Novel pathogenic variant in MED12 causing non-syndromic dilated cardiomyopathy

Figures

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  Fig. 1. The MED12 pathogenic variant is responsible for dilated cardiomyopathy (DCM). (A) The image presents the pedigree of the family with DCM. Variant carriers: black; relatives without the variant: white; slashed line: the deceased member; square: male; circle: female; arrow: proband; triangle: spontaneous abortion. (B) The cardiac magnetic resonance imaging image (CMR) presents dilated cardiomyopathy in the index patient. (C) Direct Sanger-sequencing chromatograms show the MED12 variant sequence in the father, the mother, and the DCM-affected son. The arrow shows the nucleotide position of G/A in the wild-type homozygous father, the heterozygous mother, and the hemizygous patient. (D) The CLUSTALW server was used to compare the alignment of MED12 residues among various MED12 orthologs. The valine amino acids are shown in box

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  Fig. 2. The image depicts the structural prediction of the MED12 protein. (A) The image presents the domain prediction, performed with the InterPro web server. (B) The computational model of the normal MED12 protein constructed with the aid of the AlphaFold2 web server is presented herein. The surface yellow color shows the normal amino acid. (C) The computational model of the variant MED12 protein constructed with the use of the AlphaFold2 web server is presented herein. The surface green color shows the variant amino acid. (D) Superimposed AlphaFold2 models of MED12 (amino acid 1–800) as normal (green), Val417Ile (pink)

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  Fig. 3. Confidence metrics for the forecasted structure of (A) normal MED12 structure and (B) Val417Ile variant. The Ramachandran plot illustrates the energetically permissible regions for backbone dihedral angles ψ and ϕ of amino acid residues in the MED12 structure (the normal and the Val417Ile variant). The favored, and allowed regions are depicted in green and blue, respectively. (C) The image indicates the possible functions of the native MED12 domains, predicted with the aid of the AlphaFold2 and VAST web servers

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  Fig. 4. The image demonstrates the molecular docking analysis of the MED12 protein (the normal and variant amino acids) with the CDK8 protein (PDB: 4F6U) by using PyMOL v.2.5.2. (A) The image illustrates the protein-protein interactions between the normal MED12 protein and the CDK8 protein (CDK8: purple; normal MED12: green). (B) The protein-protein interactions between the MED12 variant and the CDK8 protein (CDK8: purple; variant MED12: yellow) are shown herein

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  Fig. 5. A schematic interaction of the best docking results of the normal (A) and variant MED12 (B) with CDK8 presented by LigPlus + v.2.2.4 is shown herein. Hydrogen bonding is demonstrated in green