TY - JOUR T1 - ISL1 is a major susceptibility gene for classic bladder exstrophy and a regulator of urinary tract development. JF - Sci Rep Y1 - 2017 A1 - Zhang, Rong A1 - Knapp, Michael A1 - Suzuki, Kentaro A1 - Kajioka, Daiki A1 - Schmidt, Johanna M A1 - Winkler, Jonas A1 - Yilmaz, Öznur A1 - Pleschka, Michael A1 - Cao, Jia A1 - Kockum, Christina Clementson A1 - Barker, Gillian A1 - Holmdahl, Gundela A1 - Beaman, Glenda A1 - Keene, David A1 - Woolf, Adrian S A1 - Cervellione, Raimondo M A1 - Cheng, Wei A1 - Wilkins, Simon A1 - Gearhart, John P A1 - Sirchia, Fabio A1 - Di Grazia, Massimo A1 - Ebert, Anne-Karolin A1 - Rösch, Wolfgang A1 - Ellinger, Jörg A1 - Jenetzky, Ekkehart A1 - Zwink, Nadine A1 - Feitz, Wout F A1 - Marcelis, Carlo A1 - Schumacher, Johannes A1 - Martinón-Torres, Federico A1 - Hibberd, Martin Lloyd A1 - Khor, Chiea Chuen A1 - Heilmann-Heimbach, Stefanie A1 - Barth, Sandra A1 - Boyadjiev, Simeon A A1 - Brusco, Alfredo A1 - Ludwig, Michael A1 - Newman, William A1 - Nordenskjöld, Agneta A1 - Yamada, Gen A1 - Odermatt, Benjamin A1 - Reutter, Heiko KW - Animals KW - Bladder Exstrophy KW - Embryo, Mammalian KW - Female KW - Gene Expression Regulation, Developmental KW - Genetic Predisposition to Disease KW - Humans KW - Larva KW - LIM-Homeodomain Proteins KW - Mesoderm KW - Mice KW - Organogenesis KW - Polymorphism, Single Nucleotide KW - Pronephros KW - Protein Isoforms KW - Transcription Factors KW - Urinary Tract KW - Zebrafish 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). A meta-analysis of rs6874700 of our previous and present study showed a p value of 9.2 × 10. 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.

VL - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28176844?dopt=Abstract ER -