Abstract
Genetic factors play a critical role in the development of human diseases. Recently, several molecular genetic studies have provided multiple lines of evidence for a critical role of genetic factors in the expression of human bladder exstrophy-epispadias complex (BEEC). At this point, ISL1 (ISL LIM homeobox 1) has emerged as the major susceptibility gene for classic bladder exstrophy (CBE), in a multifactorial disease model. Here, GWAS (Genome wide association studies) discovery and replication studies, as well as the re-sequencing of ISL1, identified sequence variants (rs9291768, rs6874700, c.137C > G (p.Ala46Gly)) associated with CBE. Here, we aimed to determine the molecular and functional consequences of these sequence variants and estimate the dependence of ISL1 protein on other predicted candidates. We used: (i) computational analysis of conserved sequence motifs to perform an evolutionary conservation analysis, based on a Bayesian algorithm, and (ii) computational 3D structural modeling. Furthermore, we looked into long non-coding RNAs (lncRNAs) residing within the ISL1 region, aiming to predict their targets. Our analysis suggests that the ISL1 protein specific N-terminal LIM domain (which harbors the variant c.137C > G), limits its transcriptional ability, and might interfere with ISL1-estrogen receptor α interactions. In conclusion, our analysis provides further useful insights about the ISL1 gene, which is involved in the formation of the BEEC, and in the development of the urinary bladder.
Highlights
The bladder exstrophy–epispadias complex (BEEC) is the most severe of all 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 [1]
We found that all rsIDs showed a GWAVA score less than 0.5, which indicates that the variants are non-functional and they are likely to be associated with the disease conditions (Supplementary File 4)
Since ISL1 and PARP8 are the only protein coding genes mapped closely to rs9291768, we considered the mRNA of these two genes for further analysis
Summary
The bladder exstrophy–epispadias complex (BEEC) is the most severe of all 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 [1]. Within the severity-spectrum of the BEEC, classic bladder exstrophy (CBE) represents the most common form, with an estimated birth-prevalence of about 1 in 37,000 live births having exstrophy–epispadias complex and bladder abnormalities [2]. Using genome-wide association methods in CBE patients of Central European background, we found an association with a region of approximately 220 kb on chromosome 5q11.1. This region harbors the ISL1 (ISL LIM homeobox 1) gene, a master control gene expressed in pericloacal mesenchyme. Multiple markers in this region showed evidence for an association with CBE, including
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
