6533b833fe1ef96bd129b7b9

RESEARCH PRODUCT

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

Fabio SirchiaAdrian S. WoolfAdrian S. WoolfJonas WinklerChiea Chuen KhorSimon WilkinsBenjamin OdermattJohanna M. SchmidtWolfgang RöschJohannes SchumacherEkkehart JenetzkyEkkehart JenetzkyÖZnur YilmazHeiko ReutterChristina Clementson KockumMichael LudwigSimeon A. BoyadjievGillian BarkerDavid KeeneFederico Martinon-torresAnne K. EbertJia CaoDaiki KajiokaWilliam G. NewmanRong ZhangSandra BarthJörg EllingerNadine ZwinkMichael KnappJohn P. GearhartMichael PleschkaCarlo MarcelisGlenda M. BeamanStefanie Heilmann-heimbachKentaro SuzukiGen YamadaAgneta NordenskjöldAgneta NordenskjöldWout F.j. FeitzAlfredo BruscoGundela HolmdahlRaimondo M. CervellioneWei ChengWei ChengMassimo Di GraziaMartin L. Hibberd

subject

0301 basic medicinemedicine.medical_specialtyPathologyMesenchymeUrinary systemOrganogenesisLIM-Homeodomain ProteinsLocus (genetics)030105 genetics & heredityBiologyPolymorphism Single Nucleotidebladder extrophyArticlePronephrosMesoderm03 medical and health sciencesMiceBEEC bladder extrophy urinary tract development ISL1GenotypemedicineAnimalsHumansProtein IsoformsGenetic Predisposition to DiseaseBEECUrinary TractGeneZebrafishGeneticsMultidisciplinaryBladder ExstrophyGene Expression Regulation DevelopmentalISL1medicine.diseaseEmbryo Mammalianurinary tract developmentBladder exstrophy030104 developmental biologymedicine.anatomical_structureReconstructive and regenerative medicine Radboud Institute for Molecular Life Sciences [Radboudumc 10]LarvaISL1Medical geneticsFemaleTranscription FactorsRare cancers Radboud Institute for Health Sciences [Radboudumc 9]

description

AbstractPreviously 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.

10.1038/srep42170http://dx.doi.org/10.1038/srep42170