Key result
LMNA E161K mutation drives central displacement of chromosome 13 clusters, reducing lamina contact by ~27%.
Why the study?
Dominant LMNA gene mutations cause cardiac and skeletal myopathies by potentially disrupting normal gene expression through altered nuclear lamina-chromatin interactions.
Absolute Event Rate: 59.4% vs 81.6%
p-value: p=0.0001
Cardiomyopathic LMNA mutations alter the intranuclear positioning and compaction of chromosomal domains, providing a mechanism for disease-causing gene misexpression.
May implicate nuclear architecture in LMNA cardiomyopathy; leaves open mechanistic validation and clinical translation from animal data.
BACKGROUND: Lamins A and C, encoded by the LMNA gene, are filamentous proteins that form the core scaffold of the nuclear lamina. Dominant LMNA gene mutations cause multiple human diseases including cardiac and skeletal myopathies. The nuclear lamina is thought to regulate gene expression by its direct interaction with chromatin. LMNA gene mutations may mediate disease by disrupting normal gene expression. METHODS/FINDINGS: To investigate the hypothesis that mutant lamin A/C changes the lamina's ability to interact with chromatin, we studied gene misexpression resulting from the cardiomyopathic LMNA E161K mutation and correlated this with changes in chromosome positioning. We identified clusters of misexpressed genes and examined the nuclear positioning of two such genomic clusters, each harboring genes relevant to striated muscle disease including LMO7 and MBNL2. Both gene clusters were found to be more centrally positioned in LMNA-mutant nuclei. Additionally, these loci were less compacted. In LMNA mutant heart and fibroblasts, we found that chromosome 13 had a disproportionately high fraction of misexpressed genes. Using three-dimensional fluorescence in situ hybridization we found that the entire territory of chromosome 13 was displaced towards the center of the nucleus in LMNA mutant fibroblasts. Additional cardiomyopathic LMNA gene mutations were also shown to have abnormal positioning of chromosome 13, although in the opposite direction. CONCLUSIONS: These data support a model in which LMNA mutations perturb the intranuclear positioning and compaction of chromosomal domains and provide a mechanism by which gene expression may be altered.
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Mewborn et al. (2010) studied Dilated cardiomyopathy with LMNA mutation. LMNA E161K mutation vs. LMNA normal was evaluated on Percentage of cluster 13A FISH signals in contact with the nuclear lamina (p=0.0001). The LMNA E161K mutation caused central displacement of chromosome 13 gene clusters, reducing lamina contact for cluster 13A from 81.6% in normal nuclei to 59.4% in mutant nuclei.
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