Author(s):
David, Dezső 
; Santos, Inês ; Marques, Bárbara ; Correia, Hildeberto ; Teixeira, Filomena
Date: 2011
Persistent ID: http://hdl.handle.net/10400.18/165
Origin: Repositório Científico do Instituto Nacional de Saúde
Subject(s): SATB2; Position effect; Microdeletionlike phenotype; Toriello–Carey syndrome; Doenças Genéticas
Description
SATB2 is an AT-rich sequence-binding protein that binds to nuclear matrix attachment regions. It plays an important role in transcription regulation and chromatin loop remodelling. Deletions, chromosome translocations, as well as heterozygous nonsense mutations affecting this gene have been reported associated with overlapping conditions involving craniofacial anomalies such as the isolated cleft palate (OMIM 119540), 2q33.1 microdeletion syndrome (OMIN 612313) and Toriello–Carey syndrome (OMIM 217980). The aim of this study was the identification of the breakpoint sequences and candidate gene/s of a de novo t(1;2)(q14.1;q35) associated with severe mental retardation, behaviour disturbance, dysmorphic facies, dental anomalies, convergent strabismus and high palate but without clefting. The chromosome 2 breakpoint is localised at position 199,567,382 of the current human genome assembly (hg19), within IVS1 of the processed transcript AC019330.1. This breakpoint disrupts an evolutionarily conserved non-coding genomic element localised 566.8 kb from the 3′ end of the SATB2 gene. The chromosome 1 breakpoint is localised within IVS13 of the zyg-11 homolog A (Caenorhabditis elegans) ZYG11A gene,at position 53,355,744 (assembly hg19). Although the chromosome 1 breakpoint disrupts the ZYG11A, we consider that the SATB2 is the main candidate gene, which is substantiated by the overlap observed between the probands’ phenotype with the pathologies associated with this gene. The characterization of the translocation breakpoints allowed us to establish an accurate clinical diagnosis. As pathogenic mechanism, we propose the disruption of the genomic architecture of evolutionary conserved long-range regulatory elements leading to a socalled cis-ruption disorder. The elucidation of the pathogenic mechanism by which disruption of such an evolutionarily conserved sequence element leads to the aforementioned condition will allow us to consider new therapeutic strategies that may hinder progressive deterioration of the clinical condition in such “cis-ruption disorders”.
