© 1997 American Heart Association, Inc.
Articles |
Targeted Ablation of the Murine 
-Tropomyosin Gene
From Howard Hughes Medical Institute and Department of Genetics, Harvard Medical School, Boston, Mass (E.M.B., K.I., M.C., D.A.C., J.G.S.); the Department of Molecular Physiology and Biophysics, University of Vermont Medical School, Burlington (D.W.M.); Brigham and Women's Hospital, Boston, Mass (F.J.S.); Howard Hughes Medical Institute and Brigham and Women's Hospital, Boston, Mass (C.E.S.); and Allelix Biopharmaceuticals Inc, Mississauga, Ontario, Canada (A.G.-L.).
Correspondence to Dr Jonathan Seidman, Department of Genetics, Harvard Medical School, 200 Longwood Ave, Boston, MA 02115. E-mail seidman{at}rascal.med.harvard.edu
Abstract We created a mouse that lacks a functional
-tropomyosin gene using gene targeting in embryonic stem cells and
blastocyst-mediated transgenesis. Homozygous -tropomyosin
"knockout" mice die between embryonic day 9.5 and 13.5 and lack
-tropomyosin mRNA. Heterozygous -tropomyosin knockout mice have
50% as much cardiac -tropomyosin mRNA as wild-type littermates
but similar -tropomyosin protein levels. Cardiac gross morphology,
histology, and function (assessed by working heart preparations) of
heterozygous -tropomyosin knockout and wild-type mice were
indistinguishable. Mechanical performance of skinned papillary
muscle strips derived from mutant and wild-type hearts also revealed no
differences. We conclude that haploinsufficiency of the -tropomyosin
gene produces little or no change in cardiac function or structure,
whereas total -tropomyosin deficiency is incompatible with life.
These findings imply that in heterozygotes there is a regulatory
mechanism that maintains the level of myofibrillar tropomyosin despite
the reduction in -tropomyosin mRNA.
Key Words: -tropomyosin • haploinsufficiency • knockout mouse
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