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Genes 2018, 9(12), 609; https://doi.org/10.3390/genes9120609

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

1
Department of Neurology, University Clinic Bonn, 53105, Bonn, Germany
2
Department of Ophthalmology, University Hospital Bonn, 53127 Bonn, Germany
3
Department of Biotechnology, Mohanlal Sukhadia University Udaipur, 313001, Rajasthan, India
4
Department of Clinical Chemistry and Clinical Pharmacology, University Hospital of Bonn, 53105 Bonn, Germany
5
Bonn-Aachen International Center for IT, University of Bonn, 53115 Bonn, Germany
6
Department of Biosciences, Manipal University Jaipur, 303007 Jaipur, Rajasthan, India
7
Institute of Human Genetics, University Hospital of Bonn, 53127 Bonn, Germany
8
Department of Genomics, Life & Brain Center, 53127 Bonn, Germany
9
Department of Neonatology and Pediatric Intensive Care, Children’s Hospital, University of Bonn, 53113 Bonn, Germany
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
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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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. 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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