohamed, S.A., Mital, S., Mertens, L., Bjorck, H.M., Franco-Cereceda, A., McCallion, A.S., Laer, L. Van, Verhagen, J.M.A., Laar, I. van de, Wessels, M.W., Messas, E., Goudot, G., Nemcikova, M., Krebsova, A., Kempers, M.J.E., Salemink, S., Duijnhouwer, T., Jeunemaitre, X., Albuisson, J., Eriksson, P., Andelfinger, G., Dietz, H.C., Verstraeten, A., Loeys, B.L., Gillis, E., Kumar, A.A., Luyckx, I., Preuss, C., Cannaerts, E., Beek, G. van de, Wieschendorf, B., Alaerts, M., Bolar, N., Vandeweyer, G., Meester, J. de, Wunnemann, F., Gould, R.A., Zhurayev, R., Zerbino, D., Mohamed, S.A., Mital, S., Mertens, L., Bjorck, H.M., Franco-Cereceda, A., McCallion, A.S., Laer, L. Van, Verhagen, J.M.A., Laar, I. van de, Wessels, M.W., Messas, E., Goudot, G., Nemcikova, M., Krebsova, A., Kempers, M.J.E., Salemink, S., Duijnhouwer, T., Jeunemaitre, X., Albuisson, J., Eriksson, P., Andelfinger, G., Dietz, H.C., Verstraeten, A., and Loeys, B.L.

Abstract

Contains fulltext : 176973.pdf (publisher's version ) (Open Access), Bicuspid aortic valve (BAV) is the most common congenital heart defect. Although many BAV patients remain asymptomatic, at least 20% develop thoracic aortic aneurysm (TAA). Historically, BAV-related TAA was considered as a hemodynamic consequence of the valve defect. Multiple lines of evidence currently suggest that genetic determinants contribute to the pathogenesis of both BAV and TAA in affected individuals. Despite high heritability, only very few genes have been linked to BAV or BAV/TAA, such as NOTCH1, SMAD6, and MAT2A. Moreover, they only explain a minority of patients. Other candidate genes have been suggested based on the presence of BAV in knockout mouse models (e.g., GATA5, NOS3) or in syndromic (e.g., TGFBR1/2, TGFB2/3) or non-syndromic (e.g., ACTA2) TAA forms. We hypothesized that rare genetic variants in these genes may be enriched in patients presenting with both BAV and TAA. We performed targeted resequencing of 22 candidate genes using Haloplex target enrichment in a strictly defined BAV/TAA cohort (n = 441; BAV in addition to an aortic root or ascendens diameter >/= 4.0 cm in adults, or a Z-score >/= 3 in children) and in a collection of healthy controls with normal echocardiographic evaluation (n = 183). After additional burden analysis against the Exome Aggregation Consortium database, the strongest candidate susceptibility gene was SMAD6 (p = 0.002), with 2.5% (n = 11) of BAV/TAA patients harboring causal variants, including two nonsense, one in-frame deletion and two frameshift mutations. All six missense mutations were located in the functionally important MH1 and MH2 domains. In conclusion, we report a significant contribution of SMAD6 mutations to the etiology of the BAV/TAA phenotype.

Published
2017

57. Candidate gene resequencing in a large bicuspid aortic valve-associated thoracic aortic aneurysm cohort: SMAD6 as an important contributor

Author

Gillis, E. (Elisabeth), Kumar, A.A. (Ajay A.), Luyckx, I. (Ilse), Preuss, C. (Christoph), Cannaerts, E. (Elyssa), Beek, G. (Gerarda van de), Wieschendorf, B. (Björn), Alaerts, M. (Maaike), Bolar, N. (Nikhita), Vandeweyer, G. (Geert), Meester, J. (Josephina), Wünnemann, F. (Florian), Gould, R.A. (Russell A.), Zhurayev, R. (Rustam), Zerbino, D. (Dmytro), Mohamed, S.A. (Salah A.), Mital, S. (Seema), Mertens, L. (Luc), Björck, H.M. (Hanna M.), Franco-Cereceda, A. (Anders), McCallion, A.S. (Andrew), Laer, L. (Lut) van, Verhagen, J.M.A. (Judith), Laar, I.M.B.H. (Ingrid) van de, Wessels, M.W. (Marja), Messas, E. (Emmanuel), Goudot, G. (Guillaume), Nemcikova, M. (Michaela), Krebsova, A. (Alice), Kempers, M.J.E. (Marlies), Salemink, S. (Simone), Duijnhouwer, T. (Toon), Jeunemaître, X. (Xavier), Albuisson, J. (Juliette), Eriksson, P. (Per), Andelfinger, G. (Gregor), Dietz, H.C. (Harry ), Verstraeten, A. (Aline), Loeys, B.L. (Bart), Gillis, E. (Elisabeth), Kumar, A.A. (Ajay A.), Luyckx, I. (Ilse), Preuss, C. (Christoph), Cannaerts, E. (Elyssa), Beek, G. (Gerarda van de), Wieschendorf, B. (Björn), Alaerts, M. (Maaike), Bolar, N. (Nikhita), Vandeweyer, G. (Geert), Meester, J. (Josephina), Wünnemann, F. (Florian), Gould, R.A. (Russell A.), Zhurayev, R. (Rustam), Zerbino, D. (Dmytro), Mohamed, S.A. (Salah A.), Mital, S. (Seema), Mertens, L. (Luc), Björck, H.M. (Hanna M.), Franco-Cereceda, A. (Anders), McCallion, A.S. (Andrew), Laer, L. (Lut) van, Verhagen, J.M.A. (Judith), Laar, I.M.B.H. (Ingrid) van de, Wessels, M.W. (Marja), Messas, E. (Emmanuel), Goudot, G. (Guillaume), Nemcikova, M. (Michaela), Krebsova, A. (Alice), Kempers, M.J.E. (Marlies), Salemink, S. (Simone), Duijnhouwer, T. (Toon), Jeunemaître, X. (Xavier), Albuisson, J. (Juliette), Eriksson, P. (Per), Andelfinger, G. (Gregor), Dietz, H.C. (Harry ), Verstraeten, A. (Aline), and Loeys, B.L. (Bart)

Abstract

Bicuspid aortic valve (BAV) is the most common congenital heart defect. Although many BAV patients remain asymptomatic, at least 20% develop thoracic aortic aneurysm (TAA). Historically, BAV-related TAA was considered as a hemodynamic consequence of the valve defect. Multiple lines of evidence currently suggest that genetic determinants contribute to the pathogenesis of both BAV and TAA in affected individuals. Despite high heritability, only very few genes have been linked to BAV or BAV/TAA, such as NOTCH1, SMAD6, and MAT2A. Moreover, they only explain a minority of patients. Other candidate genes have been suggested based on the presence of BAV in knockout mouse models (e.g., GATA5, NOS3) or in syndromic (e.g., TGFBR1/2, TGFB2/3) or non-syndromic (e.g., ACTA2) TAA forms. We hypothesized that rare genetic variants in these genes may be enriched in patients presenting with both BAV and TAA. We performed targeted resequencing of 22 candidate genes using Haloplex target enrichment in a strictly defined BAV/TAA cohort (n = 441; BAV in addition to an aortic root or ascendens diameter = 4.0 cm in adults, or a Z-score = 3 in children) and in a collection of healthy controls with normal echocardiographic evaluation (n = 183). After additional burden analysis against the Exome Aggregation Consortium database, the strongest candidate susceptibility gene was SMAD6 (p = 0.002), with 2.5% (n = 11) of BAV/TAA patients harboring causal variants, including two nonsense, one in-frame deletion and two frameshift mutations. All six missense mutations were located in the functionally important MH1 and MH2 domains. In conclusion, we report a significant contribution of SMAD6 mutations to the etiology of the BAV/TAA phenotype.

Published
2017
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58. Corrigendum: Candidate gene resequencing in a large bicuspid aortic valve-associated thoracic aortic aneurysm cohort: SMAD6 as an important contributor [Front. Physiol, 8, (2017) (400)] doi: 10.3389/fphys.2017.00400

Author

Gillis, E. (Elisabeth), Kumar, A.A. (Ajay A.), Luyckx, I. (Ilse), Preuss, C. (Christoph), Cannaerts, E. (Elyssa), Van De Beek, G. (Gerarda), Wieschendorf, B. (Björn), Alaerts, M. (Maaike), Bolar, N. (Nikhita), Vandeweyer, G. (Geert), Meester, J. (Josephina), Wünnemann, F. (Florian), Gould, R.A. (Russell A.), Zhurayev, R. (Rustam), Zerbino, D. (Dmytro), Mohamed, S.A. (Salah A.), Mital, S. (Seema), Mertens, L. (Luc), Björck, H.M. (Hanna M.), Franco-Cereceda, A. (Anders), McCallion, A.S. (Andrew), Van Laer, L. (Lut), Verhagen, J.M.A. (Judith), van de Laar, I.M.B.H. (Ingrid M.B.H.), Wessels, M.W. (Marja), Messas, E. (Emmanuel), Goudot, G. (Guillaume), Nemcikova, M. (Michaela), Krebsova, A. (Alice), Kempers, M.J.E. (Marlies), Salemink, S. (Simone), Duijnhouwer, T. (Toon), Jeunemaître, X. (Xavier), Albuisson, J. (Juliette), Eriksson, P. (Per), Andelfinger, G. (Gregor), Dietz, H.C. (Harry ), Verstraeten, A. (Aline), Loeys, B.L. (Bart), Gillis, E. (Elisabeth), Kumar, A.A. (Ajay A.), Luyckx, I. (Ilse), Preuss, C. (Christoph), Cannaerts, E. (Elyssa), Van De Beek, G. (Gerarda), Wieschendorf, B. (Björn), Alaerts, M. (Maaike), Bolar, N. (Nikhita), Vandeweyer, G. (Geert), Meester, J. (Josephina), Wünnemann, F. (Florian), Gould, R.A. (Russell A.), Zhurayev, R. (Rustam), Zerbino, D. (Dmytro), Mohamed, S.A. (Salah A.), Mital, S. (Seema), Mertens, L. (Luc), Björck, H.M. (Hanna M.), Franco-Cereceda, A. (Anders), McCallion, A.S. (Andrew), Van Laer, L. (Lut), Verhagen, J.M.A. (Judith), van de Laar, I.M.B.H. (Ingrid M.B.H.), Wessels, M.W. (Marja), Messas, E. (Emmanuel), Goudot, G. (Guillaume), Nemcikova, M. (Michaela), Krebsova, A. (Alice), Kempers, M.J.E. (Marlies), Salemink, S. (Simone), Duijnhouwer, T. (Toon), Jeunemaître, X. (Xavier), Albuisson, J. (Juliette), Eriksson, P. (Per), Andelfinger, G. (Gregor), Dietz, H.C. (Harry ), Verstraeten, A. (Aline), and Loeys, B.L. (Bart)

Abstract

In the original article, we noted two mutation annotation errors. The correction of these two mistakes does not change the scientific conclusions in any way. The authors apologize for these nomenclature errors. Please find below the corrected annotations of those two mutations: (1) The correct RNA and protein annotations of the SMAD6 variant in P99 are c.455_461del and p.Pro152Profs*27, and not c.454_461del and p.Gly166Valfs*23. (2) The correct RNA and protein annotations of the SMAD6 variant in P128 are c.74_79del and p.Ser27_Gly28del, and not c.73_79del and p.Gly26_Ser27del. As a consequence, a correction has been made to RESULTS, Paragraphs 5 and 6: The SMAD6 c.726del variant leads to a frameshift (p.Lys242Asnfs*300) and a predicted protein with a C-terminal extension due to loss of the intended stop codon. The c.455_461del frameshift variant (p.Pro152Profs*27) causes the introduction of a premature stop codon, most likely resulting in haploinsufficiency due to nonsense-mediated mRNA decay (NMD). Also the two nonsense variants (p.Tyr279* and p.Tyr288*) are predicted to lead to NMD. All of the missense variants cluster in the functionally important MH1 and MH2 domains (Makkar et al., 2009) (amino acids 148-275 and 331-496, respectively), which is not the case for the sole missense variant (p.Ser130Leu) found in a control individual (Figure 2). All but one (p.Arg443His) of the identified variants were absent in the ExAC control cohort (v0.3.1; Supplementary Table 2). Moreover, the missense variants in the patient cohort (7/7) are enriched in the MH1 and MH2 domains when compared to ExAC controls (n = 228/430; p = 0.02).

Published
2017
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59. Candidate Gene Resequencing in a Large Bicuspid Aortic Valve-Associated Thoracic Aortic Aneurysm Cohort: SMAD6 as an Important Contributor

Author

Gillis, E, Kumar, AA, Luyckx, I, Preuss, C, Cannaerts, E, van de Beek, G, Wieschendorf, B, Alaerts, M, Bolar, N, Vandeweyer, G, Meester, J, Wunnemann, F, Gould, RA, Zhurayev, R, Zerbino, D, Mohamed, SA, Mital, S, Mertens, L, Bjorck, HM, Franco-Cereceda, A, McCallion, AS, Van Laer, L, Verhagen, Judith, De Graaf - van de Laar, Ingrid, Wessels, Marja, Messas, E, Goudot, G, Nemcikova, M, Krebsova, A, Kempers, M, Salemink, S, Duijnhouwer, T, Jeunemaitre, X, Albuisson, J, Eriksson, P, Andelfinger, G, Dietz, HC, Verstraeten, A (Aline), Loeys, BL, Gillis, E, Kumar, AA, Luyckx, I, Preuss, C, Cannaerts, E, van de Beek, G, Wieschendorf, B, Alaerts, M, Bolar, N, Vandeweyer, G, Meester, J, Wunnemann, F, Gould, RA, Zhurayev, R, Zerbino, D, Mohamed, SA, Mital, S, Mertens, L, Bjorck, HM, Franco-Cereceda, A, McCallion, AS, Van Laer, L, Verhagen, Judith, De Graaf - van de Laar, Ingrid, Wessels, Marja, Messas, E, Goudot, G, Nemcikova, M, Krebsova, A, Kempers, M, Salemink, S, Duijnhouwer, T, Jeunemaitre, X, Albuisson, J, Eriksson, P, Andelfinger, G, Dietz, HC, Verstraeten, A (Aline), and Loeys, BL

Published
2017

61. Mutations in Klotho are associated with survival in diverse human populations

Author

Arking, D.E., Krebsova, A., Macek, M. Jr., Macek, M., Arking, A., Mian, I.S., Fried, L.P., Hamosh, A., Day, S., McIntosh, I., and Dietz, H.C.

Subjects
Genetic research -- Analysis, Human genetics -- Research, Atherosclerosis -- Genetic aspects, Osteoporosis -- Genetic aspects, Emphysema, Pulmonary -- Genetic aspects, Biological sciences
Published
2000

62. 1222Characteristics of an arrhythmogenic substrate and results of catheter ablation of ventricular arrhythmias in patients with desmoplakin mutation associated arrhythmogenic cardiomyopathy

Author

Bashar Aldhoon, Lenka Piherová, Stanislav Kmoch, J Kautzner, Viktor Stranecky, Petr Peichl, Milos Kubanek, Robert Cihak, D Wichterle, A Krebsova, Milan Macek, Patricia Norambuena, and Kenichiro Yamagata

Subjects
medicine.medical_specialty, biology, business.industry, Desmoplakin, medicine.medical_treatment, Cardiomyopathy, Catheter ablation, Cardiac Ablation, medicine.disease, Arrhythmogenic substrate, Physiology (medical), Internal medicine, Mutation (genetic algorithm), biology.protein, Cardiology, Medicine, In patient, Cardiology and Cardiovascular Medicine, business
Published
2017
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63. 601Genetic testing identified arrhythmogenic cardiomyopathy with predominant left ventricular involvement in a cohort of patients with clinical diagnosis of familiar dilated cardiomyopathy

Author

A. Krebsova, M. Kubanek, L. Piherova, P. Norambuena, P. Peichl, S. Kmoch, M. Macek Sr, M. Macek Jr, and J. Kautzner

Subjects
medicine.medical_specialty, business.industry, Cardiomyopathy, Dilated cardiomyopathy, medicine.disease, Physiology (medical), Clinical diagnosis, Internal medicine, Cohort, medicine, Cardiology, Cardiology and Cardiovascular Medicine, business, Left ventricular involvement
Published
2017
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64. Distribution of CFTR mutations in the Czech population: Positive impact of integrated clinical and laboratory expertise, detection of novel/de novo alleles and relevance for related/derived populations

Author

Křenková, Petra, Piskáčková, Tereza, Holubová, Andrea, Balaščaková, Miroslava, Krulišová, Veronika, Čamajová, Jana, Turnovec, Marek, Libik, Malgorzata, Norambuena, Patricia, Štambergová, Alexandra, Dvořáková, Lenka, Skalická, Veronika, Bartošová, Jana, Kučerová, Tereza, Fila, Libor, Zemková, Dana, Vávrová, Věra, Koudová, Monika, Macek, Milan, Krebsová, Alice, and Macek, Milan, Jr.

Published
2013
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66. Besprechungen

Author

Schlesier, E., primary, Grootaers, W. A., additional, Schimmel, A., additional, Helck, W., additional, Björkman, W., additional, Eißfeldt, O., additional, Soden, W. V., additional, Eichhorn, W., additional, Strommenger, E., additional, Plischke, H., additional, Winter, P., additional, Hofmann, E., additional, Krebsova, B., additional, Bardtke, H., additional, Jacob, G., additional, Erdmann, K., additional, Edzard, O., additional, Morenz, S., additional, Mensching, G., additional, Höfner, M., additional, Halevy, M. A., additional, Nolle, W., additional, Rypka, J., additional, Németh, J., additional, Ruben, W., additional, Gonda, J., additional, Meyer, R., additional, Kissling, H. J., additional, Kees, H., additional, Otto, E., additional, and Franke, W., additional

Published
1958
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67. Fine mapping of autosomal dominant nonsyndromic hearing impairment DFNA21 to chromosome 6p24.1-22.3

Author

Brouwer, A.P.M. de, Kunst, H.P.M., Krebsova, A., Asseldonk, K. van, Reis, A., Snoeckx, R.L., Camp, G. van, Cremers, C.W.R.J., Cremers, F.P.M., and Kremer, J.M.J.

Subjects
Genomic disorders and inherited multi-system disorders [IGMD 3], Genetics and epigenetic pathways of disease [NCMLS 6], Perception and Action [DCN 1], Neurosensory disorders [UMCN 3.3], Functional Neurogenomics [DCN 2]
Abstract

Contains fulltext : 47856.pdf (Publisher’s version ) (Closed access) Previously, the DFNA21 locus was positioned telomeric to the DFNA13 locus based on testing of candidate loci. One family member in this region did not carry the at risk haplotype, although he had the same nonspecific midfrequency hearing impairment as other affected family members. Hence, we performed a whole genome linkage scan excluding other regions of the genome and confirming the localization of DFNA21 to 6p22.3-24.1. The DFNA21 interval was determined to span 12.4 Mb (approximately 22 cM) and is delimited on the telomeric side by BV097155 and on the centromeric side by D6S1691. A maximum lod score of 3.51 (theta = 0.066), was calculated for marker D6S1721. The DFNA21 region does not overlap the adjacent DFNA31 and DFNA13 loci and contains 31 known genes. The coding regions and exon-intron boundaries of four candidate genes, SOX4, MYLIP, CAP2, and RPEL1, were sequenced, but no mutations were identified.

Published
2005

68. 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

69. 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

71. Non-syndromic autosomal dominant progresive non-specific mid-frequency sensorineural hearing impairment with childhood to late adolescence onset (DFNA21).

Author

Kunst, H.P.M., Marres, H.A.M., Huygen, P.L.M., Duijnhoven, G.C.F. van, Krebsova, A., Velde-Visser, S.D. van der, Reis, A., Cremers, F.P.M., Cremers, C.W.R.J., Kunst, H.P.M., Marres, H.A.M., Huygen, P.L.M., Duijnhoven, G.C.F. van, Krebsova, A., Velde-Visser, S.D. van der, Reis, A., Cremers, F.P.M., and Cremers, C.W.R.J.

Abstract

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Published
2000

72. 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

73. QF-PCR Examination of Parental and Meiotic Origin of Trisomy 21 in Central and Eastern Europe

Author

Machatkova, Marina, primary, Brouckova, Martina, additional, Matejckova, Milada, additional, Krebsova, Alice, additional, Sperling, Karl, additional, Vorsanova, Svetlana, additional, Kutsev, Sergei, additional, Zerova, Tatiana, additional, Arbuzova, Svetlana, additional, Krejci, Roman, additional, Petersen, Michael, additional, and Macek, Milan, additional

Published
2005
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75. Detection of a cystic fibrosis modifier locus for meconium ileus on human chromosome 19q13

Author

Zielenski, Julian, primary, Corey, Mary, additional, Rozmahel, Richard, additional, Markiewicz, Danuta, additional, Aznarez, Isabel, additional, Casals, Teresa, additional, Larriba, Sara, additional, Mercier, Bernard, additional, Cutting, Garry R., additional, Krebsova, Alice, additional, Macek, Milan, additional, Langfelder-Schwind, Elinor, additional, Marshall, Bruce C., additional, DeCelie-Germana, J., additional, Claustres, Mirreille, additional, Palacio, Ana, additional, Bal, Jerzy, additional, Nowakowska, Aleksandra, additional, Ferec, Claude, additional, Estivill, Xavier, additional, Durie, Peter, additional, and Tsui, Lap-Chee, additional

Published
1999
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