Department of Cardiology, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, Jiangsu, 210008, China.
Department of Cardiology, Suzhou Dushu Lake Hospital, Dushu Lake Hospital Affiliated to Soochow University, Medical Center of Soochow University, Suzhou, 215000, China.
BMC Med Genomics. 2023 Oct 2;16(1):229. doi: 10.1186/s12920-023-01661-1.
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.
lamin A/C 蛋白由 LMNA 基因编码，参与核纤层的构建，LMNA 的突变导致多种被称为层粘连蛋白病的疾病。LMNA 相关扩张型心肌病（LMNA-DCM）是较为常见的层粘连蛋白病之一，其特征为进行性心力衰竭和心律失常。然而，LMNA-DCM 的突变特征尚未阐明。本研究通过全外显子组测序，描述了一个携带 LMNA 新型杂合致病性变异 c.467G>C(p.Arg156Pro)的扩张型心肌病家系。借助 Alphafold2，我们预测了突变蛋白结构，发现 lamin A/C 中有一段中断的α-螺旋区。在对 49 个已确认的层粘连蛋白病致病性错义突变的分析中，卡方检验显示 DCM 表型与α-螺旋区突变相关（p<0.017）。在基因表达综合数据库中筛选出小鼠模型和人类患者的差异表达基因（DEGs）后，我们发现 LMNA 中α-螺旋编码区的变异导致细胞迁移、富含胶原蛋白的细胞外基质和 PI3K-Akt 信号通路的转录组特征异常。随后我们构建了（TF）-mRNA-微小 RNA（miRNA）调控网络，并鉴定出 7 个关键基因（FMOD、CYP1B1、CA3、F2RL1、HAPLIN1、SNAP91 和 KANSL1），作为 LMNA-DCM 患者的潜在生物标志物或治疗靶点。
