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.
Highlights
The bladder exstrophy-epispadias complex (BEEC; OMIM %600057) represents the severe end of human congenital anomalies of the kidney and urinary tract (CAKUT), and involves the abdominal wall, pelvis, all of the urinary tract, the genitalia, and occasionally the spine and anus
The analyzed data set for the case-control study comprised 268 classic bladder exstrophy (CBE) patients of Australian (n = 31), British (n = 40), German (n = 7), Italian (n = 39), Spanish (n = 35), and Swedish (n = 116) origin and 1,354 ethnically matched controls
A significant result was observed for the marker rs6874700 at chromosome 5q11.2, representing the ISL1 locus (p = 2.22 × 10−08)
Summary
The bladder exstrophy-epispadias complex (BEEC; OMIM %600057) represents the severe end of human congenital anomalies of the kidney and urinary tract (CAKUT), and involves the abdominal wall, pelvis, all of the urinary tract, the genitalia, and occasionally the spine and anus. This region harbors the ISL1 (ISL LIM homeobox 1) gene Multiple markers in this region showed evidence for association with CBE, including 84 markers with genome-wide significance. A total of 138 markers at this locus reached genome-wide significance in the meta-analysis. The present association study followed-up on the most promising genomic regions based on the results of our previous meta-analysis defined by a total of 12 independent markers. One of these markers resides in the ISL1 region and had previously reached genome-wide significance[5]. To better understand the role of ISL1 during genito-urinary tract development, we performed expression studies in mouse embryos and zebrafish larvae (zfl)
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