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Plasma Proteomics Reveals Dysregulated Pathways Across the Spectrum LMNA Cardiomyopathy
Usman A Tahir1,2, Daniel Reichart2,3, Anisha Purohit3
1Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA (U.A.T., J.L.B., G.T., L.F.).
Insights
Pathogenic variants in the lamin A/C (LMNA) gene cause aggressive dilated cardiomyopathy (DCM). Proteomic profiling identified novel proteins and pathways linked to LMNA DCM, aiding biomarker discovery and therapeutic development.
Area of Science:
- Cardiovascular Genetics
- Proteomics
- Molecular Cardiology
Background:
- Pathogenic variants in the lamin A/C (LMNA) gene are associated with an aggressive form of dilated cardiomyopathy (DCM).
- The precise mechanisms driving LMNA DCM progression remain incompletely understood.
- LMNA DCM is characterized by advanced conduction disease, malignant ventricular arrhythmias, and heart failure.
Purpose of the Study:
- To identify proteins and biological pathways associated with pathogenic LMNA variants.
- To understand the molecular underpinnings of LMNA DCM.
- To explore potential targets for genotype-driven therapeutic development.
Main Methods:
- Plasma proteomic profiling using the OLINK platform in a cohort with LMNA DCM, sarcomeric DCM, and controls.
- Measurement of approximately 3000 plasma proteins.
- Analysis of single-cell RNA sequencing data from cardiomyocyte biopsies in advanced LMNA heart failure.
Main Results:
- Several novel proteins, including EDA2R and MYL4, were identified as associated with LMNA DCM compared to sarcomeric DCM.
- Twenty-six proteins associated with LMNA DCM showed concordant differential gene expression in cardiomyocytes.
- Proteomic signatures identified via principal component analysis correlated with left ventricular ejection fraction and complete heart block.
Conclusions:
- Proteomic profiling of individuals with pathogenic LMNA variants revealed key pathways involved in LMNA DCM.
- These findings support the advancement of genotype-driven biomarker discovery for LMNA DCM.
- The study may facilitate the development of tailored therapeutic strategies for LMNA DCM.
Background:
Pathogenic variants in the lamin A/C (LMNA) gene cause an aggressive form of dilated cardiomyopathy (DCM), marked by higher rates of advanced conduction disease, malignant ventricular tachyarrhythmias, and advanced heart failure compared with other causes of nonischemic cardiomyopathy. However, the mechanisms that drive the development and progression of LMNA DCM are incompletely understood.
Methods:
To identify proteins and biological pathways associated with likely pathogenic/pathogenic LMNA variants, we measured ≈3000 plasma proteins using the OLINK platform in a genetic DCM cohort consisting of LMNA (n=41) and sarcomeric (n=18) DCM, along with phenotype-negative individuals from family-based cascade screening (n=55) with (LMNA, n=16; sarcomere, n=12) or without the family variant (genotype negative, n=27).
Results:
We identified several novel proteins associated with LMNA DCM compared with sarcomeric DCM, including EDA2R (ectodysplasin A2 receptor; per log2 fold change in relative protein abundance, β=3.0; P=4×10-³) and MYL4 (myosin light chain 4; β=2.32; P=5×10-³). Among the proteins associated with LMNA DCM, 26 showed concordant differential gene expression from single-cell sequencing in cardiomyocytes from myocardial biopsies in advanced LMNA heart failure compared with control hearts (false discovery rate, <5%). We performed principal component analyses on these 26 proteins to identify proteomic signatures of LMNA DCM and found the first principal component to be associated with left ventricular ejection fraction and complete heart block in the LMNA DCM cohort. Six proteins-EDA2R, MYL4, CRIM1 (cysteine-rich transmembrane bone morphogenetic protein regulator 1), TPR (translocated promoter region), FSTL3 (follistatin-like 3), and NFYA (nuclear transcription factor Y)-were associated with LMNA pathogenic variants across phenotype-negative individuals, DCM, and their respective cardiomyocyte RNA expression profiles in advanced heart failure.
Conclusions:
Proteomic profiling in individuals with likely pathogenic/pathogenic LMNA variants illuminated integral pathways across the spectrum of LMNA DCM. These findings may help advance genotype-driven biomarker discovery and tailored therapeutic development in LMNA DCM.
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