A novel causative functional mutation in GATA6 gene is responsible for familial dilated cardiomyopathy as supported by in silico functional analysis

Figures

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  Figure 1. The Pedigree of a family suffering early-onset FDCM. WES was performed for III-4 (proband); a novel heterozygous variant (c.985C > T, p.H329Y) in GATA6 was identified in the III-4, IV-2, III-3, and II-4 patients. Healthy individuals (non-affected such as III-1 and III-5) had normal genotype (CC). Deceased members are shown by slashes. Solid symbols are indicating the family members diagnosed with FDCM. Genotypes are shown as: Wile-type allele = C, Mutant allele = T.

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  Figure 2. DNA sequence of a segment flanking H329Y in GATA6 gene from an affected member. Histidine converts to Tyrosine following a single base substitution; the substitution of a Histidine by Tyrosine takes place at position 329. Red highlight denotes a heterozygote C > T nucleotide substitution.

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  Figure 3. (A) In silico modelled structure of the wild-type of GATA6. The 3D model of the wild-type of GATA6 generated using I-TASSER. The residue His329 is highlighted in stick model (Green colour). The α‐helices are represented by cyan ribbons, the β‐strands are represented by magentas arrows, and the coiled regions are represented in light pink. (B) The residue Tyr329 in the H329Y variant is highlighted in stick model (red colour).

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  Figure 4. (A) Backbone root-mean-square-deviation (RMSD) of the wild-type of GATA6 and the H329Y mutant protein for 50,000 ps molecular dynamics simulation. The wild-type of GATA6 is represented in blue, and mutant H329Y in red. (B) RMSF diagram of GATA6 protein backbone atoms and mutant H329Y. The root-mean-square fluctuation for each residue of GATA6 is shown. (C) Radius of gyration of GATA6 protein and the H329Y mutant. The Radius of gyration of Cα atoms of the wild-type of GATA6 and the H329Y mutant during the MD trajectory is shown. (D) Total number of intramolecular hydrogen bonds for GATA6 protein and the H329Y mutant.