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Genes 2018, 9(12), 609;

Towards a Central Role of ISL1 in the Bladder Exstrophy–Epispadias Complex (BEEC): Computational Characterization of Genetic Variants and Structural Modelling

Department of Neurology, University Clinic Bonn, 53105, Bonn, Germany
Department of Ophthalmology, University Hospital Bonn, 53127 Bonn, Germany
Department of Biotechnology, Mohanlal Sukhadia University Udaipur, 313001, Rajasthan, India
Department of Clinical Chemistry and Clinical Pharmacology, University Hospital of Bonn, 53105 Bonn, Germany
Bonn-Aachen International Center for IT, University of Bonn, 53115 Bonn, Germany
Department of Biosciences, Manipal University Jaipur, 303007 Jaipur, Rajasthan, India
Institute of Human Genetics, University Hospital of Bonn, 53127 Bonn, Germany
Department of Genomics, Life & Brain Center, 53127 Bonn, Germany
Department of Neonatology and Pediatric Intensive Care, Children’s Hospital, University of Bonn, 53113 Bonn, Germany
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Received: 26 November 2018 / Accepted: 28 November 2018 / Published: 5 December 2018
(This article belongs to the Section Technologies and Resources for Genetics)
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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. View Full-Text
Keywords: ISL1; classic bladder exstrophy; STRING analysis ISL1; classic bladder exstrophy; STRING analysis

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Sharma, A.; Dakal, T.C.; Ludwig, M.; Fröhlich, H.; Mathur, R.; Reutter, H. Towards a Central Role of ISL1 in the Bladder Exstrophy–Epispadias Complex (BEEC): Computational Characterization of Genetic Variants and Structural Modelling. Genes 2018, 9, 609.

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