TY - JOUR
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 P.
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
N1 - Funding Information:
We acknowledge the assistance of the German (www.blasenekstrophie.de), Spanish (www.extrofia.info/ asafex), and Italian (www.estrofiavescicale.it) self-help organizations in the recruitment of patients with CBE. A.-K.E., W.R., E.J., N.Z., M.L., and H.R. are members of the "Network for the Systematic Investigation of the Molecular Causes, Clinical Implications, and Psychosocial Outcome of Congenital Uro-Rectal Malformations (CURE-Net)". H.R. is supported by grant RE 1723/1-1 from the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG). J.M.S. is supported by the BONFOR program of the University of Bonn (grant number O-149.0112). E.J. is supported by grant JE 681/3-1 from the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG). A.S.W. is supported by a grant from the Medical Research Council (MR/ L002744/1), Kids Kidney Research, Newlife Foundation and Kidneys for Life. F.M.-T. has received support from Consellería de Sanidade, Xunta de Galicia (RHI07/2-intensificación actividad investigadora, PS09749 and 10PXIB918184PR), Instituto Carlos III (Intensificación de la actividad investigadora 2007-2012), Convenio de colaboración de investigación (Wyeth España-Fundación IDICHUS 2007-2011), Convenio de colaboración de investigación (Novartis España-Fundación IDICHUS 2010-2011), Fondo de Investigación Sanitaria (FIS; PI070069/PI1000540) del plan nacional de I + D + I and 'fondos FEDER' (F.M.T.). More information at: www. esigem.org/www.genvip.org. S.A.B. was partially funded by the grant and Endowed Chair from the Children's Miracle Network. W.C. and S.W. were supported by grants from Jack Brockhoff Foundation (#3095, 2010), the Helen Macpherson Smith Trust (#6940, 2010), and the Marian and E.H. Flack Trust.
Publisher Copyright:
© The Author(s) 2017.
PY - 2017/2/8
Y1 - 2017/2/8
N2 - 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.
AB - 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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U2 - 10.1038/srep42170
DO - 10.1038/srep42170
M3 - Article
C2 - 28176844
AN - SCOPUS:85011949097
SN - 2045-2322
VL - 7
JO - Scientific reports
JF - Scientific reports
M1 - 42170
ER -