STRUCTURE-BASED ANALYSIS OF GENETIC VARIANTS IN NKX2.5, GATA4 AND ZIC3 AND THEIR IMPLICATION IN CONGENITAL HEART DISEASE

BRUQUE, C.D.; FERNANDEZ CECILIA; NADRA, A.D.; KOLOMENSKI, JORGE E.; SIMONETTI L; BUZZALINO N.; DELEA, MARISOL; ESPECHE LD; DAIN L

Ciudad Autónoma de Buenos Aires

Congreso; Reunion conjunta de las sociedades de biociencias; 2017

Congenital heart diseases (CHDs) are the most prevalent type of human structural birth defect worldwide, affecting between 4 to 9 per 1000 births. The etiology of CHDs includes both genetic and environmental factors. In 5-10% of the patients, CHD is caused by a single gene variation. Although several genes have been described, NKX2.5, ZIC3 and GATA4 are some of the most frequently involved.The aim of this work was to perform a structure-based analysis of genetic variants (GVs) found in the three genes, using the crystal structure of human NKX2.5 and building molecular models of ZIC3 and GATA4 human genes.With the aid of MODELLER v9.18, we modeled the human ZIC3 and GATA4 proteins using homologous proteins domains as templates retrieved from the Protein Data Bank (PDB). NMR and X-ray crystal structures were used for NKX2.5 as templates. Since too many templates were available, a clustering analysis was performed in order to remove redundant information. DISOPRED3 was also used to annotate naturally disordered regions. For NKX2.5, we have used FoldX to generate point mutations and to analyze changes in protein stability or protein interaction with DNA.We generated a molecular model for each of the core regions of GATA4 and ZIC3. In addition, we performed a structural evaluation of the pathogenic implication of 32 GVs in the NKX2.5 involved DNA interaction region and protein destabilization.These models can be used to frame known Single Nucleotide Variants (SNV) and predict the effects of unknown variants that may appear in the future. This would be especially useful in these genes as they have been associated with sudden death and other cardiac defects, and an early diagnosis can mean palliative measures as the inclusion of a peacemaker in time.