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 5

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

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An FTI (ABT-100) ameliorates disease phenotypes in Lm...
(A) FTI treatment in LmnaHG/+ and Lmna+/+ mice leads to the appearance of wild-type prelamin A (with antibodies against prelamin A and lamin A/C) and the appearance of nonfarnesylated HDJ-2 (with an antibody against HDJ-2; nonfarnesyl–HDJ-2) in liver extracts of FTI-treated mice. Red arrows indicate prelamin A, which migrates slightly above mature lamin A. (B and C) Effect of FTI treatment on body weight in female (B) and male (C) mice. Lmna+/+ (circles) and LmnaHG/+ (squares) mice were given the FTI (red symbols) or vehicle alone (open symbols), beginning at 4 weeks of age, and body weights were measured weekly. Body weight curves for the FTI-treated LmnaHG/+ mice were significantly improved, compared with those for vehicle-treated LmnaHG/+ mice (P < 0.0001 for both males and females). Male LmnaHG/+ mice on vehicle, n = 9; male LmnaHG/+ mice on FTI, n = 7; female LmnaHG/+mice on vehicle, n = 5; female LmnaHG/+ mice on FTI, n = 10; male Lmna+/+ mice on vehicle, n = 5; male Lmna+/+ mice on FTI, n = 5; female Lmna+/+ mice on vehicle, n = 9; female Lmna+/+ mice on FTI, n = 4. (D) Body fat weights in LmnaHG/+ mice on FTI or on the vehicle alone. The weight of body fat in LmnaHG/+ mice was significantly lower than in Lmna+/+ mice (P < 0.0001) and was significantly increased after FTI treatment (P = 0.002). (E) Representative H&E-stained sections of skin from 6-month-old Lmna+/+, vehicle-treated LmnaHG/+, and FTI-treated LmnaHG/+ mice; n = 4 mice in each group examined. The black line spans the layer of subcutaneous fat.