Preliminary functional characterization of the LMNA c.929 A > G (p.Gln310Arg) variant identified in a patient with dilated cardiomyopathy.
4 affiliations
- 1Qingdao Medical College, Qingdao university, Qingdao, Shandong, China.
- 2Department of Cardiology, Yantai Yuhuangding Hospital, Yantai, Shandong, China.
- 3Department of Cardiology, Yantai Yuhuangding Hospital, Yantai, Shandong, China. [email protected].
- 4Department of Cardiology, Yantai Yuhuangding Hospital, Yantai, Shandong, China. [email protected].
Abstract
Background
Variants in LMNA are established causes of inherited dilated cardiomyopathy (DCM); however, the clinical significance of many rare missense variants remains uncertain. We identified the rare LMNA c.929 A > G (p.Gln310Arg) variant in a patient with progressive DCM and performed preliminary variant-specific functional characterization in an AC16 transient overexpression model.Methods
Duo whole-exome sequencing and copy-number variation analysis were performed in the proband and his son. Wild-type and p.Gln310Arg lamin A expression constructs were transiently transfected into AC16 cells. Flag-tagged protein expression, Flag-based transfection efficiency, and lamin A/C distribution were assessed by western blotting and immunofluorescence staining. Mitochondrial membrane potential and intracellular ROS-associated fluorescence were assessed using JC-1 and DCFH-DA staining, respectively. ERK1/2, JNK, and p38 MAPK phosphorylation was evaluated by western blotting. Hypertrophy-associated NPPA and NPPB expression was measured by RT-qPCR, and cell area was quantified after phalloidin staining.Results
The LMNA c.929 A > G variant was classified as a variant of uncertain significance. Wild-type and p.Gln310Arg lamin A constructs showed comparable Flag-tagged protein expression and Flag-based transfection efficiency. Expression of p.Gln310Arg lamin A was associated with an increased proportion of cells displaying ring-like lamin A/C staining patterns. Variant-expressing cells showed increased intracellular DCF fluorescence, reduced JC-1 red-to-green fluorescence ratio, and selectively increased ERK1/2 phosphorylation, whereas no significant changes were detected in JNK or p38 MAPK phosphorylation. The same cells also showed a hypertrophy-like phenotype characterized by increased NPPA and NPPB expression and enlarged cell area.Conclusion
In an AC16 transient overexpression model, expression of p.Gln310Arg lamin A was associated with altered lamin A/C distribution, increased intracellular ROS-associated fluorescence, reduced mitochondrial membrane potential, selectively increased ERK1/2 phosphorylation, and a hypertrophy-like cellular phenotype. These findings provide preliminary variant-specific functional evidence but do not establish the pathogenicity of the variant or the causal relationships among the observed cellular abnormalities. Further validation in endogenous and physiologically relevant cardac models is required.
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BibTeX
@article{han2026preliminary,
title = {{Preliminary functional characterization of the LMNA c.929 A > G (p.Gln310Arg) variant identified in a patient with dilated cardiomyopathy.}},
author = {Zikang Han and Yonghao Sheng and Han Sun and Mengchen Sun and Haibin Dong and Lei Gong and Chunxiao Wang and Guangqiang Wang and Lin Zhong},
journal = {Hereditas},
year = {2026},
month = aug,
doi = {10.1186/s41065-026-00722-6},
url = {https://europepmc.org/article/MED/42958366},
note = {CC BY},
}
RIS
TY - JOUR
TI - Preliminary functional characterization of the LMNA c.929 A > G (p.Gln310Arg) variant identified in a patient with dilated cardiomyopathy.
AU - Zikang Han
AU - Yonghao Sheng
AU - Han Sun
AU - Mengchen Sun
AU - Haibin Dong
AU - Lei Gong
AU - Chunxiao Wang
AU - Guangqiang Wang
AU - Lin Zhong
PY - 2026
DA - 2026/08/01
JO - Hereditas
DO - 10.1186/s41065-026-00722-6
UR - https://europepmc.org/article/MED/42958366
AB - Background Variants in LMNA are established causes of inherited dilated cardiomyopathy (DCM); however, the clinical significance of many rare missense variants remains uncertain. We identified the rare LMNA c.929 A > G (p.Gln310Arg) variant in a patient with progressive DCM and performed preliminary variant-specific functional characterization in an AC16 transient overexpression model.Methods Duo whole-exome sequencing and copy-number variation analysis were performed in the proband and his son. Wild-type and p.Gln310Arg lamin A expression constructs were transiently transfected into AC16 cells. Flag-tagged protein expression, Flag-based transfection efficiency, and lamin A/C distribution were assessed by western blotting and immunofluorescence staining. Mitochondrial membrane potential and intracellular ROS-associated fluorescence were assessed using JC-1 and DCFH-DA staining, respectively. ERK1/2, JNK, and p38 MAPK phosphorylation was evaluated by western blotting. Hypertrophy-associated NPPA and NPPB expression was measured by RT-qPCR, and cell area was quantified after phalloidin staining.Results The LMNA c.929 A > G variant was classified as a variant of uncertain significance. Wild-type and p.Gln310Arg lamin A constructs showed comparable Flag-tagged protein expression and Flag-based transfection efficiency. Expression of p.Gln310Arg lamin A was associated with an increased proportion of cells displaying ring-like lamin A/C staining patterns. Variant-expressing cells showed increased intracellular DCF fluorescence, reduced JC-1 red-to-green fluorescence ratio, and selectively increased ERK1/2 phosphorylation, whereas no significant changes were detected in JNK or p38 MAPK phosphorylation. The same cells also showed a hypertrophy-like phenotype characterized by increased NPPA and NPPB expression and enlarged cell area.Conclusion In an AC16 transient overexpression model, expression of p.Gln310Arg lamin A was associated with altered lamin A/C distribution, increased intracellular ROS-associated fluorescence, reduced mitochondrial membrane potential, selectively increased ERK1/2 phosphorylation, and a hypertrophy-like cellular phenotype. These findings provide preliminary variant-specific functional evidence but do not establish the pathogenicity of the variant or the causal relationships among the observed cellular abnormalities. Further validation in endogenous and physiologically relevant cardac models is required.
SN - 0018-0661
SN - 1601-5223
ER -