An alpha-helix variant p.Arg156Pro in LMNA as a cause of hereditary dilated cardiomyopathy: genetics and bioinfomatics exploration

LMNA gene encodes lamin A/C protein which participates in the construction of nuclear lamina, the mutations of LMNA result in a wide variety of diseases known as laminopathies. LMNA-related dilated cardiomyopathy(LMNA-DCM) is one of the more common laminopathy which characterized by progressive heart failure and arrhythmia. However, the mutation features of LMNA-DCM are yet to be elucidated. Herein we described a dilated cardiomyopathy family carrying novel variant c.467G > C(p.Arg156Pro) of LMNA as heterozygous pathogenic variant identified by whole-exome sequencing. With the help of Alphafold2, we predicted mutant protein structure and found an interrupted alpha-helix region in lamin A/C. In the analysis of 49 confirmed pathogenic missense of laminopathies, Chi-square test showed the DCM phenotype was related to the alpha-helix region mutation (p < 0.017). After screening the differentially expressed genes (DEGs) in both mice models and human patients in Gene Expression Omnibus database, we found the variation of alpha-helix-coding region in LMNA caused abnormal transcriptomic features in cell migration, collagen-containing extracellular matrix, and PI3K-Akt signaling pathway. Subsequently we constructed (TF)-mRNA-microRNA (miRNA) regulatory network and identified 7 key genes (FMOD, CYP1B1, CA3, F2RL1, HAPLIN1, SNAP91, and KANSL1) as potential biomarkers or therapeutic targets in LMNA-DCM patients.

Automated summary

LMNA gene mutations can result in a variety of laminopathies. LMNA-DCM, characterized by heart failure and arrhythmia, is a common laminopathy. In this study, a novel LMNA variant was identified in a dilated cardiomyopathy family using whole-exome sequencing. Mutant protein structure prediction and analysis of confirmed laminopathy mutations revealed a correlation between DCM phenotype and alpha-helix region mutation. Further analysis indicated that variations in the alpha-helix-coding region of LMNA caused abnormal transcriptomic features in cell migration, collagen-containing extracellular matrix, and PI3K-Akt signaling pathway. A regulatory network was constructed, identifying 7 key genes as potential biomarkers or therapeutic targets in LMNA-DCM patients.