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 - TY - JOUR T1 - CNV analysis in 169 patients with bladder exstrophy-epispadias complex. JF - BMC Med Genet Y1 - 2016 A1 - von Lowtzow, Catharina A1 - Hofmann, Andrea A1 - Zhang, Rong A1 - Marsch, Florian A1 - Ebert, Anne-Karoline A1 - Rösch, Wolfgang A1 - Stein, Raimund A1 - Boemers, Thomas M A1 - Hirsch, Karin A1 - Marcelis, Carlo A1 - Feitz, Wouter F J A1 - Brusco, Alfredo A1 - Migone, Nicola A1 - Di Grazia, Massimo A1 - Moebus, Susanne A1 - Nöthen, Markus M A1 - Reutter, Heiko A1 - Ludwig, Michael A1 - Draaken, Markus AB -

BACKGROUND: The bladder exstrophy-epispadias complex (BEEC) represents the severe end of the congenital uro-rectal malformation spectrum. Initial studies have implicated rare copy number variations (CNVs), including recurrent duplications of chromosomal region 22q11.21, in BEEC etiology.

METHODS: To detect further CNVs, array analysis was performed in 169 BEEC patients. Prior to inclusion, 22q11.21 duplications were excluded using multiplex ligation-dependent probe amplification.

RESULTS: Following the application of stringent filter criteria, seven rare CNVs were identified: n = 4, not present in 1307 in-house controls; n = 3, frequency of <0.002 in controls. These CNVs ranged from 1 to 6.08 Mb in size. To identify smaller CNVs, relaxed filter criteria used in the detection of previously reported BEEC associated chromosomal regions were applied. This resulted in the identification of six additional rare CNVs: n = 4, not present in 1307 in-house controls; n = 2, frequency <0.0008 in controls. These CNVs ranged from 0.03-0.08 Mb in size. For 10 of these 13 CNVs, confirmation and segregation analyses were performed (5 of maternal origin; 5 of paternal origin). Interestingly, one female with classic bladder extrophy carried a 1.18 Mb duplication of 22q11.1, a chromosomal region that is associated with cat eye syndrome.

CONCLUSIONS: A number of rare CNVs were identified in BEEC patients, and these represent candidates for further evaluation. Rare inherited CNVs may constitute modifiers of, or contributors to, multifactorial BEEC phenotypes.

VL - 17 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27138190?dopt=Abstract ER -