Journal Article

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

Chang, Lei, Chen, Jianzhou, Wang, Lian, Huang, Rong, Li, Guannan, Shi, Guangfei, Xu, Biao

2023

Overview

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 α-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 α-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 α-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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: 1-Phosphatidylinositol 3-kinase / Advanced machine learning and health-related multi-omics data / AKT protein / Alpha-helix / Alphafold2 / Amino acids / Animal models / Arrhythmia / Bioinformatics analysis / Biomedical and Life Sciences / Biomedicine / C protein / Cardiac arrhythmia / Cardiomyopathy / Cardiomyopathy, Dilated / Causes of / Cell migration / Collagen / Congestive heart failure / Datasets / Development and progression / Dilated cardiomyopathy / Extracellular matrix / Gene Expression / Genes / Genetic aspects / Genetic variation / Genotype & phenotype / Health aspects / Heart / Heart diseases / Human Genetics / Immunoglobulins / Intermediate filament proteins / Kinases / LMNA / Microarrays / MicroRNA / miRNA / Mutation / Nuclear lamina / Pathogenesis / Patients / Phenotypes / Physiological aspects / Protein structure / Proteins / Signal transduction / Statistical analysis / Therapeutic targets / Transcriptomics