ISL1 is a major susceptibility gene for classic bladder exstrophy and a regulator of urinary tract development

Rong Zhang, Michael Knapp, Kentaro Suzuki, Daiki Kajioka, Johanna M. Schmidt, Jonas Winkler, Öznur Yilmaz, Michael Pleschka, Jia Cao, Christina Clementson Kockum, Gillian Barker, Gundela Holmdahl, Glenda Beaman, David Keene, Adrian S. Woolf, Raimondo M. Cervellione, Wei Cheng, Simon Wilkins, John P. Gearhart, Fabio SirchiaMassimo Di Grazia, Anne Karolin Ebert, Wolfgang Rösch, Jörg Ellinger, Ekkehart Jenetzky, Nadine Zwink, Wout F. Feitz, Carlo Marcelis, Johannes Schumacher, Federico Martinón-Torres, Martin Lloyd Hibberd, Chiea Chuen Khor, Stefanie Heilmann-Heimbach, Sandra Barth, Simeon Boyd, Alfredo Brusco, Michael Ludwig, William Newman, Agneta Nordenskjöld, Gen Yamada, Benjamin Odermatt, Heiko Reutter

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Previously genome-wide association methods in patients with classic bladder exstrophy (CBE) found association with ISL1, a master control gene expressed in pericloacal mesenchyme. This study sought to further explore the genetics in a larger set of patients following-up on the most promising genomic regions previously reported. Genotypes of 12 markers obtained from 268 CBE patients of Australian, British, German Italian, Spanish and Swedish origin and 1,354 ethnically matched controls and from 92 CBE case-parent trios from North America were analysed. Only marker rs6874700 at the ISL1 locus showed association (p = 2.22 × 10-08). A meta-analysis of rs6874700 of our previous and present study showed a p value of 9.2 × 10-19. Developmental biology models were used to clarify the location of ISL1 activity in the forming urinary tract. Genetic lineage analysis of Isl1-expressing cells by the lineage tracer mouse model showed Isl1-expressing cells in the urinary tract of mouse embryos at E10.5 and distributed in the bladder at E15.5. Expression of isl1 in zebrafish larvae staged 48 hpf was detected in a small region of the developing pronephros. Our study supports ISL1 as a major susceptibility gene for CBE and as a regulator of urinary tract development.

Original languageEnglish (US)
Article number42170
JournalScientific Reports
Volume7
DOIs
StatePublished - Feb 8 2017

ASJC Scopus subject areas

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    Zhang, R., Knapp, M., Suzuki, K., Kajioka, D., Schmidt, J. M., Winkler, J., Yilmaz, Ö., Pleschka, M., Cao, J., Kockum, C. C., Barker, G., Holmdahl, G., Beaman, G., Keene, D., Woolf, A. S., Cervellione, R. M., Cheng, W., Wilkins, S., Gearhart, J. P., ... Reutter, H. (2017). ISL1 is a major susceptibility gene for classic bladder exstrophy and a regulator of urinary tract development. Scientific Reports, 7, [42170]. https://doi.org/10.1038/srep42170