Cardiac defects and altered ryanodine receptor function in mice lacking FKBP12

Weinian Shou, Bahman Aghdasi, Dawna L. Armstrong, Qiuxia Guo, Shideng Bao, Min-Ji Charng, Lawrence M. Mathews, Michael D. Schneider, Susan L. Hamilton and Martin M. Matzuk
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Weinian Shou: Departments of Pathology
Bahman Aghdasi: Departments of Molecular Physiology and Biophysics
Dawna L. Armstrong: Departments of Pathology
Qiuxia Guo: Departments of Pathology
Shideng Bao: Departments of Pathology
Min-Ji Charng: Baylor College of Medicine
Lawrence M. Mathews: University of Michigan
Michael D. Schneider: Baylor College of Medicine
Susan L. Hamilton: Departments of Molecular Physiology and Biophysics
Martin M. Matzuk: Departments of Pathology

Nature, 1998, vol. 391, issue 6666, 489-492

Abstract: Abstract FKBP12, a cis–trans prolyl isomerase that binds the immunosuppressants FK506 and rapamycin, is ubiquitouslyexpressed and interacts with proteins in several intracellular signal transduction systems1.Although FKBP12 interacts with the cytoplasmic domains of type I receptors of the transforming growth factor-β(TGF-β) superfamily in vitro, the function of FKBP12 in TGF-β superfamily signalling iscontroversial2,3,4,5,6. FKBP12 also physicallyinteracts stoichiometrically with multiple intracellular calcium release channels including the tetrameric skeletal muscle ryanodine receptor(RyR1)7,8. In contrast, the cardiacryanodine receptor, RyR2, appears to bind selectively theFKBP12 homologue, FKBP12.6 (9, 10). To define the functions of FKBP12 in vivo, we generated mutantmice deficient in FKBP12 using embryonic stem (ES) cell technology. FKBP12-deficient mice have normal skeletal muscle buthave severe dilated cardiomyopathy and ventricular septal defects that mimic a human congenital heart disorder, noncompaction of leftventricular myocardium11,12. About 9% of themutants exhibit exencephaly secondary to a defect in neural tube closure. Physiological studies demonstrate that FKBP12 is dispensable forTGF-β-mediated signalling, but modulates the calcium release activity of both skeletal and cardiac ryanodinereceptors.

Date: 1998
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DOI: 10.1038/35146

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