These authors contributed equally to this work.
Embryonic expression of the common progeroid lamin A splice mutation arrests postnatal skin development
Article first published online: 24 JAN 2014
© 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Volume 13, Issue 2, pages 292–302, April 2014
How to Cite
McKenna, T., Rosengardten, Y., Viceconte, N., Baek, J.-H., Grochová, D. and Eriksson, M. (2014), Embryonic expression of the common progeroid lamin A splice mutation arrests postnatal skin development. Aging Cell, 13: 292–302. doi: 10.1111/acel.12173
- Issue published online: 11 MAR 2014
- Article first published online: 24 JAN 2014
- Accepted manuscript online: 4 DEC 2013 09:25AM EST
- Manuscript Accepted: 13 OCT 2013
- Swedish medical research council
- OE & Edla Johansson
- Lars Hiertas minne
- Svenska läkare sällskapet
- Åke Wiberg
- Karolinska Institutet KID founding
- Royal Swedish Academy of Sciences
- Knut and Alice Wallenberg Foundation
- Swedish Research Council
- Center for Biosciences
- HGPS ;
- lamin B;
- lamin B receptor;
- restrictive dermopathy
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.