XB-ART-46554Nucleus July 1, 2011; 2 (4): 310-9.
Amphibian oocyte nuclei expressing lamin A with the progeria mutation E145K exhibit an increased elastic modulus.
Mutations in the human lamin A gene (LMNA) cause a wide range of diseases (laminopathies). Among these is the Hutchinson-Gilford progeria syndrome (HGPS), a rare premature aging disease. Most HGPS patients carry a silent point mutation, which activates a cryptic splice site resulting in the expression of a permanently isoprenylated and truncated lamin AΔ50/progerin. Another type of mutant lamin A namely, E145K-lamin A, also causes HGPS. E145K-lamin A induces profound changes in the nuclear architecture of patient cells as well as after expression in cultured cells. The E145K mutation is located in the α-helical central domain of lamin A, which is involved in lamin filament assembly. In vitro analyses of purified E145K-lamin A have revealed severe assembly defects into higher order lamin structures, which indicates an abnormal lateral association of protofilaments. To analyze how the altered assembly observed in vitro might influence the mechanics of a nuclear lamina formed by E145K-lamin A, mutant and wild type lamin A were ectopically expressed in amphibian oocytes. Both types form a lamina consisting of multi-layered sheets of filaments at the inner side of the nuclear envelope. The mechanical properties of isolated nuclei were measured by atomic force microscopy (AFM). From the resulting force curves, the stiffness of the lamina was estimated. The thickness of the resulting lamin A layer was then measured by TEM. The two parameters allowed us to estimate the elastic modulus (Young''s modulus) of the lamina. Lamin A sheets made from E145K filaments have a higher Young''s modulus compared to wild type filaments, i.e. the E145K-lamin A sheets are more rigid than wild type laminae of comparable thickness.
PubMed ID: 21941106
Article link: Nucleus
Genes referenced: lmna robo3
GO keywords: lamin filament
Disease Ontology terms: progeria
OMIMs: HUTCHINSON-GILFORD PROGERIA SYNDROME; HGPS