Mouse models for understanding the molecular mechanism of bone disease in Hutchinson-Gilford progeria syndrome

Aging is a complex process affecting all people. Intense research is applied to elucidate the biological basis of aging and disease that develop with aging. Studies of progeroid syndromes, where aging happens in an accelerated speed, might be useful to understand the molecular mechanisms in physiological aging. Hutchinson-Gilford progeria syndrome (HGPS or progeria) is a very rare, fatal genetic disease, with an incidence of 1 in 4-8 million live births, which causes segmental premature aging in children. Affected individuals are born looking healthy, but develop symptoms of disease within their first years of life. Signs of progeria include growth retardation, loss of body fat and hair, skin changes, stiffness of joints, hip dislocations and generalized atherosclerosis and cardiovascular disease. Children with HGPS die of heart disorders or stroke at an average age of 13 years. The aim of this thesis is to increase the understanding of the molecular mechanisms underlying progeria. For this purpose, we developed tissue- specific inducible mouse models for the most common HGPS mutation in the LMNA gene (c.1824C

We demonstrate that the disease pathology in HGPS is reversible in a mouse model with keratin 5-targeted transgenic expression of the HGPS mutation. The mice had a progressive phenotype with similar abnormalities to those seen in the skin and teeth of HGPS patients. These abnormalities improved in mice following 6 and 13 weeks of suppressed expression of the HGPS mutation. Our results give hope for the future development of treatments for children with HGPS.

We report our negative experience with a previously functional transactivator mice that failed to target the expression of the lamin A minigenes to the bone. To share this result with the scientific community will help to raise caution and to point out the importance for controls.

List of scientific papers

I. Sagelius H, Rosengardten Y, Schmidt E, Sonnabend C, Rozell B, Eriksson M. Reversible phenotype in a mouse model of Hutchinson-Gilford progeria syndrome. Journal of Medical Genetics. 2008; 45 (12): 794-801.
https://doi.org/10.1136/jmg.2008.060772

II. Schmidt E, Eriksson M. A previously functional tetracycline- regulated transactivator fails to target gene expression to the bone. BMC Research Notes. 2011; 4 (1): 282.
https://doi.org/10.1186/1756-0500-4-282

III. Schmidt E, Nilsson O, Koskela A, Tuukkanen J, Ohlsson C, Rozell B, Eriksson M. Expression of the Hutchinson-Gilford progeria mutation during osteoblast development leads to irregular bone mineralization and impaired skeletal integrity. [Submitted]

IV. Schmidt E, Rodríguez S, Rozell B, Mugnaini E, Eriksson M. Effects from brain-specific expression of the Hutchinson-Gilford progeria syndrome mutation. [Manuscript]