A farnesyltransferase inhibitor improves disease phenotypes in mice with a Hutchinson-Gilford progeria syndrome mutation
Shao H. Yang, Margarita Meta, Xin Qiao, David Frost, Joy Bauch, Catherine Coffinier, Sharmila Majumdar, Martin O. Bergo, Stephen G. Young, Loren G. Fong
Shao H. Yang, Margarita Meta, Xin Qiao, David Frost, Joy Bauch, Catherine Coffinier, Sharmila Majumdar, Martin O. Bergo, Stephen G. Young, Loren G. Fong
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Research Article Genetics

A farnesyltransferase inhibitor improves disease phenotypes in mice with a Hutchinson-Gilford progeria syndrome mutation

Abstract

Hutchinson-Gilford progeria syndrome (HGPS) is caused by the production of a truncated prelamin A, called progerin, which is farnesylated at its carboxyl terminus. Progerin is targeted to the nuclear envelope and causes misshapen nuclei. Protein farnesyltransferase inhibitors (FTI) mislocalize progerin away from the nuclear envelope and reduce the frequency of misshapen nuclei. To determine whether an FTI would ameliorate disease phenotypes in vivo, we created gene-targeted mice with an HGPS mutation (LmnaHG/+) and then examined the effect of an FTI on disease phenotypes. LmnaHG/+ mice exhibited phenotypes similar to those in human HGPS patients, including retarded growth, reduced amounts of adipose tissue, micrognathia, osteoporosis, and osteolytic lesions in bone. Osteolytic lesions in the ribs led to spontaneous bone fractures. Treatment with an FTI increased adipose tissue mass, improved body weight curves, reduced the number of rib fractures, and improved bone mineralization and bone cortical thickness. These studies suggest that FTIs could be useful for treating humans with HGPS.

Authors

Shao H. Yang, Margarita Meta, Xin Qiao, David Frost, Joy Bauch, Catherine Coffinier, Sharmila Majumdar, Martin O. Bergo, Stephen G. Young, Loren G. Fong

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Figure 6

An FTI (ABT-100) ameliorates bone disease in LmnaHG/+ mice.

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An FTI (ABT-100) ameliorates bone disease in LmnaHG/+...
(A) Radiographs of a 6-month-old vehicle-treated LmnaHG/+ mouse and a littermate FTI-treated LmnaHG/+ mouse. (B) Kyphotic index in FTI-treated and vehicle-treated LmnaHG/+ and Lmna+/+ mice. The degree of kyphosis in LmnaHG/+ mice was greater (a smaller kyphotic index) than in Lmna+/+ mice (P < 0.0001) and was significantly reduced (a larger kyphotic index) after FTI treatment (P = 0.02; n = 10 per group). (C) Reduced number of rib fractures in FTI-treated LmnaHG/+ mice. After 24 weeks, surviving mice were euthanized, and the number of rib fractures was counted. The number of rib fractures in the FTI-treated LmnaHG/+ mice was significantly lower than in vehicle-treated LmnaHG/+ mice (P < 0.0001). (D) μCT scans illustrating reduced numbers of rib fractures in FTI-treated LmnaHG/+ mice. Red arrowheads indicate rib fractures and surrounding callus. In the FTI-treated mouse, there was thinning of 1 rib along with a small amount of callus. No rib fractures were observed in Lmna+/+ mice. (E and F) FTI treatment improved bone mineralization (E) and bone cortical thickness (F) in LmnaHG/+ mice without affecting the bones of Lmna+/+ mice. Error bars are too small to be seen in E. gHA/cm3, grams of hydroxyapatite per cubic centimeter.