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Tafazzin knockdown in mice leads to a developmental cardiomyopathy with early diastolic dysfunction preceding myocardial noncompaction.
MedLine Citation:
PMID:  23130124     Owner:  NLM     Status:  PubMed-not-MEDLINE    
BACKGROUND: Barth syndrome is a rare, multisystem disorder caused by mutations in tafazzin that lead to cardiolipin deficiency and mitochondrial abnormalities. Patients most commonly develop an early-onset cardiomyopathy in infancy or fetal life.
METHODS AND RESULTS: Knockdown of tafazzin (TAZKD) in a mouse model was induced from the start of gestation via a doxycycline-inducible shRNA transgenic approach. All liveborn TAZKD mice died within the neonatal period, and in vivo echocardiography revealed prenatal loss of TAZKD embryos at E12.5-14.5. TAZKD E13.5 embryos and newborn mice demonstrated significant tafazzin knockdown, and mass spectrometry analysis of hearts revealed abnormal cardiolipin profiles typical of Barth syndrome. Electron microscopy of TAZKD hearts demonstrated ultrastructural abnormalities in mitochondria at both E13.5 and newborn stages. Newborn TAZKD mice exhibited a significant reduction in total mitochondrial area, smaller size of individual mitochondria, reduced cristae density, and disruption of the normal parallel orientation between mitochondria and sarcomeres. Echocardiography of E13.5 and newborn TAZKD mice showed good systolic function, but early diastolic dysfunction was evident from an abnormal flow pattern in the dorsal aorta. Strikingly, histology of E13.5 and newborn TAZKD hearts showed myocardial thinning, hypertrabeculation and noncompaction, and defective ventricular septation. Altered cellular proliferation occurring within a narrow developmental window accompanied the myocardial hypertrabeculation-noncompaction.
CONCLUSIONS: In this murine model, tafazzin deficiency leads to a unique developmental cardiomyopathy characterized by ventricular myocardial hypertrabeculation-noncompaction and early lethality. A central role of cardiolipin and mitochondrial functioning is strongly implicated in cardiomyocyte differentiation and myocardial patterning required for heart development. (J Am Heart Assoc. 2012;1:jah3-e000455 doi: 10.1161/JAHA.111.000455.).
Colin K L Phoon; Devrim Acehan; Michael Schlame; David L Stokes; Irit Edelman-Novemsky; Dawen Yu; Yang Xu; Nitya Viswanathan; Mindong Ren
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Publication Detail:
Type:  Journal Article     Date:  2012-04-24
Journal Detail:
Title:  Journal of the American Heart Association     Volume:  1     ISSN:  2047-9980     ISO Abbreviation:  J Am Heart Assoc     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-11-06     Completed Date:  2012-11-07     Revised Date:  2013-05-30    
Medline Journal Info:
Nlm Unique ID:  101580524     Medline TA:  J Am Heart Assoc     Country:  England    
Other Details:
Languages:  eng     Pagination:  -     Citation Subset:  -    
Department of Pediatrics (Pediatric Cardiology), New York University School of Medicine, New York (C.K.L.P., N.V.).
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