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A new KLF13 loss-of-function mutation responsible for sporadic dilated cardiomyopathy
Xiang Tang1, Yin Wang1, Chen-Xi Yang2
1Department of Cardiology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 Xianxia Road, Shanghai, 200336, China.
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.
Insights
Researchers identified a novel KLF13 gene mutation in patients with sporadic dilated cardiomyopathy (DCM). This discovery sheds light on DCM
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Genetic Basis of Heart Disease
Background:
- KLF13 mutations are known to cause familial dilated cardiomyopathy (DCM).
- The prevalence and spectrum of KLF13 mutations in sporadic DCM cases were previously unexplored.
- Understanding genetic factors in sporadic DCM is crucial for diagnosis and treatment.
Purpose of the Study:
- To identify novel KLF13 mutations associated with sporadic DCM.
- To investigate the functional consequences of identified KLF13 mutations.
- To elucidate the role of KLF13 in the molecular pathogenesis of DCM.
Main Methods:
- Sequencing of the KLF13 gene in 212 sporadic DCM patients and 256 healthy controls.
- Clinical investigation of affected individuals.
- Dual-luciferase reporter assays to assess the functional impact of KLF13 mutations on target genes (ACTC1, MYH7, ANP).
Main Results:
- A novel heterozygous truncating KLF13 mutation (NM_015995.3:c.534C>G;p.(Tyr178*)) was identified in two unrelated sporadic DCM patients.
- This mutation was absent in the control group.
- The Tyr178* mutant KLF13 protein demonstrated reduced transactivation of ACTC1 and MYH7, and impaired synergistic transactivation of ANP with GATA4.
Conclusions:
- KLF13 is implicated as a novel gene predisposing to sporadic DCM.
- The findings enhance understanding of DCM's molecular pathology.
- This research may inform personalized prevention and treatment strategies for DCM patients.
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