Figure 1.
Fibroblast nuclei from the LMNAK542/K542N patient and healthy control.
(A) Immunofluorescence staining for lamin A and lamin B1. (B) Immunofluorescence microscopy using lamin A and emerin antibodies. (C) Confocal microscopy using lamin A and LAP2 antibodies. Scale bar, 10 µM.
Figure 2.
Immunohistochemical analysis in skin and liver autoptic specimens from a deceased LMNAK542/K542N patient.
(A) Immunohistochemistry for lamin A. (B) Immunohistochemical staining for Twist2. Arrow indicates Twist2 loss in the periadenexial cells (PC) of the dermis in the skin and in the Kupffer (KC) and endothelial cells (EC) of the liver. (C) Immunohistochemistry for Wnt5a. Scale bar, 10 µM.
Table 1.
Overlap between LMNA K542N and G608G expression signatures.
Table 2.
Phenotypic overlap between HGPS, Setleis syndrome patients, and Twist2−/− mice.
Figure 3.
Effects of the LMNA K542N mutation on bone remodeling and energy metabolism through the insulin/osteocalcin axis.
(A) Energy regulation and bone turnover by insulin signaling, adapted from Rosen and Motyl [74]. Insulin binds to the insulin receptor (IR) and activates bone remodeling by increasing bone formation by osteoblasts (through down-regulation of Twist2) and resorption by osteoclasts (though down-regulatin of OPG). Bone formation is coupled with the production of inactive (carboxylated) osteocalcin which is then released in an active form (undercarboxylated) during bone resorption and enters into the circulation. The active, hormonal form of osteocalcin enhances insulin secretion and increases the insulin sensitivity of adipocytes. (B) Altered regulation of energy metabolism and bone turnover in hereditary HGPS. In a homozygous state, the LMNA K542N mutation leads to the down-regulation of TWIST2 and subsequent increased production of inactive osteocalcin. Decreased expression of OPG in LMNA K542N homozygotes enhances bone resorption, which then increases the release of the active, hormonal form of osteocalcin, and consequently results in increased insulin sensitivity. In a heterozygous state, the LMNA K542N mutation might overrule increased insulin sensitivity.