Functional study of genes associated with intelectual disability (MED23 and MED25) in human in vitro model

• Grant number: 16/09835-6
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: August 01, 2016
• End date: July 31, 2017
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Mayana Zatz
• Grantee: Carolina Rauffus Vilela da Silva
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

A part of the population from Brazil Northeastern region is relatively isolated geographically and keeps, for generations, the tradition of consanguineous marriages. These two factors together (geographic isolation and inbreeding) increase the risk of children born with autosomal recessive disorders such as Intellectual Disability (ID). In a prospective study in Brazil Northeastern backlands, we identified two families with individuals showing ID and facial dismorphism. Using next generation sequencing (Exome), we identified the pathogenic mutations c. 4000C>T (p. Arg1334Cys) in the gene MED23 in homozygosity in a family with only one affected; and c. 418C>T (p. Arg140Trp) in the gene MED25 in homozygosity in seven patients from a second family located in the same geographic region as the former one. These genes are part of the Mediator Complex, which is involved in the regulation of transcription factors dependent on RNA polymerase II expression. Mutations in genes from the Mediator Complex have been previously associated with ID, accompanied or not by dismorphisms, since modifications in this complex can disturb the central nervous system development. In this project we propose to collect fibroblasts skin samples from patients and familiar controls in order to analyze the pathogenicity of the two mutations identified in our study families, using human in vitro model. Molecular and functional analysis using patients' cells will allow us to investigate the pathogenic effects of both mutations detected in the MED family genes and their possible role in defects of cell development.