A farnesyltransferase inhibitor improves disease phenotypes in mice with a Hutchinson-Gilford progeria syndrome mutation
Shao H. Yang, … , Stephen G. Young, Loren G. Fong
Shao H. Yang, … , Stephen G. Young, Loren G. Fong
Published August 1, 2006
Citation Information: J Clin Invest. 2006;116(8):2115-2121. https://doi.org/10.1172/JCI28968.
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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 2

Phenotypes in LmnaHG/+ mice.

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Phenotypes in LmnaHG/+ mice. ...
(A) Radiograph of a 6-month-old LmnaHG/+ mouse and a littermate Lmna+/+ mouse. (B) Kyphotic index of LmnaHG/+ and Lmna+/+ mice at 1 month (P = 0.076), 4 months (P = 0.009), and 7 months (P < 0.0001) of age (n = 4 per group). (C) Thorax of a 6-month-old LmnaHG/+ mouse and a littermate Lmna+/+ mouse. Black arrowheads indicate fracture callus surrounding broken ribs. (D) Number of rib fractures in 2-month-old LmnaHG/+ female (n = 3) and male (n = 4) mice, 4-month-old LmnaHG/+ female (n = 10) and male (n = 8) mice, and 7-month-old LmnaHG/+ female (n = 7) and male (n = 7) mice. No rib fractures were observed in Lmna+/+ mice. (E) Surface renderings of μCT scans of the skulls of 4-month-old LmnaHG/+ and Lmna+/+ mice. Red arrows indicate a characteristic absence of the zigzag appearance of the cranial sutures and osteolytic lesions of the zygomatic arch. (F) Surface renderings of μCT scans of the skulls of 4-month-old LmnaHG/+ and Lmna+/+ mice. Red arrows in the LmnaHG/+ skull indicate micrognathia and the site of an osteolytic lesion of the zygomatic arch. (G) Percentage of 4.5-month-old Zmpste24–/– (n = 16), littermate Zmpste24+/+ (n = 11), LmnaHG/+ (n = 30), and littermate Lmna+/+ mice (n = 12) with normal grip strength (ability to hang upside down from a grid for 60 seconds). P < 0.0001 for both Zmpste24–/– versus Zmpste24+/+ mice and Zmpste24–/– versus LmnaHG/+ mice. (H) H&E-stained sections of the ascending aorta from a 7-month-old LmnaHG/+ mouse and a littermate Lmna+/+ mouse. Original magnification, ×20.