Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis
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We presented an unreported T96R mutation induced transthyretin cardiac amyloidosis (ATTR). The biochemical and biophysical properties were explored to support its pathogenicity. ⋯ A novel T96R mutation was identified for TTR protein. Biochemical and biophysical analyses revealed slightly destabilized kinetic stability. T96R mutation destabilized heterozygous protein but not proteolytic degradation, explaining its pathogenicity. Inhibitory effect of small molecule drugs on T96R mutation was different, suggesting personalized treatment may be required.
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Tafamidis inhibits progression of transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) by binding TTR tetramer and inhibiting dissociation to monomers capable of denaturation and deposition in cardiac tissue. While the phase 3 ATTR-ACT trial demonstrated the efficacy of tafamidis, the degree to which the approved dose captures the full potential of the mechanism has yet to be assessed. ⋯ NCT01994889.