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Sci Rep. 2017 Feb 8;7:42170. doi: 10.1038/srep42170.

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

Author information

1
Institute of Human Genetics, University of Bonn, Bonn, Germany.
2
Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany.
3
Institute of Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany.
4
Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical University, Japan.
5
Institute of Anatomy, University of Bonn, Bonn, Germany.
6
Department of Women´s and Children´s Health and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
7
Department of Pediatric Surgery, University Hospital Lund, Lund, Sweden.
8
Department of Women's and Children's Health, Uppsala Academic Children Hospital, Uppsala, Sweden.
9
Department of Pediatric Surgery, Queen Silvias Children's Hospital, Gothenburg, Sweden.
10
Centre for Genomic Medicine, University of Manchester, Manchester, UK.
11
Paediatric Urology, Royal Manchester Children's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
12
Institute of Human Development, University of Manchester, Manchester Academic Health Science, Centre, Manchester, UK.
13
Royal Manchester Children's Hospital, Manchester, Manchester, UK.
14
Department of Pediatric Surgery, Capital Institute of Pediatrics, Beijing, People's Republic of China.
15
Department of Paediatrics and Department of Surgery, Southern Medical School, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia.
16
Department of Surgery, Beijing United Family Hospital, Beijing, People's Republic of China.
17
Cabrini Monash University Department of Surgery, Cabrini Hospital, Melbourne, Australia.
18
Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Australia.
19
Division of Pediatric Urology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
20
Department of Medical Sciences and Medical Genetics Unit, Città della Salute e della Scienza University Hospital, University of Torino, Torino, Italy.
21
Institute for Maternal and Child Health, IRCCS Burlo Garofalo, Trieste, Italy.
22
Department of Urology and Pediatric Urology, University Hospital of Ulm, Germany.
23
Department of Pediatric Urology, St. Hedwig Hospital Barmherzige Brüder, Regensburg, Germany.
24
Department of Urology, University Hospital Bonn, Bonn, Germany.
25
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany.
26
Department of Child and Adolescent Psychiatry and Psychotherapy, Johannes-Gutenberg University, Mainz, Germany.
27
Department of Urology, Pediatric Urology Center, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
28
Department of Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
29
Translational Pediatrics and Infectious Diseases, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain.
30
GENVIP Research Group (www.genvip.org), Instituto de Investigación Sanitaria de Santiago, Galicia, Spain.
31
Genome Institute of Singapore, Singapore.
32
Division of Genomic Medicine, Department of Pediatrics, University of California Davis Medical Center, Sacramento, CA, USA.
33
Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany.
34
Pediatric Surgery, Astrid Lindgren Children Hospital, Karolinska University Hospital, Stockholm, Sweden.
35
Department of Neonatology &Pediatric Intensive Care, Children's Hospital; University of Bonn, Bonn, Germany.

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.

PMID:
28176844
PMCID:
PMC5296905
DOI:
10.1038/srep42170
[Indexed for MEDLINE]
Free PMC Article

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