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

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.

“Summer Shift”: A Potential Effect of Sunshine on the Time Onset of ST‐Elevation Acute Myocardial Infarction

“…Other important issues that need clarification are the genetic and ethnic background, which could influence circadian rhythms and seasonal patterns, even if this study found that the pattern of a summer shift can be observed in different ethnic and genetic backgrounds. Discovering molecular pathways associated with diseases plays a pivotal role in understanding the relation between cardiological pathologies and genetic factors 37. We hope our findings will represent a convincing starting point for future studies to elucidate the molecular control factors and mechanisms behind these and even more complicated seasonal/circadian physiopathological phenomena, and we posit they could well have clinical implications on prognosis and treatment of cardiovascular disease 38…”

Molecular mechanisms of cryptorchidism development: update of the database, disease comorbidity, and initiative for standardization of reporting in scientific literature

“…Disease comorbidity has been also reported, for instance, cryptorchidism is also commonly associated to hypospadias and micropenis (Klonisch et al, 2004). Additionally, a molecular explanation for co-presence of cryptorchidism and cardiomyopathy; frequent clinical features co-present in RASopathies has also been proposed (Cannistraci et al, 2013).…”

“…Diverse candidate genomic variations involved in cryptorchidism development have been reported and 217 genomic variations from seven mammalian species (human, horse, sheep, dog, cattle, rat, and mouse) were cataloged in our previously developed Cryptorchidism gene database (CryptoGene DB) (Cannistraci et al, 2013). A comparative approach is important when researching complex diseases such as cryptorchidism.…”

“…Beside environmental factors like endocrine disruptors, cryptorchidism is at least in part determined by genetic causes (Klonisch et al, 2004;Cannistraci et al, 2013). Diverse candidate genomic variations involved in cryptorchidism development have been reported and 217 genomic variations from seven mammalian species (human, horse, sheep, dog, cattle, rat, and mouse) were cataloged in our previously developed Cryptorchidism gene database (CryptoGene DB) (Cannistraci et al, 2013).…”

Initiative for standardization of reporting genetics of male infertility

“…Considering risks of transmitting an abnormal paternal genotype to the descendant, an appropriate database would enable the quantification of such risks. Similarly, we have developed catalogs of genomics data in other fields, for instance molecular mechanisms involved in cryptorchidism development [Cannistraci et al 2013]. Standardization of reporting may be necessary when combining data sets from several manuscripts.…”