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Background <p>The <i>KLF13</i> mutations have been reported to cause familial dilated cardiomyopathy (DCM). Nevertheless, the mutational prevalence and spectrum of <i>KLF13</i> in patients with sporadic DCM remain to be explored. The current research aimed to discover a novel <i>KLF13</i> mutation contributing to human sporadic dilated cardiomyopathy (DCM) and characterize its functional impacts.</p> Materials and methods <p>A cohort of 212 patients suffering from sporadic DCM and a total of 256 unrelated healthy volunteers (utilized as controls) were recruited. Clinical investigation and sequencing assay of <i>KLF13</i> were performed in all study participants. The functional impacts of an identified DCM-causative mutant on its downstream target genes, <i>ACTC1</i>, <i>MYH7</i>, and <i>ANP</i>, were quantitatively assessed by dual-luciferase reporter analysis.</p> Results <p>A novel heterozygous truncating <i>KLF13</i> mutation, i.e., NM_015995.3:c.534&#xa0;C &gt; G;p.(Tyr178*), was discovered in two of 212 unrelated patients affected with sporadic DCM, including a 42-year-old male patient and a female case 51 years old. The nonsense mutation was not found in 256 control people. Functional measurements revealed that the Tyr178*-mutant KLF13 protein showed diminished transactivation effects on its two target genes, <i>ACTC1</i> and <i>MYH7</i>, which are causative of DCM. Furthermore, the Tyr178* mutation significantly reduced the synergistic transactivation of <i>ANP</i> between KLF13 and GATA4, another gene causally linked to DCM.</p> Conclusion <p>The present findings support the notion that KLF13 is a new gene predisposing humans to sporadic DCM, providing further insight into the molecular pathogenesis of DCM and suggesting an improved strategy for personalized prophylaxis and treatment of DCM patients.</p>

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A new KLF13 loss-of-function mutation responsible for sporadic dilated cardiomyopathy

  • 期刊论文

  • 发表日期：

    2025年11月7日

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  • Xiang Tang,
  • Yin Wang,
  • Chen-Xi Yang,
  • Zun-Ping Ke,
  • Fang Yuan,
  • Yi-Qing Yang,
  • Ying-Jie Xu

摘要

Background

The KLF13 mutations have been reported to cause familial dilated cardiomyopathy (DCM). Nevertheless, the mutational prevalence and spectrum of KLF13 in patients with sporadic DCM remain to be explored. The current research aimed to discover a novel KLF13 mutation contributing to human sporadic dilated cardiomyopathy (DCM) and characterize its functional impacts.

Materials and methods

A cohort of 212 patients suffering from sporadic DCM and a total of 256 unrelated healthy volunteers (utilized as controls) were recruited. Clinical investigation and sequencing assay of KLF13 were performed in all study participants. The functional impacts of an identified DCM-causative mutant on its downstream target genes, ACTC1, MYH7, and ANP, were quantitatively assessed by dual-luciferase reporter analysis.

Results

A novel heterozygous truncating KLF13 mutation, i.e., NM_015995.3:c.534 C > G;p.(Tyr178*), was discovered in two of 212 unrelated patients affected with sporadic DCM, including a 42-year-old male patient and a female case 51 years old. The nonsense mutation was not found in 256 control people. Functional measurements revealed that the Tyr178*-mutant KLF13 protein showed diminished transactivation effects on its two target genes, ACTC1 and MYH7, which are causative of DCM. Furthermore, the Tyr178* mutation significantly reduced the synergistic transactivation of ANP between KLF13 and GATA4, another gene causally linked to DCM.

Conclusion

The present findings support the notion that KLF13 is a new gene predisposing humans to sporadic DCM, providing further insight into the molecular pathogenesis of DCM and suggesting an improved strategy for personalized prophylaxis and treatment of DCM patients.