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Genomewide association study in a mouse model of Barth syndrome

Suya Wang (1) Yang Xu (2), Douglas Strathdee (3), Michael Schlame (2), William T. Pu (1,4)

(1) Department of Cardiology, Boston Children’s Hospital, Boston, MA, USA
(2) Department of Anesthesiology and Cell Biology, New York University School of Medicine, New York, NY, USA
(3) Transgenic Technology Laboratory, Cancer Research UK Beatson Institute, Glasgow, UK
(4) Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA

Rationale: Barth syndrome (BTHS) is an X-linked recessive disorder caused by mutation of the gene Tafazzin (TAZ). Major clinical features include cardiomyopathy, skeletal myopathy, and neutropenia. Patients show wide variation in disease manifestations and severity. Genetic modifiers may contribute to this variable disease expression.

Objective: To investigate the contribution of genetic modifiers to the manifestation of BTHS in a mouse model. Methods: We studied a TAZKO/Y mouse model of BTHS in which the TAZ gene is ablated. Mice were maintained in the C57BL/6J strain background. Female TAZKO/WT [C57BL/6J] carriers were crossed to males from 8 inbred backgrounds. F1 progeny from this cross were tested for skeletal and cardiac muscle disease by treadmill endurance and echocardiography, respectively. Tissues were further studied for histological and molecular manifestations of BTHS.

Results: When maintained on C57BL/6J strain background, TAZKO/Y mice displayed significant neonatal lethality. Surviving TAZKO/Y mice developed dilated cardiac and skeletal myopathy. F1 TAZKO/Y mice from inter-strain breeding had markedly improved survival and variable expression of skeletal and cardiac myopathy. For instance, TAZKO/Y [CAST-F1] had severe cardiomyopathy but minimal skeletal myopathy; TAZKO/Y [WSB-F1] had moderate skeletal myopathy and mild cardiomyopathy; and TAZKO/Y [A/J-F1] had normal skeletal and cardiac muscle function. Despite this phenotypic variability, all F1 TAZKO/Y heart tissues displayed severe reductions of CL and elevated MLCL/CL ratio. In ongoing work, we are mapping genetic modifiers by SNP mapping, using an outcross to the Diversity Outbred strain, generated by controlled crosses between the 8 inbred lines used for this study.

Conclusions: The strong effect of genetic background on phenotype of TAZ knockout points to substantial influence of genetic modifiers on BTHS expression. These genetic modifiers are unlikely to modulate cardiolipin biosynthesis; rather, they likely work downstream and modulate the impact of altered CL composition on muscle function.

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