Abstract
Background and Objective: Mild hypospadias is a birth congenital condition characterized by the relocation of the male urethral meatus from its typical anatomical position near the tip of the glans penis, to a lower ventral position up to the brim of the glans corona, which can also be accompanied by foreskin ventral deficiency. For the most part, a limited number of cases have known etiology. We have followed a high-throughput proteomics approach to study the proteome in mild hypospadias patients.Methods: Foreskin samples from patients with mild hypospadias were collected during urethroplasty, while control samples were collected during elective circumcision (n = 5/group). A high-throughput, quantitative proteomics approach based on multiplexed peptide stable isotope labeling (SIL) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis was used to ascertain protein abundance changes in hypospadias patients when compared to control samples.Results: A total of 4,815 proteins were quantitated (2,522 with at least two unique peptides). One hundred and thirty-three proteins from patients with mild hypospadias showed significant abundance changes with respect to control samples, where 38 proteins were increased, and 95 proteins were decreased. Unbiased functional biological analysis revealed that both mitochondrial energy production and apoptotic signaling pathways were enriched in mild hypospadias.Conclusions: This first comprehensive proteomics characterization of mild hypospadias shows molecular changes associated with essential cellular processes related to energy production and apoptosis. Further evaluation of the proteome may expand the search of novel candidates in the etiology of mild hypospadias and could also lead to the identification of biomarkers for this congenital urogenital condition.
Highlights
Hypospadias is characterized by the localization of the urethral opening at any anatomical position on the ventral-medial side of the penis rather than near the tip of the glans
Polymorphisms, mutations, and epigenetic changes in the androgen receptor (AR), CYR61, hydroxysteroid (17-beta) dehydrogenase 3 (HSD17B3), HSD3B1, mastermind like domain containing 1 (MAMLD1), steroid-5-alphareductase 2 (SRD5A2), and stAR-related lipid transfer domain containing 3 (STARD3) have been associated to hypospadias risk in severe types of hypospadias that have not been found in mild hypospadias [26,27,28,29,30]
A multiplexed, quantitative proteomics approach based on 10plex TMT labeling and LC-MS/MS analysis was employed to identify and quantify proteins of foreskin tissue from mild hypospadias and control samples (n = 5/group)
Summary
Hypospadias is characterized by the localization of the urethral opening at any anatomical position on the ventral-medial side of the penis rather than near the tip of the glans. Polymorphisms, mutations, and epigenetic changes in the AR, CYR61, HSD17B3, HSD3B1, MAMLD1, SRD5A2, and STARD3 have been associated to hypospadias risk in severe types of hypospadias that have not been found in mild hypospadias [26,27,28,29,30]. Some examples of these include reduced AR gene methylation [31] and increased GGN or CAG repeat sequence of the AR gene [(32, 33); respectively]. We have followed a high-throughput proteomics approach to study the proteome in mild hypospadias patients
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