@article {10492, title = {ISL1 is a major susceptibility gene for classic bladder exstrophy and a regulator of urinary tract development.}, journal = {Sci Rep}, volume = {7}, year = {2017}, month = {2017 02 08}, pages = {42170}, 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 {\texttimes} 10). A meta-analysis of rs6874700 of our previous and present study showed a p value of 9.2 {\texttimes} 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.

}, keywords = {Animals, Bladder Exstrophy, Embryo, Mammalian, Female, Gene Expression Regulation, Developmental, Genetic Predisposition to Disease, Humans, Larva, LIM-Homeodomain Proteins, Mesoderm, Mice, Organogenesis, Polymorphism, Single Nucleotide, Pronephros, Protein Isoforms, Transcription Factors, Urinary Tract, Zebrafish}, issn = {2045-2322}, doi = {10.1038/srep42170}, author = {Zhang, Rong and Knapp, Michael and Suzuki, Kentaro and Kajioka, Daiki and Schmidt, Johanna M and Winkler, Jonas and Yilmaz, {\"O}znur and Pleschka, Michael and Cao, Jia and Kockum, Christina Clementson and Barker, Gillian and Holmdahl, Gundela and Beaman, Glenda and Keene, David and Woolf, Adrian S and Cervellione, Raimondo M and Cheng, Wei and Wilkins, Simon and Gearhart, John P and Sirchia, Fabio and Di Grazia, Massimo and Ebert, Anne-Karolin and R{\"o}sch, Wolfgang and Ellinger, J{\"o}rg and Jenetzky, Ekkehart and Zwink, Nadine and Feitz, Wout F and Marcelis, Carlo and Schumacher, Johannes and Martin{\'o}n-Torres, Federico and Hibberd, Martin Lloyd and Khor, Chiea Chuen and Heilmann-Heimbach, Stefanie and Barth, Sandra and Boyadjiev, Simeon A and Brusco, Alfredo and Ludwig, Michael and Newman, William and Nordenskj{\"o}ld, Agneta and Yamada, Gen and Odermatt, Benjamin and Reutter, Heiko} } @article {8352, title = {CNV analysis in 169 patients with bladder exstrophy-epispadias complex.}, journal = {BMC Med Genet}, volume = {17}, year = {2016}, month = {2016}, pages = {35}, abstract = {

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.

}, issn = {1471-2350}, doi = {10.1186/s12881-016-0299-x}, author = {von Lowtzow, Catharina and Hofmann, Andrea and Zhang, Rong and Marsch, Florian and Ebert, Anne-Karoline and R{\"o}sch, Wolfgang and Stein, Raimund and Boemers, Thomas M and Hirsch, Karin and Marcelis, Carlo and Feitz, Wouter F J and Brusco, Alfredo and Migone, Nicola and Di Grazia, Massimo and Moebus, Susanne and N{\"o}then, Markus M and Reutter, Heiko and Ludwig, Michael and Draaken, Markus} }