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 Phillip 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 A. Boyadjiev, Alfredo Brusco, Michael Ludwig, William Newman, Agneta Nordenskjöld, Gen Yamada, Benjamin Odermatt, Heiko Reutter

Research output: Contribution to journalArticle

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

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Bladder Exstrophy
Urinary Tract
Genes
Pronephros
Developmental Biology
Cell Lineage
Mesoderm
Zebrafish
North America
Larva
Meta-Analysis
Urinary Bladder
Embryonic Structures
Genotype
Genome

ASJC Scopus subject areas

  • General

Cite this

Zhang, R., Knapp, M., Suzuki, K., Kajioka, D., Schmidt, J. M., Winkler, J., ... 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

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; Kockum, Christina Clementson; Barker, Gillian; Holmdahl, Gundela; Beaman, Glenda; Keene, David; Woolf, Adrian S.; Cervellione, Raimondo M.; Cheng, Wei; Wilkins, Simon; Gearhart, John Phillip; Sirchia, Fabio; Di Grazia, Massimo; Ebert, Anne Karolin; Rösch, Wolfgang; Ellinger, Jörg; Jenetzky, Ekkehart; Zwink, Nadine; Feitz, Wout F.; Marcelis, Carlo; Schumacher, Johannes; Martinón-Torres, Federico; Hibberd, Martin Lloyd; Khor, Chiea Chuen; Heilmann-Heimbach, Stefanie; Barth, Sandra; Boyadjiev, Simeon A.; Brusco, Alfredo; Ludwig, Michael; Newman, William; Nordenskjöld, Agneta; Yamada, Gen; Odermatt, Benjamin; Reutter, Heiko.

In: Scientific Reports, Vol. 7, 42170, 08.02.2017.

Research output: Contribution to journalArticle

Zhang, R, Knapp, M, Suzuki, K, Kajioka, D, Schmidt, JM, Winkler, J, Yilmaz, Ö, Pleschka, M, Cao, J, Kockum, CC, Barker, G, Holmdahl, G, Beaman, G, Keene, D, Woolf, AS, Cervellione, RM, Cheng, W, Wilkins, S, Gearhart, JP, Sirchia, F, Di Grazia, M, Ebert, AK, Rösch, W, Ellinger, J, Jenetzky, E, Zwink, N, Feitz, WF, Marcelis, C, Schumacher, J, Martinón-Torres, F, Hibberd, ML, Khor, CC, Heilmann-Heimbach, S, Barth, S, Boyadjiev, SA, Brusco, A, Ludwig, M, Newman, W, Nordenskjöld, A, Yamada, G, Odermatt, B & Reutter, H 2017, 'ISL1 is a major susceptibility gene for classic bladder exstrophy and a regulator of urinary tract development', Scientific Reports, vol. 7, 42170. https://doi.org/10.1038/srep42170
Zhang, Rong ; Knapp, Michael ; Suzuki, Kentaro ; Kajioka, Daiki ; Schmidt, Johanna M. ; Winkler, Jonas ; Yilmaz, Öznur ; Pleschka, Michael ; Cao, Jia ; Kockum, Christina Clementson ; Barker, Gillian ; Holmdahl, Gundela ; Beaman, Glenda ; Keene, David ; Woolf, Adrian S. ; Cervellione, Raimondo M. ; Cheng, Wei ; Wilkins, Simon ; Gearhart, John Phillip ; Sirchia, Fabio ; Di Grazia, Massimo ; Ebert, Anne Karolin ; Rösch, Wolfgang ; Ellinger, Jörg ; Jenetzky, Ekkehart ; Zwink, Nadine ; Feitz, Wout F. ; Marcelis, Carlo ; Schumacher, Johannes ; Martinón-Torres, Federico ; Hibberd, Martin Lloyd ; Khor, Chiea Chuen ; Heilmann-Heimbach, Stefanie ; Barth, Sandra ; Boyadjiev, Simeon A. ; Brusco, Alfredo ; Ludwig, Michael ; Newman, William ; Nordenskjöld, Agneta ; Yamada, Gen ; Odermatt, Benjamin ; Reutter, Heiko. / ISL1 is a major susceptibility gene for classic bladder exstrophy and a regulator of urinary tract development. In: Scientific Reports. 2017 ; Vol. 7.
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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.",
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T1 - ISL1 is a major susceptibility gene for classic bladder exstrophy and a regulator of urinary tract development

AU - Zhang, Rong

AU - Knapp, Michael

AU - Suzuki, Kentaro

AU - Kajioka, Daiki

AU - Schmidt, Johanna M.

AU - Winkler, Jonas

AU - Yilmaz, Öznur

AU - Pleschka, Michael

AU - Cao, Jia

AU - Kockum, Christina Clementson

AU - Barker, Gillian

AU - Holmdahl, Gundela

AU - Beaman, Glenda

AU - Keene, David

AU - Woolf, Adrian S.

AU - Cervellione, Raimondo M.

AU - Cheng, Wei

AU - Wilkins, Simon

AU - Gearhart, John Phillip

AU - Sirchia, Fabio

AU - Di Grazia, Massimo

AU - Ebert, Anne Karolin

AU - Rösch, Wolfgang

AU - Ellinger, Jörg

AU - Jenetzky, Ekkehart

AU - Zwink, Nadine

AU - Feitz, Wout F.

AU - Marcelis, Carlo

AU - Schumacher, Johannes

AU - Martinón-Torres, Federico

AU - Hibberd, Martin Lloyd

AU - Khor, Chiea Chuen

AU - Heilmann-Heimbach, Stefanie

AU - Barth, Sandra

AU - Boyadjiev, Simeon A.

AU - Brusco, Alfredo

AU - Ludwig, Michael

AU - Newman, William

AU - Nordenskjöld, Agneta

AU - Yamada, Gen

AU - Odermatt, Benjamin

AU - Reutter, Heiko

PY - 2017/2/8

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