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Abstract

Background: The autosomal dominant form of Emery-Dreifuss muscular dystrophy (AD-EDMD) is caused by mutations in the gene encoding for the lamins A and C (LMNA). Lamins are intermediate filament proteins which form the nuclear lamina underlying the inner nuclear membrane. We have studied the expression and the localization of nuclear envelope proteins in three different cell types and muscle tissue of an AD-EDMD patient carrying a point mutation R377H in the lamin A/C gene.

AFM single-cell force spectroscopy links altered nuclear and cytoskeletal mechanics to defective cell adhesion in cardiac myocytes with a nuclear lamin mutation

“…Since NRVMs expressing wild-type LMNA displayed stiffness comparable to uninfected cells, the higher stiffness in LMNA D192G NRVM appears to be related to the expression of the defective LMNA D192G protein. The time-course of expression of the introduced construct, along with the half-life of the LMNA proteins described by others, [25][26][27] suggests that these mutant proteins compete with endogenous LMNA to cause the abnormal mechanical properties seen. Indeed, consistent with this model, the subsequent introduction of additional wild-type LMNA competes with mutant protein and "rescues" the biomechanical properties of the cells expressing the LMNA D192G mutation.…”

“…[15][16][17] In support of this being the mechanism of our investigations with the LMNA protein, work by others has shown a very rapid turn-over for LMNA precursor incorporation into the nuclear membrane, on the order of 4 hours: this would mean that our exogenous protein should have the ability to effectively compete for incorporation under both MT and WT (rescue) circumstances over the time-course examined in our work. [25][26][27] The AFM force-deformation curves demonstrate that the alterations in nuclear stiffness of the LMNA D192G cardiomyocytes are accompanied by a series of complex cellular changes ranging from the cell membrane work of adhesion properties to altered whole-cell deformation. By measuring the force curves on cultured NRVMs, we observed that CT and WT cells display similar detachment behavior, with curves showing an initial, large de-adhesion peak followed by smaller peaks, reflecting the energy required to detach the adhesion molecules of the cell membrane from the AFM tip ('steps' of the detachment curve).…”

Uncoordinated Transcription and Compromised Muscle Function in the Lmna-Null Mouse Model of Emery-Dreifuss Muscular Dystrophy

“…Therefore, the marked reduction/absence of acetyl-histone H3 from a significant number of lmna -null myonuclei was more than counterbalanced by the relative hyperacetylation in other myonuclei. Global epigenetic defects have been reported in myoblasts from A-EDMD patients carrying either the R377H or R545C mutations [47] , [48] , and also occur following over-expression of the A-EDMD-causing lamin A mutation R453W in C2 myoblasts [49] . Epigenetic modifications are also found in fibroblasts from patients with the premature aging disorder Hutchinson-Gilford progeria syndrome [50] , indicating that it may be a feature common to laminopathies in general.…”

The Nuclear Envelope, a Key Structure in Cellular Integrity and Gene Expression

“…The LBR, that seems to depend on both A-and Btype lamins for its intra-nuclear localization [83,84], is also involved in DNA and chromatin interaction and may provide another chromatin-anchorage site at the INM [85,86]. In addition, titin, a giant molecule previously thought to be only involved in sarcomere organization in striated muscle, was recently found in the nucleus where it is involved in chromatin condensation during mitosis [87].…”

“…a component of the transcription factor TFIID, while transcription by RNA polymerase I and III was not affected [113]. Interestingly, the LMNA mutation R377H causing Emery-Dreifuss muscular dystrophy (EDMD) alters the electrostatic potential of the affected rod domain region without destabilizing the dimer structure [17] and results in aberrant localization of transcriptionally active RNA polymerase II [83].…”