PUBLICATION
Familial atrial myopathy in a large multi-generational heart-hand syndrome pedigree carrying LMNA missense variant in rod 2B domain (p.R335W)
- Authors
- Zhang, Y., Lin, Y., Zhang, Y., Wang, Y., Li, Z., Zhu, Y., Liu, H., Ju, W., Cui, C., Chen, M.
- ID
- ZDB-PUB-211123-20
- Date
- 2021
- Source
- Heart rhythm 19(3): 466-475 (Journal)
- Registered Authors
- Chen, Minglong, Cui, Chang
- Keywords
- DNA repair, LMNA, aging, atrial fibrillation, atrial myopathy, induced pluripotent stem cell
- MeSH Terms
-
- Pedigree
- Lamin Type A/genetics
- Humans
- Laminopathies*
- Abnormalities, Multiple
- Animals
- Heart Septal Defects, Atrial
- Muscular Diseases*
- Heart Defects, Congenital
- Brachydactyly*
- Mutation
- Lower Extremity Deformities, Congenital
- Induced Pluripotent Stem Cells*
- Zebrafish/genetics
- Upper Extremity Deformities, Congenital
- PubMed
- 34808346 Full text @ Heart Rhythm
Citation
Zhang, Y., Lin, Y., Zhang, Y., Wang, Y., Li, Z., Zhu, Y., Liu, H., Ju, W., Cui, C., Chen, M. (2021) Familial atrial myopathy in a large multi-generational heart-hand syndrome pedigree carrying LMNA missense variant in rod 2B domain (p.R335W). Heart rhythm. 19(3):466-475.
Abstract
Background The literature on laminopathy with ventricular phenotype is extensive. However, the pathogenicity of LMNA variations in atrial lesions still lacks research.
Objective To characterize the atrial phenotype and possible mechanisms in a large Chinese family with heart-hand syndrome carrying LMNA missense variant in rod 2B domain (c.1003C>T p.R335W).
Methods Clinical characteristics were collected based on the pedigree investigation. Comprehensive functional analyses, including molecular dynamic simulation, cellular, and animal functional assays, determined the pathogenicity in atrial myopathy.
Results In the pedigree investigation, 6/13 of the mutation carriers showed heterogeneous cardiac phenotypes, and eight carriers also had brachydactyly. In silico molecular dynamics simulations predicted increased binding energy of R335W mutant lamin A. Atrial cardiomyocytes (HL-1, hiPSC-derived atrial cardiomyocytes) expressing R335W showed abnormal nuclear morphology, compromised DNA repair, and dysfunctional contraction. Adult zebrafish expressing mutant lamin A showed increased P wave duration in the electrocardiogram, decreased A peak velocity in echocardiography, and atrial lesions under the transmission electron microscope.
Conclusion The LMNA p.R335W mutation leads to a familial heart-hand syndrome characterized by an overlapping phenotype of prominent atrial lesions and brachydactyly. The unstable lamin dimerization and impaired DNA repair are possible mechanisms underlying cardiac phenotypes. Our findings consolidated the genetic role in the course of atrial arrhythmias and cardiac aging, which is helpful to the diagnosis and treatment of cardiac laminopathy.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping