Cardiac α-actin over-expression therapy in dominant ACTA1 disease

More than 200 mutations in the skeletal muscle alpha-actin gene ( ACTA1) cause either dominant or recessive skeletal muscle disease. Currently, there are no specific therapies. Cardiac alpha-actin is 99% identical to skeletal muscle alpha-actin and the predominant actin isoform in fetal muscle. We previously showed cardiac alpha-actin can substitute for skeletal muscle alpha-actin, preventing the early postnatal death of Acta1 knock-out mice, which model recessive ACTA1 disease. Dominant ACTA1 disease is caused by the presence of 'poison' mutant actin protein. Experimental and anecdotal evidence nevertheless indicates that the severity of dominant ACTA1 disease is modulated by the relative amount of mutant skeletal muscle alpha-actin protein present. Thus, we investigated whether transgenic over-expression of cardiac alpha-actin in postnatal skeletal muscle could ameliorate the phenotype of mouse models of severe dominant ACTA1 disease. In one model, lethality of ACTA1(D286G). Acta1(+/-) mice was reduced from similar to 59% before 30 days of age to similar to 12%. In the other model, Acta1(H40Y), in which similar to 80% of male mice die by 5 months of age, the cardiac alpha-actin transgene did not significantly improve survival. Hence cardiac alpha-actin over-expression is likely to be therapeutic for at least some dominant ACTA1 mutations. The reason cardiac alpha-actin was not effective in the Acta1(H40Y) mice is uncertain. We showed that the Acta1(H40Y) mice had endogenously elevated levels of cardiac alpha-actin in skeletal muscles, a finding not reported in dominant ACTA1 patients.