Three-dimensional FISH of chromosome 13 and 7 was carried out in fibroblast cells using chromosome 13 or 7 paint as a probe and the chromosome territory volumes were calculated. Mutations in the nuclear membrane gene, LMNA, cause inherited human disease. Many LMNA mutations have been linked to striated muscle disease where there is progressive weakness of skeletal and cardiac muscle and often concomitant cardiac conduction system disease. Within LMNA mutant families, there are strikingly variable phenotypes and the mechanism by which an individual LMNA missense mutation causes disease may be mutation specific. In this study, we examined the gene expression changes and chromosomal positioning of misexpressed loci from a LMNA mutation, E161K. This mutation was previously associated with inherited cardiomyopathy. The distribution of LMNA mutations has challenged genotype-phenotype correlations since mutations associated with striated muscle disease can map anywhere within lamins A and C and may be associated with gain of function, dominant negative effects, loss of function, as well as haploinsufficiency. Only the lipodystrophy and progeria phenotypes have shown some evidence of a genotypephenotype relationship. We hypothesize that distinct mutations, even those mutations associated with a similar phenotype, may produce disease through unique and differential effects on chromosome positioning and gene expression. We analyzed heart from a single LMNA mutation, E161K. We found that while nuclear architecture was disturbed, the appearance and positioning of the heterochromatin and protein components of the LINC complex, including lamin A/C, were intact. From this, we expect that the inner nuclear membrane complex is INCB18424 distributor normally LY2109761 TGF-beta inhibitor localized but abnormally assembled at its site. Incorporation of mutant lamin A/C into the nuclear lamina may provide an uneven surface that fails to normally interact with chromatin. The precise chromosomal markings for lamin A/C interaction have yet to be defined, but our data would suggest that chromosome 13 may harbor sequences more likely to be altered by a mutant nuclear lamina. It is interesting to note that chromosome 13 is among the most gene poor chromosome with a high percentage of noncoding region. Gene expression profiling of LMNA E161K heart revealed genomic clustering of misexpressed genes.