Key result
LMNA E161K mutation displaces chromosome 13 centrally, altering expression of striated muscle disease genes.
Why the study?
Dominant LMNA mutations cause cardiac and skeletal myopathies, and mutant lamin A/C was hypothesized to disrupt gene expression by altering the nuclear lamina's interaction with chromatin.
Absolute Event Rate: 2% vs 0.9%
p-value: p=0.0088
Cardiomyopathic LMNA mutations alter the intranuclear positioning and compaction of chromosomal domains, providing a mechanism for altered gene expression in striated muscle disease.
LMNA mutations may disrupt chromatin positioning in striated muscle; leaves open translation to human cardiomyopathy and therapeutic targets.
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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Mewborne et al. (2010) studied Dilated cardiomyopathy. LMNA E161K mutation vs. LMNA normal was evaluated on Minimum distance from the edge of chromosome 13 territory to the edge of DAPI staining (µm) (p=0.0088). The LMNA E161K mutation displaced the chromosome 13 territory towards the nuclear center (2.0 vs 0.9 µm from the edge, p=0.0088) and altered the expression of genes relevant to striated muscle disease.
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