Abstract
Hutchinson–Gilford progeria syndrome (HGPS) and restrictive dermopathy (RD) are two laminopathies caused by mutations leading to cellular accumulation of prelamin A or one of its truncated forms, progerin. One proposed mechanism for the more severe symptoms in patients with RD compared with HGPS is that higher levels of farnesylated lamin A are produced in RD. Here, we show evidence in support of that hypothesis. Overexpression of the most common progeroid lamin A mutation (LMNA c.1824C>T, p.G608G) during skin development results in a severe phenotype, characterized by dry scaly skin. At postnatal day 5 (PD5), progeroid animals showed a hyperplastic epidermis, disorganized sebaceous glands and an acute inflammatory dermal response, also involving the hypodermal fat layer. PD5 animals also showed an upregulation of multiple inflammatory response genes and an activated NF-kB target pathway. Careful analysis of the interfollicular epidermis showed aberrant expression of the lamin B receptor (LBR) in the suprabasal layer. Prolonged expression of LBR, in 14.06% of the cells, likely contributes to the observed arrest of skin development, clearly evident at PD4 when the skin had developed into single-layer epithelium in the wild-type animals while progeroid animals still had the multilayered appearance typical for skin at PD3. Suprabasal cells expressing LBR showed altered DNA distribution, suggesting the induction of gene expression changes. Despite the formation of a functional epidermal barrier and proven functionality of the gap junctions, progeroid animals displayed a greater rate of water loss as compared with wild-type littermates and died within the first two postnatal weeks.
Highlights
Hutchinson–Gilford progeria syndrome (HGPS or progeria, OMIM #176670) and restrictive dermopathy (RD, OMIM #275210) are two diseases with multiple clinical characteristics of premature aging (Merideth et al, 2008; Rodriguez & Eriksson, 2010)
Using an antibody directed against human lamin A/C, the transgenic expression was detected in the basal layer of the interfollicular epidermis and the hair follicle of the skin from embryos at the embryonic day 17.5 (E17.5) (Fig. 1B–G)
Our results showed that while the transgenic expression of progerin was unchanged (Fig. 1K), the expression of lamin A was slightly reduced, in PD8 compared with postnatal day 5 (PD5) (Fig. 1L), which was reflected by the relative increased ratio of progerin to lamin A (Fig. 1M)
Summary
Hutchinson–Gilford progeria syndrome (HGPS or progeria, OMIM #176670) and restrictive dermopathy (RD, OMIM #275210) are two diseases with multiple clinical characteristics of premature aging (Merideth et al, 2008; Rodriguez & Eriksson, 2010). Both are laminopathies, Accepted for publication 13 October 2013 diseases associated with mutations in the LMNA gene. In the final processing step, a proteolytic cleavage removes the last 15 amino acids of the C-terminal to yield mature lamin A. The enzyme responsible for the last cleavage step is Zmpste, the metalloproteinase known as Face-1 in humans (Hutchison et al, 2001; Pendas et al, 2002; Capell & Collins, 2006; Smigiel et al, 2010)
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