ISL1 is a major susceptibility gene for classic bladder exstrophy and a regulator of urinary tract development.
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.
Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany.
Rong
R
Zhang
Institute of Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany.
Michael
M
Knapp
Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical University, Japan.
Kentaro
K
Suzuki
Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical University, Japan.
Daiki
D
Kajioka
Institute of Human Genetics, University of Bonn, Bonn, Germany.|Institute of Anatomy, University of Bonn, Bonn, Germany.
Johanna M
JM
Schmidt
Institute of Anatomy, University of Bonn, Bonn, Germany.
Jonas
J
Winkler
Institute of Anatomy, University of Bonn, Bonn, Germany.
Öznur
Ö
Yilmaz
Institute of Anatomy, University of Bonn, Bonn, Germany.
Michael
M
Pleschka
Department of Women´s and Children´s Health and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Jia
J
Cao
Department of Pediatric Surgery, University Hospital Lund, Lund, Sweden.
Christina Clementson
CC
Kockum
Department of Women's and Children's Health, Uppsala Academic Children Hospital, Uppsala, Sweden.
Gillian
G
Barker
Department of Pediatric Surgery, Queen Silvias Children's Hospital, Gothenburg, Sweden.
Gundela
G
Holmdahl
Centre for Genomic Medicine, University of Manchester, Manchester, UK.
Glenda
G
Beaman
Paediatric Urology, Royal Manchester Children's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
David
D
Keene
Institute of Human Development, University of Manchester, Manchester Academic Health Science, Centre, Manchester, UK.|Royal Manchester Children's Hospital, Manchester, Manchester, UK.
Adrian S
AS
Woolf
Paediatric Urology, Royal Manchester Children's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
Raimondo M
RM
Cervellione
Department of Pediatric Surgery, Capital Institute of Pediatrics, Beijing, People's Republic of China.|Department of Paediatrics and Department of Surgery, Southern Medical School, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia.|Department of Surgery, Beijing United Family Hospital, Beijing, People's Republic of China.
Wei
W
Cheng
Cabrini Monash University Department of Surgery, Cabrini Hospital, Melbourne, Australia.|Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Australia.
Simon
S
Wilkins
Division of Pediatric Urology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
John P
JP
Gearhart
Department of Medical Sciences and Medical Genetics Unit, Città della Salute e della Scienza University Hospital, University of Torino, Torino, Italy.
Fabio
F
Sirchia
Institute for Maternal and Child Health, IRCCS Burlo Garofalo, Trieste, Italy.
Massimo
M
Di Grazia
Department of Urology and Pediatric Urology, University Hospital of Ulm, Germany.
Anne-Karolin
AK
Ebert
Department of Pediatric Urology, St. Hedwig Hospital Barmherzige Brüder, Regensburg, Germany.
Wolfgang
W
Rösch
Department of Urology, University Hospital Bonn, Bonn, Germany.
Jörg
J
Ellinger
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany.|Department of Child and Adolescent Psychiatry and Psychotherapy, Johannes-Gutenberg University, Mainz, Germany.
Ekkehart
E
Jenetzky
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany.
Nadine
N
Zwink
Department of Urology, Pediatric Urology Center, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
Wout F
WF
Feitz
Department of Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
Carlo
C
Marcelis
Institute of Human Genetics, University of Bonn, Bonn, Germany.
Johannes
J
Schumacher
Translational Pediatrics and Infectious Diseases, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain.|GENVIP Research Group (www.genvip.org), Instituto de Investigación Sanitaria de Santiago, Galicia, Spain.
Federico
F
Martinón-Torres
Genome Institute of Singapore, Singapore.
Martin Lloyd
ML
Hibberd
Division of Genomic Medicine, Department of Pediatrics, University of California Davis Medical Center, Sacramento, CA, USA.
Chiea Chuen
CC
Khor
Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany.
Stefanie
S
Heilmann-Heimbach
Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany.
Sandra
S
Barth
Division of Genomic Medicine, Department of Pediatrics, University of California Davis Medical Center, Sacramento, CA, USA.
Simeon A
SA
Boyadjiev
Department of Medical Sciences and Medical Genetics Unit, Città della Salute e della Scienza University Hospital, University of Torino, Torino, Italy.
Alfredo
A
Brusco
Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany.
Michael
M
Ludwig
Centre for Genomic Medicine, University of Manchester, Manchester, UK.
William
W
Newman
Department of Women´s and Children´s Health and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.|Pediatric Surgery, Astrid Lindgren Children Hospital, Karolinska University Hospital, Stockholm, Sweden.
Agneta
A
Nordenskjöld
Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical University, Japan.
Gen
G
Yamada
Institute of Anatomy, University of Bonn, Bonn, Germany.
Benjamin
B
Odermatt
Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Neonatology &Pediatric Intensive Care, Children's Hospital; University of Bonn, Bonn, Germany.
Heiko
H
Reutter
D000818:Animals; D001746:Bladder Exstrophy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004622:Embryo, Mammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental; D020022:Genetic Predisposition to Disease; D006801:Humans; D060850:LIM-Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D007814:Larva / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D008648:Mesoderm / Q000002:abnormalities / Q000254:growth & development / Q000378:metabolism*; D051379:Mice; D038081:Organogenesis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D060910:Pronephros / Q000254:growth & development / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014551:Urinary Tract / Q000002:abnormalities / Q000254:growth & development / Q000378:metabolism*; D015027:Zebrafish
D060850:LIM-Homeodomain Proteins; D020033:Protein Isoforms; D014157:Transcription Factors; C063843:insulin gene enhancer binding protein Isl-1