The novel p.E89K mutation in the SRY gene inhibits DNA binding and causes the 46,XY disorder of sex development

• Grant number: 11/01276-4
• Support Opportunities: Regular Research Grants - Publications - Scientific article
• Start date: March 01, 2011
• End date: August 31, 2011
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Maricilda Palandi de Mello
• Grantee: Maricilda Palandi de Mello
• Host Institution: Centro de Biologia Molecular e Engenharia Genética (CBMEG). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

In humans, male sex determination is controlled by the SRY gene, which encodes a transcriptional regulator with a conserved high mobility group box domain (HMG) required for DNA-binding. Mutations in the SRY HMG-box are known to affect the protein function leading to sex reversal phenotypes. In this study, we describe the novel p.E89K missense mutation in the SRY HMG-box. It was identified in a patient with 46,XY complete gonadal dysgenesis as a de novo mutation. Electrophoretic mobility shift assays showed that p.E89K almost completely abolished the SRY DNA-binding activity, suggesting that it is the cause of SRY function impairment. In addition, we report the occurrence of the p.G95R mutation in a 46,XY female with complete gonadal dysgenesis. Based on the three-dimensional structure of the SRY HMG-box, we discuss that the change of the acidic glutamic acid by the basic lysine in residue 89 introduces a positive charge adjacently to R86 and K92 residues and may cause electrostatic repulsion and destabilization of the interaction between SRY HMG-box helix 2 and its target DNA sequence. (AU)