Open Access Research article

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

Carlo V Cannistraci123*, Jernej Ogorevc4, Minja Zorc4, Timothy Ravasi1, Peter Dovc4 and Tanja Kunej4*

Author Affiliations

1 Integrative Systems Biology Laboratory, Biological and Environmental Sciences and Engineering Division, Computer, Electrical and Mathematical Sciences and Engineering Division, Computational Bioscience Research Center, King Abdullah University for Science and Technology (KAUST), Thuwal, Saudi Arabia

2 Department of Mechanics, Politecnico di Torino, Turin, Italy

3 Proteome Biochemistry Unit, San Raffaele Scientific Institute, Milan, Italy

4 Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Domzale, Slovenia

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BMC Medical Genomics 2013, 6:5  doi:10.1186/1755-8794-6-5

Published: 14 February 2013



Cryptorchidism 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.


Literature 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 ( 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).


The 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: 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.


The 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.

Cryptorchidism; Muscle-contraction pathway; Cardiomyopathy; Comparative integratomics; Protein-protein interactions; Systems biology; Undescended testes; RASopathy