Faculty Collaboration Database

Transgenic over-expression of a motor protein at high levels results in severe cardiac pathology. Transgenic Res 1999 Feb;8(1):9-22

Date

07/10/1999

Pubmed ID

10399364

DOI

10.1023/a:1008894507995

Scopus ID

2-s2.0-0033082739 (requires institutional sign-in at Scopus site)   33 Citations

Abstract

Transgenesis has become a useful tool in effecting a complete or partial remodeling of the cardiac contractile apparatus. Although gene dosage effects were initially a concern, recent data showed that the heart is able to accommodate varying levels of transgenic over-expression without detectable ill effects. The present study was designed to test the limits of the transgenic paradigm in terms of the production of a cardiac phenotype due simply to the over-expression of a contractile protein. To this end, eight lines of mice which express an isoform of the essential myosin light chain 1 that is normally found in the adult ventricle (ELC1v) were generated. Overt phenotype was correlated both with the level of expression/protein replacement and copy number of the transgene. Two of the lines showed essentially complete replacement of the atrial isoform (ELC1a) with ELC1v. However, the phenotypes of the two lines differed dramatically. The line with the lower copy number (37 copies), and moderate over-expression (16 fold) showed no overt pathology while a line with very high copy number (94 copies) and extremely high levels of over-expression (27-50 fold) developed a significant atrial hypertrophy, dilation and cardiomyopathy. These data indicate that very high expression levels of a contractile protein can cause a cardiac pathology that is unrelated to its degree of replacement in the sarcomere and the unique role(s) it may assume in motor protein function.

Author List

James J, Osinska H, Hewett TE, Kimball T, Klevitsky R, Witt S, Hall DG, Gulick J, Robbins J

MESH terms used to index this publication - Major topics in bold

Actins
Amino Acid Sequence
Animals
Atrial Natriuretic Factor
Base Sequence
Biomarkers
Calcium-Transporting ATPases
Cardiomegaly
Connectin
Gene Dosage
Gene Expression
Heart Atria
Heart Defects, Congenital
Heart Ventricles
Mice
Mice, Transgenic
Molecular Sequence Data
Muscle Proteins
Myocardial Contraction
Myocardium
Myosin Light Chains
Protein Biosynthesis
Protein Isoforms
Protein Kinases
RNA, Messenger
Sequence Homology, Amino Acid
Transcription, Genetic
Ventricular Dysfunction, Left