A Farnesyltransferase Inhibitor Improves Disease Phenotypes in Mice with a Hutchinson-Gilford Progeria Syndrome Mutation

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2006 Jul 25

PMID 16862216

Citations 150

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

Affiliations

Soon will be listed here.

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.

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References

Sullivan T, Escalante-Alcalde D, Bhatt H, Anver M, Bhat N, Nagashima K . Loss of A-type lamin expression compromises nuclear envelope integrity leading to muscular dystrophy. J Cell Biol. 1999; 147(5):913-20. PMC: 2169344. DOI: 10.1083/jcb.147.5.913. View

Fong L, Frost D, Meta M, Qiao X, Yang S, Coffinier C . A protein farnesyltransferase inhibitor ameliorates disease in a mouse model of progeria. Science. 2006; 311(5767):1621-3. DOI: 10.1126/science.1124875. View

Stehbens W, Delahunt B, Shozawa T, Gilbert-Barness E . Smooth muscle cell depletion and collagen types in progeric arteries. Cardiovasc Pathol. 2001; 10(3):133-6. DOI: 10.1016/s1054-8807(01)00069-2. View

Ackerman J, Gilbert-Barness E . Hutchinson-Gilford progeria syndrome: a pathologic study. Pediatr Pathol Mol Med. 2002; 21(1):1-13. DOI: 10.1080/pdp.21.1.1.13. View

Bergo M, Gavino B, Ross J, Schmidt W, Hong C, Kendall L . Zmpste24 deficiency in mice causes spontaneous bone fractures, muscle weakness, and a prelamin A processing defect. Proc Natl Acad Sci U S A. 2002; 99(20):13049-54. PMC: 130584. DOI: 10.1073/pnas.192460799. View

Eriksson M, Brown W, Gordon L, Glynn M, Singer J, Scott L . Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature. 2003; 423(6937):293-8. PMC: 10540076. DOI: 10.1038/nature01629. View

Mounkes L, Kozlov S, Hernandez L, Sullivan T, Stewart C . A progeroid syndrome in mice is caused by defects in A-type lamins. Nature. 2003; 423(6937):298-301. DOI: 10.1038/nature01631. View

Goldman R, Shumaker D, Erdos M, Eriksson M, Goldman A, Gordon L . Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci U S A. 2004; 101(24):8963-8. PMC: 428455. DOI: 10.1073/pnas.0402943101. View

Laws N, Hoey A . Progression of kyphosis in mdx mice. J Appl Physiol (1985). 2004; 97(5):1970-7. DOI: 10.1152/japplphysiol.01357.2003. View

10.

DeBusk F . The Hutchinson-Gilford progeria syndrome. Report of 4 cases and review of the literature. J Pediatr. 1972; 80(4):697-724. DOI: 10.1016/s0022-3476(72)80229-4. View

11.

Steinert P, Zackroff R, Goldman R . Isolation and characterization of intermediate filaments. Methods Cell Biol. 1982; 24:399-419. DOI: 10.1016/s0091-679x(08)60667-6. View

12.

Arimura T, Helbling-Leclerc A, Massart C, Varnous S, Niel F, Lacene E . Mouse model carrying H222P-Lmna mutation develops muscular dystrophy and dilated cardiomyopathy similar to human striated muscle laminopathies. Hum Mol Genet. 2004; 14(1):155-69. DOI: 10.1093/hmg/ddi017. View

13.

Fong L, Ng J, Meta M, Cote N, Yang S, Stewart C . Heterozygosity for Lmna deficiency eliminates the progeria-like phenotypes in Zmpste24-deficient mice. Proc Natl Acad Sci U S A. 2004; 101(52):18111-6. PMC: 536056. DOI: 10.1073/pnas.0408558102. View

14.

Scaffidi P, Misteli T . Reversal of the cellular phenotype in the premature aging disease Hutchinson-Gilford progeria syndrome. Nat Med. 2005; 11(4):440-5. PMC: 1351119. DOI: 10.1038/nm1204. View

15.

Ferguson D, Rodriguez L, Palma J, Refici M, Jarvis K, OConnor J . Antitumor activity of orally bioavailable farnesyltransferase inhibitor, ABT-100, is mediated by antiproliferative, proapoptotic, and antiangiogenic effects in xenograft models. Clin Cancer Res. 2005; 11(8):3045-54. DOI: 10.1158/1078-0432.CCR-04-2041. View

16.

Mounkes L, Kozlov S, Rottman J, Stewart C . Expression of an LMNA-N195K variant of A-type lamins results in cardiac conduction defects and death in mice. Hum Mol Genet. 2005; 14(15):2167-80. DOI: 10.1093/hmg/ddi221. View

17.

Yang S, Bergo M, Toth J, Qiao X, Hu Y, Sandoval S . Blocking protein farnesyltransferase improves nuclear blebbing in mouse fibroblasts with a targeted Hutchinson-Gilford progeria syndrome mutation. Proc Natl Acad Sci U S A. 2005; 102(29):10291-6. PMC: 1174929. DOI: 10.1073/pnas.0504641102. View

18.

Capell B, Erdos M, Madigan J, Fiordalisi J, Varga R, Conneely K . Inhibiting farnesylation of progerin prevents the characteristic nuclear blebbing of Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci U S A. 2005; 102(36):12879-84. PMC: 1200293. DOI: 10.1073/pnas.0506001102. View

19.

Toth J, Yang S, Qiao X, Beigneux A, Gelb M, Moulson C . Blocking protein farnesyltransferase improves nuclear shape in fibroblasts from humans with progeroid syndromes. Proc Natl Acad Sci U S A. 2005; 102(36):12873-8. PMC: 1193538. DOI: 10.1073/pnas.0505767102. View

20.

Glynn M, Glover T . Incomplete processing of mutant lamin A in Hutchinson-Gilford progeria leads to nuclear abnormalities, which are reversed by farnesyltransferase inhibition. Hum Mol Genet. 2005; 14(20):2959-69. DOI: 10.1093/hmg/ddi326. View