Human Molecular Genetics Advance Access originally published online on April 28, 2008
Human Molecular Genetics 2008 17(15):2357-2369; doi:10.1093/hmg/ddn136
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Epidermal expression of the truncated prelamin A causing Hutchinson–Gilford progeria syndrome: effects on keratinocytes, hair and skin
1 Department of Medicine 2 Department of Pathology and Cell Biology 3 Department of Dermatology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA 4 Division of Surgery and Molecular Oncology, College of Medicine, Dentistry and Nursing, University of Dundee, Dundee DD1 9SY, UK 5 Institute of Medical Biology, 138668 Singapore, Singapore
* To whom correspondence should be addressed at: Department of Medicine, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, 10th Floor, Room 509, New York, NY 10032, USA. Tel: +1 2123058156; Fax: +1 2123056443; Email: hjw14{at}columbia.edu
Received March 25, 2008; Accepted April 21, 2008
Hutchinson–Gilford progeria syndrome (HGPS) is an accelerated aging disorder caused by point mutation in LMNA encoding A-type nuclear lamins. The mutations in LMNA activate a cryptic splice donor site, resulting in expression of a truncated, prenylated prelamin A called progerin. Expression of progerin leads to alterations in nuclear morphology, which may underlie pathology in HGPS. We generated transgenic mice expressing progerin in epidermis under control of a keratin 14 promoter. The mice had severe abnormalities in morphology of skin keratinocyte nuclei, including nuclear envelope lobulation and decreased nuclear circularity not present in transgenic mice expressing wild-type human lamin A. Primary keratinocytes isolated from these mice had a higher frequency of nuclei with abnormal shape compared to those from transgenic mice expressing wild-type human lamin A. Treatment with a farnesyltransferase inhibitor significantly improved nuclear shape abnormalities and induced the formation of intranuclear foci in the primary keratinocytes expressing progerin. Similarly, spontaneous immortalization of progerin-expressing cultured keratinocytes selected for cells with normal nuclear morphology. Despite morphological alterations in keratinocyte nuclei, mice expressing progerin in epidermis had normal hair grown and wound healing. Hair and skin thickness were normal even after crossing to Lmna null mice to reduce or eliminate expression of normal A-type lamins. Although progerin induces significant alterations in keratinocyte nuclear morphology that are reversed by inhibition of farnesyltransferasae, epidermal expression does not lead to alopecia or other skin abnormalities typically seen in human subjects with HGPS.