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

Zhang, Rong; Knapp, Michael; Suzuki, Kentaro; Kajioka, Daiki; Schmidt, Johanna M.; Winkler, Jonas; Yilmaz, Öznur; Pleschka, Michael; Cao, Jia and Kockum, Christina Clementson LU , et al. (2017) In Scientific Reports 7.
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 ×... (More)

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.

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@article{f5de4f8e-14d6-41e0-962c-cd49948703b2,
  abstract     = {<p>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<sup>-08</sup>). A meta-analysis of rs6874700 of our previous and present study showed a p value of 9.2 × 10<sup>-19</sup>. 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.</p>},
  articleno    = {42170},
  author       = {Zhang, Rong and Knapp, Michael and Suzuki, Kentaro and Kajioka, Daiki and Schmidt, Johanna M. and Winkler, Jonas and Yilmaz, Öznur and Pleschka, Michael and Cao, Jia and Kockum, Christina Clementson and Barker, Gillian and Holmdahl, Gundela and Beaman, Glenda and Keene, David and Woolf, Adrian S. and Cervellione, Raimondo M. and Cheng, Wei and Wilkins, Simon and Gearhart, John P. and Sirchia, Fabio and Di Grazia, Massimo and Ebert, Anne-Karolin and Rösch, Wolfgang and Ellinger, Jörg and Jenetzky, Ekkehart and Zwink, Nadine and Feitz, Wout F. and Marcelis, Carlo and Schumacher, Johannes and Martinón-Torres, Federico and Hibberd, Martin Lloyd and Khor, Chiea-Chuen and Heilmann-Heimbach, Stefanie and Barth, Sandra and Boyadjiev, Simeon A. and Brusco, Alfredo and Ludwig, Michael and Newman, William and Nordenskjöld, Agneta and Yamada, Gen and Odermatt, Benjamin and Reutter, Heiko},
  issn         = {2045-2322},
  language     = {eng},
  month        = {02},
  publisher    = {Nature Publishing Group},
  series       = {Scientific Reports},
  title        = {ISL1 is a major susceptibility gene for classic bladder exstrophy and a regulator of urinary tract development},
  url          = {http://dx.doi.org/10.1038/srep42170},
  volume       = {7},
  year         = {2017},
}