Discovery of SOX5 as a New Causative Gene for Atrial Fibrillation

Figures

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  Figure 1. Pedigree with idiopathic atrial fibrillation. The family was named arbitrarily as Pedigree AF-001. “+” denotes an individual carrying the observed SOX5 variation; “−” signifies a member without the found SOX5 variation.

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  Figure 2. A representative 12-lead electrocardiogram from the proband (member II-6 in Pedigree AF-001). The standard electrocardiogram documents the occurrence of atrial fibrillation.

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  Figure 3. A novel SOX5 variation accountable for atrial fibrillation. Sequencing electropherograms delineating the heterogeneous SOX5 variation discovered in the proband with atrial fibrillation (Mutant), along with its wild-type control from a healthy person (Wild type). An arrow pinpoints where the variation occurs. * means a stop codon.

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  Figure 4. A de novo SOX5 variation predisposing to atrial fibrillation. The heterogeneous SOX5 variation (Mutant) was detected in one of 236 patients with atrial fibrillation, and its wild type as a sequence control was detected in a healthy subject (Wild type). A vertical arrow orients the nucleotide site where the variation occurs. * means a stop codon.

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  Figure 5. A representative 12-lead electrocardiogram recorded from the AF case carrying the SOX5 c.640G>T variation. This electrocardiogram manifests atrial fibrillation.

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  Figure 6. Failure of Gln119*- or Glu214*-mutant SOX5 to transactivate GJA1. In cultured COS-7 cells in vitro, dual-reporter (Firefly luciferase and Renilla luciferase) gene analysis revealed that both the Gln119* mutant (A) and the Glu214* mutant (B) failed to transcriptionally activate GJA1. Herein, “a” and “c” signify p < 0.001, and “b” and “d” denote p < 0.005, in comparison with wild-type human SOX5 (400 ng). + means plus, − means empty plasmid (negative control).

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  Figure 7. Synergistic activation of SCN5A between SOX5 and SHOX2 disrupted by the Gln119*- or Glu214* mutation. In the HEK293 cells maintained in vitro and transfected with multiple expression plasmids, dual-luciferase activity measurement demonstrated that the synergistic activation of SCN5A by SOX5 and SHOX2 was disrupted by the Gln119* mutation (A) or the Glu214* mutation (B). Herein, “e”, “f”, “g”, and “h” all mean p < 0.001, in contrast to the corresponding wild-type counterparts. + means plus, − means empty plasmid (negative control).