Abstract: Although it can be farnesylated, the mutant lamin A protein expressed in Hutchison Gilford Progeria Syndrome (HGPS) cannot be defarnesylated because the characteristic mutation causes deletion of a cleavage site necessary for binding the protease ZMPSTE24 and effecting defarnesylation. The result is an aberrant farnesylated protein (called “progerin”) that alters normal lamin A function as a dominant negative, as well as assuming its own aberrant function through its association with the nuclear membrane. The retention of farnesylation, and potentially other abnormal properties of progerin and other abnormal lamin gene protein products, produces disease. Farnesyltransferase inhibitors (FTIs) (both direct effectors and indirect inhibitors) will inhibit the formation of progerin, cause a decrease in lamin A protein, and/or an increase prelamin A protein. Decreasing the amount of aberrant protein improves cellular effects caused by and progerin expression.
Type:
Application
Filed:
July 25, 2007
Publication date:
June 5, 2008
Inventors:
Leslie B. Gordon, Francis S. Collins, Thomas Glover, Michael W. Glynn, Brian C. Capell, Adrienne D. Cox, Channing J. Der
Abstract: Although it can be farnesylated, the mutant lamin A protein expressed in Hutchinson Gilford Progeria Syndrome (HGPS) cannot be defarnesylated because the characteristic mutation causes deletion of a cleavage site necessary for binding the protease ZMPSTE24 and effecting defarnesylation. The result is an aberrant farnesylated protein (called “progerin”) that alters normal lamin A function as a dominant negative, as well as assuming its own aberrant function through its association with the nuclear membrane. The retention of farnesylation, and potentially other abnormal properties of progerin and other abnormal lamin gene protein products, produces disease. Farnesyltransferase inhibitors (FTIs) (both direct effectors and indirect inhibitors) will inhibit the formation of progerin, cause a decrease in lamin A protein, and/or an increase prelamin A protein. Decreasing the amount of aberrant protein improves cellular effects caused by and progerin expression.
Type:
Grant
Filed:
April 4, 2013
Date of Patent:
September 9, 2014
Assignees:
Progeria Research Foundation, Inc., The United States of America as represented by the Secretary of the Department of Health and Human Services, The University of North Carolina at Chapel Hill, The Regents of the University of Michigan
Inventors:
Leslie B. Gordon, Francis S. Collins, Thomas Glover, Michael W. Glynn, Brian C. Capell, Adrienne D. Cox, Channing J. Der
Abstract: Although it can be farnesylated, the mutant lamin A protein expressed in Hutchison Gilford Progeria Syndrome (HGPS) cannot be defarnesylated because the characteristic mutation causes deletion of a cleavage site necessary for binding the protease ZMPSTE24 and effecting defarnesylation. The result is an aberrant farnesylated protein (called “progerin”) that alters normal lamin A function as a dominant negative, as well as assuming its own aberrant function through its association with the nuclear membrane. The retention of farnesylation, and potentially other abnormal properties of progerin and other abnormal lamin gene protein products, produces disease. Farnesyltransferase inhibitors (FTIs) (both direct effectors and indirect inhibitors) will inhibit the formation of progerin, cause a decrease in lamin A protein, and/or an increase prelamin A protein. Decreasing the amount of aberrant protein improves cellular effects caused by and progerin expression.
Type:
Grant
Filed:
July 25, 2007
Date of Patent:
November 23, 2010
Assignees:
The United States of America as represented by the Department of Health and Human Services, The Regents of the University of Michiga, Progeria Research Foundation, Inc., The University of North Carolina at Chapel Hill
Inventors:
Leslie B. Gordon, Francis S. Collins, Thomas Glover, Michael W. Glynn, Brian C. Capell, Adrienne D. Cox, Channing J. Der