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Nature Research, Scientific Reports, 1(7), 2017

DOI: 10.1038/srep42170

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

Journal article published in 2017 by 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 and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

AbstractPreviously 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.