Pivotal role of the muscle-contraction pathway in cryptorchidism and evidence for genomic connections with cardiomyopathy pathways in RASopathies

Carlo V Cannistraci,Timothy Ravasi,Peter Dovc,Tanja Kunej,Minja Zorc,Jernej Ogorevc

doi:10.1186/1755-8794-6-5

Abstract

BackgroundCryptorchidism is the most frequent congenital disorder in male children; however the genetic causes of cryptorchidism remain poorly investigated. Comparative integratomics combined with systems biology approach was employed to elucidate genetic factors and molecular pathways underlying testis descent.MethodsLiterature mining was performed to collect genomic loci associated with cryptorchidism in seven mammalian species. Information regarding the collected candidate genes was stored in MySQL relational database. Genomic view of the loci was presented using Flash GViewer web tool (http://gmod.org/wiki/Flashgviewer/). DAVID Bioinformatics Resources 6.7 was used for pathway enrichment analysis. Cytoscape plug-in PiNGO 1.11 was employed for protein-network-based prediction of novel candidate genes. Relevant protein-protein interactions were confirmed and visualized using the STRING database (version 9.0).ResultsThe developed cryptorchidism gene atlas includes 217 candidate loci (genes, regions involved in chromosomal mutations, and copy number variations) identified at the genomic, transcriptomic, and proteomic level. Human orthologs of the collected candidate loci were presented using a genomic map viewer. The cryptorchidism gene atlas is freely available online: http://www.integratomics-time.com/cryptorchidism/. Pathway analysis suggested the presence of twelve enriched pathways associated with the list of 179 literature-derived candidate genes. Additionally, a list of 43 network-predicted novel candidate genes was significantly associated with four enriched pathways. Joint pathway analysis of the collected and predicted candidate genes revealed the pivotal importance of the muscle-contraction pathway in cryptorchidism and evidence for genomic associations with cardiomyopathy pathways in RASopathies.ConclusionsThe developed gene atlas represents an important resource for the scientific community researching genetics of cryptorchidism. The collected data will further facilitate development of novel genetic markers and could be of interest for functional studies in animals and human. The proposed network-based systems biology approach elucidates molecular mechanisms underlying co-presence of cryptorchidism and cardiomyopathy in RASopathies. Such approach could also aid in molecular explanation of co-presence of diverse and apparently unrelated clinical manifestations in other syndromes.

Highlights

Cryptorchidism is the most frequent congenital disorder in male children; the genetic causes of cryptorchidism remain poorly investigated
The developed gene atlas represents an important resource for the scientific community researching genetics of cryptorchidism
In search for CO associated candidate loci seven different research approaches were considered: (i) chromosomal abnormalities associated with CO, (ii) copy number variations, (iii) clinical syndromes with known genetic mutations that feature CO, (iv) transgenes and knock-outs that result in CO associated phenotypes, (v) association studies/mutation screening that show association between sequence variation/mutation screening and CO, (vi) expression patterns associated with CO, and (vii) candidates associated with CO at proteomic level

Summary

Introduction

Cryptorchidism is the most frequent congenital disorder in male children; the genetic causes of cryptorchidism remain poorly investigated. Cryptorchidism (CO) is the most frequent congenital disorder in male children (2-4% of full-term male births) and is defined as incomplete descent of one (unilateral) or both (bilateral) testes and associated structures. Cryptorchidism has a potential effect on health; defects in testes descent usually cause impaired spermatogenesis, resulting in reduced fertility and increased rates of testicular neoplasia, and testicular torsion (reviewed in [1]). In most species, including human, the complete descent of testes usually occurs prenatally, while in some (e.g. dogs), postnatally. Beside environmental factors like endocrine disruptors, CO is at least in part determined by genetic causes (chromosome or gene mutations), and is often a common feature of different syndromes. Klinefelter syndrome and mutations in INSL3 gene have already been recognized as a cause of CO in some cases [3]

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