Mouse model of human Barth syndrome
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1 Mouse model of human Barth syndrome Zaza Khuchua, PhD Cincinnati Children s Research Foundation Cincinnati, OH, USA Barry J. Byrne, MD, PhD University of Florida Department of Pediatrics Gainesville, FL, USA
2 Background Barth (BTHS) syndrome is X linked genetic disorder. Common symptoms include: Cardiomyopathy Skeletal myopathy Neutropenia 3 methylglutaconic aciduria BTHS caused by mutations in tafazzin (taz) gene. Taz gene is located on Xq28. Taz encodes mitochondrial acyltransferase. Mutations in taz gene cause cardiolipin deficiency. Cardiolipin is mitochondrial phospholipid and constitutes about 20% of inner mitochondrial membrane.
3 MODELS OF TAFAZZIN DEFICIENCY Yeast; Drosophila; Zebrafish; Various cell cultures. Urgent need for mouse model of Barth syndrome Several floxed alleles of taz have been generated in mouse ES cells; Problems lay with germline transmission of floxed taz allele. 3
4 Tafazzin tet on shrna transgenic mice were generated by TaconicArtemis in Work was initiated and funded by Barth Syndrome Foundation ( Mice available from Jackson Laboratory: Gt(ROSA)26Sor<tm37(H1/tetO RNAi:Taz)Arte
5 RECOMBINASE MEDIATED CASSETE EXCHANGE ROSA 26 (RMCE) ATG F3 FRT ZsGreen- Exon 1 SA pa Hyg R FLPe Exon 2 site specific recombination by FLPe Neo R H1-tet0-shRNA:taz exchange vector tet-r Resulted locus ATG Exon 1 SA Neo R H1-tet0-shRNA:taz tet-r Exon 2 5
6 Taz RNA R tet H1-tet0-shRNA:taz shrna Taz 6
7 Dox R tet shrna Taz RNA H1-tet0-shRNA:taz Taz 7
8 Important Questions: 1. How efficient is shrna mediated silencing in different tissues? 2. How tight is regulation by Dox? 3. What are side effects of chronic Dox administration? 4. Is it reversible?
9 Induction of Taz knockdown Doxycycline was administered with rodent chow, formulated by Purina Mills (625 mg / kg) 5 days 0 4 days Dox Dox WT X Taz shrna Tg Dox 9
10 Taz silencing WT + Dox TG Dox TG + Dox 10
11 Un silencing WT + Dox TG Dox TG + Dox TG +/ Dox 1 M TG +/ Dox 2½ M 11
12 Cardiolipin analysis Acehan et al. JBC 2010 (in press) 12
13 CARDIOLIPIN IN HEART AND MUSCLE NTG Taz KD Acehan et al. JBC 2010 (in press) 13
14 CARDIOLIPIN IN HEART AND MUSCLE NTG Taz KD 4x(18:2) 14
15 MLCLs IN HEART AND MUSCLE NTG Taz KD 15
16 CARDIAC MRI Acehan et al. JBC 2010 (in press) 16
17 ECHOCARDIOGRAPHY (8M) NTG Taz KD Acehan et al. JBC
18 LOSS OF TAZ ALTERS CARDIAC PARAMETERS Wall thickness and LV wall mass mm M mm 0.8 IVS;d 0.7 P=0.06 * M 2M LVPW * n = 3 8M µl LV mass * * 60 2M 8M NTG Taz knockdown 18
19 CONTROL HEART TAFAZZIN KNOCKDOWN HEART Acehan et al. JBC
20 20
21 TAFAZZIN KNOCKDOWN SKELETAL MUSCLE Acehan et al. JBC
22 Questions Answered: 1. How efficient is shrna mediated silencing? An shrna mediated silencing of taz is very efficient in heart, muscle, liver and brain 2. How tight is regulation by Dox? Dox very efficiently controls shrna expression in heart, skeletal muscle and liver. In brain control is less tight and we observed ~35% reduction of taz mrna level. 3. What are side effects of chronic Dox administration? We didn t find any adverse effects of prolonged dox administration in control animals. 4. Is it reversible? We found that withdrawal from dox restores taz level to 75 90% of normal in 2.5 months.
23 Impact of Cardiolipin on IMM Claypool et al. 2008
24 Dox shrna induction causes significant TAZ knockdown RQ * * TAZKD CON * TAZKD CON TAZKD CON TAZKD * CON N=4 Cardiac TA Liver Brain Soustek et al., HGT, 2011
25 TAZKD Results in Impaired Contractility in the Soleus Force (N/cm 2 ) * * CON TAZKD 0 Tw Frequency (Hz) Soustek et al., HGT, 2011
26 TAZKD Results in Reduced Cardiac Function Ejection Fraction (%) * * CON TAZKD Age (mths) Soustek et al., HGT, 2011
27 Transduction of ptr Myc TAZ FL in HEK293 Cells 33KDa HEK 293 UF11 GFP Myc TAZ FL 15 μg Western Blot : C Myc Antibody (1:200)
28 Acknowledgements University of Florida Meghan Soustek Al Lewin Cathryn Mah Denise Cloutier Darien Falk Supported by NIH/NHLBI, NIDDK, NCRR, Barth Syndrome Foundation, Muscular Dystrophy Association and the University of Florida.
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