A novel variant of DHH in a familial case of 46,XY disorder of sex development: Insights from molecular dynamics simulations.

摘要: SummaryObjective Disorders of sex development (DSD) are a heterogeneous group conditions affecting the differentiation and internal external genitalia. Here, we aimed at identifying genetic cause DSD in two 46,XY sisters from consanguineous family. Design We performed whole-exome sequencing female individuals. Sanger was used to validate most likely candidate variant, desert hedgehog (DHH) gene. Molecular dynamics simulations were get insights into impact variant on protein structure its interaction with partner BOC (brother CDO/cell adhesion molecule, downregulated by oncogenes). Patients The index patient presented phenotype, primary amenorrhea (low estradiol testosterone high FSH LH). She also had an apparent absence intra-abdominal gonads uterus, facial dysmorphy, psychomotor retardation neuropathy. Her sister displayed similar gonadal endocrinological picture, without dysmorphy or retardation. Results Whole-exome revealed homozygous DHH leading p.Trp173Cys substitution. The relevant Trp residue is conserved alteration predicted be deleterious. Dynamic showed that mutation increases conformational flexibility alters BOC, positive regulator Hedgehog signaling. We do not exclude interference DHH-intein-mediated auto-processing. Conclusions This report number described mutations highlights importance advanced bioinformatic tools better understand pathogenicity human mutations. This article protected copyright. All rights reserved.