Functional Characterization of Two New Variants in the Bone Morphogenetic Protein 7 Prodomain in Two Pairs of Monozygotic Twins With Hypospadias

• DOI: 10.1210/js.2018-00333
• Publication Date: 2019-02-22T22:51:48Z
• Authors: Aurore Bouty; Kelly Walton; Nurin Aisyiyah Li...; Gorjana Robevska; Jocelyn Van den B...; Ardy Santosa; Sultana M H Faradz; Craig Harrison; Katie L Ayers; Andrew H Sinclair
• Keywords: Characterization

Variants in bone morphogenetic protein 7 (BMP7) have been reported patients with hypospadias. Here we report and analyze two variants the BMP7 prodomain monozygotic twins hypospadias.Patients hypospadias were prospectively recruited. After informed consent was obtained, DNA extracted from blood. The coding regions of 1034 genes [including 64 known diagnostic candidate for disorder/difference sex development (DSD)] sequenced using a targeted capture approach (HaloPlex, Agilent, Santa Clara, CA), combined massively parallel sequencing. resulting filtered rarity general population (<1%) our screen. Quality, depth reads, predicted pathogenicity also considered. consequences identified mutations on expression determined by Western blot analysis culture media transfected cells, activity measured SMAD 1/5-responsiveness luciferase assay.We analyzed 46 Two pairs concordant exhibiting proximal Both are heterozygous, nonsynonymous, affect highly conserved amino acids to be important assembly/folding. Functional analyses demonstrated that both disrupt synthesis or secretion.Through DSD panel By decreasing synthesis, these likely limit bioavailability during closure urethral plate.Further may uncover additional cause this DSD.