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New frontiers on the molecular underpinnings of hypospadias according to severity.

ABSTRACT: Hypospadias, which is characterised by the displacement of the urethral meatus from its typical anatomical location in males, shows various degrees of severity. In this systematic review, we surveyed our current understanding of the genetics of isolated hypospadias in humans according to the severity of the condition. We found that sequencing and genotyping approaches were the preferred methods of study and that single nucleotide polymorphisms were the most common finding associated with hypospadias. Most genes fell into four gene-pathway categories related to androgens, oestrogens, growth factors, or transcription factors. Few hypospadias studies classify their findings by severity. Taken together, we argue that it is advantageous to take into consideration the severity of the condition in search of novel candidates in the aetiology of hypospadias. Abbreviations: AR: androgen receptor; ATF3: activating transcription factor 3; BMP4: bone morphogenetic protein 4; BMP7: bone morphogenetic protein 7; CYP17: steroid 17-alpha-hydroxylase/17,20 lyase; CYP1A1: cytochrome P450 1A1; CYP3A4: cytochrome P450 3A4; CNVs: copy number variants; DGKK: diacylglycerol kinase kappa; ESR1: oestrogen receptor 1; ESR2: oestrogen receptor 2; FGF8: fibroblast growth factor 8; FGF10: fibroblast growth factor 10; FGFR2: fibroblast growth factor receptor 2; HOXA4: homeobox protein Hox-A4; HOXB6: homeobox protein Hox-B6; HSD17B3: hydroxysteroid 17-beta dehydrogenase 3; MAMLD1: mastermind-like domain-containing protein 1; SF-1: splicing factor 1; SHH: sonic hedgehog; SNPs: single nucleotide polymorphisms; SOX9: SRY-box 9; SRD5A2: steroid 5 alpha-reductase 2; SRY: sex-determining region Y protein; STAR: steroidogenic acute regulatory protein; STARD3: StAR-related lipid transfer protein 3; STS: steryl-sulfatase; WT1: Wilms tumour protein; ZEB1: zinc finger oestrogen-box binding homeobox 1.

SUBMITTER: Pineyro-Ruiz C

PROVIDER: S-EPMC7717703 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Hypospadias, characterized by the displacement of the opening of the urethra at any point in the medial-ventral side of the penis, is classified upon severity as mild (Type I) and severe (Type II and Type III) hypospadias. Hypospadias’ etiology is idiopathic in the majority of cases, and underlying causes seem of multifactorial origin. Studies regarding genetic variants support this notion. It is unknown whether downstream gene products fit this profile. This study evaluated the metabolome of hypospadias by using the emerging technology of metabolomics in the search for distinct cellular processes associated with hypospadias’ etiology according to the severity of this congenital urogenital condition. Foreskin samples were collected during urethroplasty from boys with Type I, II, and III hypospadias or undergoing elective circumcision (N=28) between 5 to 28 months of age. Samples were processed and submitted to gas chromatography-mass spectrometry (GC/MS). MetaboloAnalyst (http://www.metaboanalyst.ca/) online platform was used for bioinformatic analyses. The metabolome of Type II and Type III hypospadias patients differs from the metabolome of Type I hypospadias and control patients. Thirty-five metabolites were identified by GC/MS. Of those, 14 metabolites, amino acids, were found in significantly low concentrations in Type II and Type III hypospadias in comparison to Type I hypospadias and controls. Amino acids comprised asparagine, aspartate, glutamate, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, and tyrosine. The difference observed in the metabolome between severe and mild hypospadias supports previous research work of plausible severity-dependent etiologies for hypospadias. The observed downregulation of specific amino acids in severe hypospadias provides alternative routes for future research aiming to identify disrupted networks and pathways while considering the severity of hypospadias.

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New frontiers on the molecular underpinnings of hypospadias according to severity.

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