Identifizierung und Charakterisierung von Krankheitsgenen für den Blasenekstrophie-Epispadie Komplex (BEEK)
Zusammenfassung der Projektergebnisse
The Exstrophy-Epispadias Complex EEC represents the severe end of the uro-rectal malformation spectrum, and has a profound impact on continence, and on sexual and renal function. Our presented work provides several lines of evidence for variable underlying genetic factors. Here we identified new copy number variations (CNVs), susceptibility regions and genes through the systematic application of array based analysis, candidate gene and genome-wide association studies (GWAS) provide strong evidence. We demonstrate the importance of ISL1-pathway in human EEC and propose WNT3, SLC20A1 and CELSR3 as the first EEC candidate genes, identified through systematic whole-exome sequencing (WES). In our future work we plan further analysis of additional GWAS loci and systematic deep exome respectively genome sequencing in EEC cohorts to ultimately identify all high and low penetrant coding and non-coding genetic factors, that contribute to this heterogeneous severe birth defect. The CRISPR/Cas system, mouse and zebrafish experiments will be employed to characterize these genetic factors. Ultimately our research will lead to a profound understanding of the molecular biological mechanisms underlying the normal and disturbed embryology of the human urogenital system. The identification of high penetrance causative genes will provide new diagnostic possibilities, and allow precise estimation of recurrence risk in affected families.
Projektbezogene Publikationen (Auswahl)
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Candidate gene association study implicates p63 in the etiology of nonsyndromic bladder-exstrophyepispadias complex. Birth Defects Res A Clin Mol Teratol, (2013) 97:759-763
Qi L, Wang M, Yagnik G, Mattheisen M, Gearhart JP, Lakshmanan Y, Ebert A-K, Rösch W, Ludwig M, Draaken M, Reutter H and Boyadjiev SA
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Bladder Exstrophy-Epispadias-Complex and triple-X syndrome: incidental finding or causality? Birth Defects Res A Clin Mol Teratol, (2014) 100:797-800
Ramaekers P, Loeys B, von Lowtzow C, Reutter H, Jacquemyn Y, Leroy Y, Colpaert C, Parizel M
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Classic bladder exstrophy: frequent 22q11.21 duplications and definition of a 414 kb phenocritical region. Birth Defects Res A Clin Mol Teratol, (2014) 100:512-517
Draaken M, Baudisch F, Timmermann B, Kuhl H, Kerick M, Proske J, Wittler L, Pennimpede T, Ebert A-K, Rösch W, Stein R, Bartels E, von Lowtzow C, Boemers TM, Herms S, Gearhart JP, Lakshmanan Y, Kockum CC, Holmdahl G, Läckgren G, Nordenskjöld A, Boyadjiev SA, Herrmann BG, Nöthen MM, Ludwig M, Reutter HR
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Genome-wide association study and mouse expression data identify a highly conserved 32kb intergenic region between WNT3 and WNT9b as possible susceptibility locus for isolated classic exstrophy of the bladder. Hum Mol Genet, (2014) 23:5536-5544
Reutter H, Draaken M, Pennimpede T, Wittler L, Brockschmidt FF, Ebert A-K, Bartels E, Rösch W, Boemers TM, Hirsch K, Schmiedeke E, Meesters C, Becker T, Stein R, Utsch B, Mangold E, Nordenskjöld A, Barker G, Clementsson Kockum C, Zwink N, Holmdahl G, Läckgren G, Jenetzky E, Feitz WFJ, Marcelis C, Wijers CHW, van Rooij IALM, Gearhart JP, Herrmann BG, Ludwig M, Boyadjiev SA, Nöthen MM, Mattheisen M
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Genome-wide association study and meta-analysis identify ISL1 as genome-wide significant susceptibility gene for bladder exstrophy. PLoS Genet, (2015) 11:e1005024
Draaken M, Knapp M, Pennimpede T, Schmidt JM, Ebert AK, Rösch W, Stein R, Utsch B, Hirsch K, Boemers TM, Mangold E, Heilmann S, Ludwig KU, Jenetzky E, Zwink N, Moebus S, Herrmann BG, Mattheisen M, Nöthen MM, Ludwig M, Reutter H
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Leveraging the power of high performance computing for next generation sequencing data analysis: tricks and twists from a high throughput exome workflow. PLoS One. 2015 May 5;10(5)
Kawalia A, Motameny S, Wonczak S, Thiele H, Nieroda L, Jabbari K, Borowski S, Sinha V, Gunia W, Lang U, Achter V, Nürnberg P
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WNT3 involvement in human bladder exstrophy and cloaca development in zebrafish. Hum Mol Genet, 2015 Jun 23
Baranowska Körberg I, Hofmeister W, Markljung E, Cao J, Nilsson D, Ludwig M, Draaken M, Holmdahl G, Barker G, Reutter H, Vukojević V, Kockum CC, Lundin J, Lindstrand A, Nordenskjöld A
