Chromosomal rearrangements and their relevance in the etiology of genetic disorders: cytogenomic and molecular investigation

Abstract

A great challenge for cytogeneticists is to understand the genetic basis of the phenotypic variations and its implication for human diseases. Chromosomal rearrangements are an efficient tool for the investigation of the consequences of deletion, duplication or disruption of genes. This project contains three subprojects as follows: Subproject 1: Analysis of women with balanced X-autosome translocations whose breakpoints were previously determined by array painting. Lymphoblastoid cell lines will be established in order to study the reorganization of chromatin in the interphase nucleus and for gene function studies. Two genes will be analyzed in detail: (a) The AMMECR1 gene, disrupted in one of the patients, whose function is still unknown. AMMECR1's expression will be evaluated in different tissues of mouse embryos, in embryonic stem cells as well as in lymphoblastoid cell lines from both patient and control subject, with and without gene silencing, (b) The chimeric IL1RAPL1-ZNF61 gene, originated by the rearrangement in another patient with translocation, whose structure and consequences will be investigated. Subproject 2: In patients with 22q11.2 deletion syndrome with genomic losses of different sizes, the expression profile of genes and microRNAs will be analyzed; additionally, an investigation of allelic variants of genes in the deleted region will be performed. Subproject 3: In patients with congenital anomalies and intellectual disability, cytogenomic imbalances and their breakpoints will be investigated, and correlated to phenotype. The results obtained with these subprojects will allow a better comprehension of the etiology of clinical conditions as well as the role of gene variations and a better understanding of the molecular mechanisms for the formation of cytogenomic rearrangements. (AU)