Abstract
<b><i>Introduction:</i></b> Amyloidosis caused by TTR mutations (ATTRv) is a rare inherited and autosomal dominant disease. More than 150 mutants of TTR have been reported, whereas some of them remain to be investigated. <b><i>Methods:</i></b> A 52-year-old male presented with heart failure and clinically diagnosed ATTR cardiac amyloidosis (ATTR-CA) was recruited. Whole-exome sequencing (WES) was performed. Biochemical and biophysical experiments characterized protein stability using urea-mediated tryptophan fluorescence. Drug response was analyzed by fibril formation assay. Finally, tetramer TTR concentration in patient’s serum sample was measured by ultra-performance liquid chromatography (UPLC). <b><i>Results:</i></b> For the proband, WES revealed a mutation (c.200G>T; <i>p.Gly67Val</i> and referred to as G47V) in TTR gene. Biochemical and biophysical kinetics study showed that the thermodynamic stability of G47V-TTR (C<sub>m</sub> = 2.4 <sc>m</sc>) was significantly lower than that of WT-TTR (C<sub>m</sub> = 3.4 <sc>m</sc>) and comparable to that of L55P-TTR (C<sub>m</sub> = 2.3 <sc>m</sc>), an early age-of-onset mutation. G47V:WT-TTR heterozygous tetramer kinetic stability (t<sub>1/2</sub> = 1.4 h) was further compromised compared to that of the homozygous G47V-TTR (t<sub>1/2</sub> = 3.1 h). Among three small molecule stabilizers, AG10 exhibited the best inhibition of the fibrillation of G47V-TTR homozygous protein. Using a UPLC assay, nearly 40% of TTR in this patient was calculated to be non-tetrameric. <b><i>Conclusion:</i></b> In this work, we reported a patient presented early onset of clinically typical ATTR-CA due to G47V-TTR mutation. Our work for the first time not only characterized the biochemical properties of G47V-TTR mutation, but also provided hints for the pathogenicity of this mutation.