At present, there are several models of Barth syndrome, each of which has its own unique characteristics. All models show a cardiolipin dysfunction. For any questions or comments, please reach out to firstname.lastname@example.org
1) TAFAZZIN Knockout Mouse (KO) is available via Doug Strathdee, Beatson Institute. Two articles have discussed the KO mouse, the first by Doug Strathdee et al (2015) describes the meiotic challenges in generating the model. The second by Bill Pu et al (2020) characterizes the model and and assesses the impact of AAV-TAFAZZIN gene replacement therapy in a global and cardiac-specific KO models.
2) A second TAFAZZIN FLOXED mouse model was generated by utilizing the CRISPR/ Cas9 system (Xi Fang et al, 2020). Cardiomyocyte-specific TAFAZZIN KO mice display dilated cardiomyopathy with impaired but stable fractional shortening. Mitochondrial contact sites, the cristae organizing system, and F1F0-ATP synthase complexes, required for cristae morphogenesis, were abnormal, resulting in onion-shaped mitochondria. Organization of high molecular weight respiratory chain supercomplexes was also impaired.
Knockdown model: PLEASE NOTE - breeding pairs are no longer available, and new requests will involve cryorecovery.
Knockdown mouse model (KDown) is available from Jackson Laboratories (B6.Cg-Gt(ROSA)26Sortm37(H1/tetO-RNAi:Taz)Arte/ZkhuJ. and was made using a siRNA transgene at the ROSA26 locus to lower the expression of the endogenous mouse tafazzin gene. The model is inducible using doxycycline, and it was made using the proprietary technology of TaconicArtemis, GmbH (Köln, Germany) under contract from BSF.
Kdown mouse review: A critical appraisal of the tafazzin knockdown mouse model of Barth syndrome: what have we learned about pathogenesis and potential treatments? Ren M, Miller PC, Schlame M, Phoon CKL. Am J Physiol Heart Circ Physiol. 2019 Dec 1;317(6):H1183-H1193. doi: 10.1152/ajpheart.00504.2019
Cellular models of Barth syndrome have used shRNAs in rodent cardiac cells to lower tafazzin gene expression in different primary cell lines. The publications for these models are listed below.
- He Q, Harris N, Ren J, Han X. Mitochondria-targeted antioxidant prevents cardiac dysfunction induced by tafazzin gene knockdown in cardiac myocytes. Oxid Med Cell Longev. 2014;2014:654198. Epub 2014 Aug 27. (PubMed – Open Access)*
- He Q, Wang M, Harris N, Han X. Tafazzin knockdown interrupts cell cycle progression in cultured neonatal ventricular fibroblasts. Am J Physiol Heart Circ Physiol. 2013 Nov 1;305(9):H1332-43. doi: 10.1152/ajpheart.00084.2013. Epub 2013 Aug 30. (PubMed – Open Access)*▼
- He Q. Tafazzin knockdown causes hypertrophy of neonatal ventricular myocytes. Am J Physiol Heart Circ Physiol. 2010 Jul;299(1):H210-6. Epub 2010 Mar 26. (PubMed – Open Access)*
Drosophila models of Barth syndrome utilize the imprecise excision of a P element from stock y. Below is a list of publications.
- Xu Y, Phoon CK, Berno B, D'Souza K, Hoedt E, Zhang G, Neubert TA, Epand RM, Ren M, Schlame M. Loss of protein association causes cardiolipin degradation in Barth syndrome. Nat Chem Biol. 2016 Aug;12(8):641-7. doi: 10.1038/nchembio.2113. Epub 2016 Jun 27. (PubMed – Open Access)*▼
- Xu Y, Malhotra A, Claypool CM, Ren M, Schlame M. Tafazzins from Drosophila and mammalian cells assemble in large protein complexes with a short half-life. Mitochondrion. 2015 Mar;21:27-32. doi: 10.1016/j.mito.2015.01.002. Epub 2015 Jan 15. (PubMed – Open Access)
- Xu Y, Condell M, Plesken H, Edelman-Novemsky I, Ma J, Ren M, Schlame M. A Drosophila model of Barth syndrome. Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11584-8. Epub 2006 Jul 19. (PubMed – Open Access)*
A yeast model of Barth syndrome has also been used extensively. Below is a list of publications.
- Lu YW, Galbraith L, Herndon JD, Lu YL, Pras-Raves M, Vervaart M, van Kampen A, Luyf A, Koehler CM, McCaffery JM, Gottlieb E, Vaz FM, Claypool SM. Defining functional classes of Barth syndrome mutation in humans. Hum Mol Genet. 2016 May 1;25(9):1754-70. doi: 10.1093/hmg/ddw046. Epub 2016 Feb 16. (PubMed – Open Access)*
- Rijken PJ. Phosphatidylcholine-protein interactions and remodeling of cardiolipin in yeast mitochondria. Doctoral Thesis. Scheikunde Proefschriften, 2010. (Full Text)*
- Chen S, Liu D, Finley RL Jr, Greenberg ML. Loss of mitochondrial DNA in the yeast cardiolipin synthase crd1 mutant leads to up-regulation of the protein kinase Swe1p that regulates the G2/M transition. J Biol Chem. 2010 Apr 2;285(14):10397-407. Epub 2010 Jan 19. (PubMed – Open Access)*
- Joshi AS, Zhou J, Gohil VM, Chen S, Greenberg ML. Cellular functions of cardiolipin in yeast. Biochim Biophys Acta. 2009 Jan;1793(1):212-8. Epub 2008 Aug 7. (PubMed – Open Access)*
- Chen S, He Q, Greenberg ML. Loss of tafazzin in yeast leads to increased oxidative stress during respiratory growth. Mol Microbiol. 2008 May;68(4):1061-72. (PubMed – Open Access)*
- Zhong Q, Li G, Gvozdenovic-Jeremic J, Greenberg ML. Up-regulation of the cell integrity pathway in saccharomyces cerevisiae suppresses temperature sensitivity of the pgs1Delta mutant. J Biol Chem. 2007 Jun 1;282(22):15946-53. Epub 2007 Apr 9. (PubMed – Open Access)*
- Li G, Chen S, Thompson MN, Greenberg ML. New insights into the regulation of cardiolipin biosynthesis in yeast: Implications for Barth syndrome. Biochim Biophys Acta. 2007 Mar;1771(3):432-41. Epub 2006 Jul 8. Review. (PubMed Abstract)*
- Davey KM, Parboosingh JS, McLeod DR, Chan A, Casey R, Ferreira P, Snyder FF, Bridge PJ, Bernier FP. Mutation of DNAJC19, a human homolog of yeast inner mitochondrial membrane co-chaperones, causes DCMA syndrome, a novel autosomal recessive Barth syndrome-like condition. J Med Genet. 2006 May;43(5):385-93. Epub 2005 Jul 31. (PubMed – Open Access)
- Testet E, Laroche-Traineau J, Noubhani A, Coulon D, Bunoust O, Camougrand N, Manon S, Lessire R, Bessoule JJ. Ypr140wp, 'the yeast tafazzin', displays a mitochondrial lysophosphatidylcholine (lyso-PC) acyltransferase activity related to triacylglycerol and mitochondrial lipid synthesis. Biochem J. 2005 May 1;387(Pt 3):617-26. (PubMed – Open Access)
- Ma L, Vaz FM, Gu Z, Wanders RJ, Greenberg ML. The human TAZ gene complements mitochondrial dysfunction in the yeast taz1delta mutant-implications for Barth syndrome. J Biol Chem. 2004 Oct 22;279(43):44394-9. Epub 2004 Aug 10. (PubMed – Open Access)*
- Gu Z, Valianpour F, Chen S, Vaz FM, Hakkaart GA, Wanders RJA, Greenberg ML. Aberrant cardiolipin metabolism in the yeast taz1 mutant: A model for Barth syndrome. Mol Microbiol 2004 Jan; 51(1):149-158. (PubMed Abstract)*
Human iPS cells and mouse embryonic fibroblasts are also represented in Barth syndrome as shown in the publications below.
- Dudek J, Cheng IF, Chowdhury A, Wozny K, Balleininger M, Reinhold R, Grunau S, Callegari S, Toischer K, Wanders RJ, Hasenfuß G, Brügger B, Guan K, Rehling P. Cardiac-specific succinate dehydrogenase deficiency in Barth syndrome. EMBO Mol Med. 2015 Dec 23. pii: e201505644. doi: 10.15252/emmm.201505644. (PubMed – Open Access)▼
- Hsu P, Liu X, Zhang J, Wang HG, Ye JM, Shi Y. Cardiolipin remodeling by TAZ/Tafazzin is selectively required for the initiation of mitophagy. Autophagy. 2015 Apr 3;11(4):643-52. doi: 10.1080/15548627.2015.1023984. (PubMed – Open Access)*
- Wang G, McCain ML, Yang L, He A, Pasqualini FS, Agarwal A, Yuan H, Jiang D, Zhang D, Zangi L, Geva J, Roberts AE, Ma Q, Ding J, Chen J, Wang DZ, Li K, Wang J, Wanders RJA, Kulik W, Vaz FM, Laflamme MA, Murry CE, Chien KR, Kelley RI, Church GM, Parker K, Pu WT. Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies. Nat Med. 2014 Jun;20(6):616-23. doi:10.1038/nm.3545 Epub. 2014 May 11. (PubMed – Open Access)*▼
A zebra fish model has also been described.
- Khuchua Z, Yue Z, Batts L, Strauss AW. A zebrafish model of human Barth syndrome reveals the essential role of tafazzin in cardiac development and function. Circ Res. 2006 Jul 21;99(2):201-8. Epub 2006 Jun 22. (PubMed – Open Access)*
*Publications that acknowledge financial support contributed by BSF and/or BSF Affiliates.
▼Publications that acknowledge biological samples (and/or information) from Barth families, the Barth Syndrome Registry and Repository (BRR), and/or BSF Affiliates.