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First published online 11 March 2008
doi: 10.1242/jcs.022913

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Targeted transgenic expression of the mutation causing Hutchinson-Gilford progeria syndrome leads to proliferative and degenerative epidermal disease

¹ Department of Biosciences and Nutrition, Karolinska Institutet, Karolinska University Hospital, Huddinge, Novum, SE-14186 Stockholm, Sweden
² Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, 50 South Drive, Bethesda, MD 20892, USA
³ Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, SE-14186 Stockholm, Sweden

^* Author for correspondence (e-mail: maria.eriksson{at}mednut.ki.se)

Accepted 19 January 2008

Hutchinson-Gilford progeria syndrome (HGPS) is a rare human genetic disorder characterized by striking progeroid features. Clinical findings in the skin include scleroderma, alopecia and loss of subcutaneous fat. HGPS is usually caused by a dominant-negative mutation in LMNA, a gene that encodes two major proteins of the inner nuclear lamina: lamin A and lamin C. We have generated tetracycline-inducible transgenic lines that carry a minigene of human LMNA under the control of a tet-operon. Two mouse lines were created: one carrying the wild-type sequence of LMNA and the other carrying the most common HGPS mutation. Targeted expression of the HGPS mutation in keratin-5-expressing tissues led to abnormalities in the skin and teeth, including fibrosis, loss of hypodermal adipocytes, structural defects in the hair follicles and sebaceous glands, and abnormal incisors. The severity of the defects was related to the level of expression of the transgene in different mouse lines. These transgenic mice appear to be good models for studies of the molecular mechanisms of skin abnormalities in HGPS and other related disorders.

Key words: Hutchinson-Gilford Progeria Syndrome, Progerin, LMNA gene, Lamin A/C, Prelamin A, Tet-off system, K5tTA, Epidermal hyperplasia