An additive destabilising effect of compound T60I and V122I substitutions in ATTRv amyloidosis

Abstract

Background

The amyloidogenic transthyretin (TTR) variant, V122I, occurs in 4% of the African American population and frequently presents as a restricted cardiomyopathy. While heterozygosity for TTR V122I predominates, several compound heterozygous cases have been previously described. Herein, we detail features of ATTRv amyloidosis associated with novel compound heterozygous TTR mutation, T60I/V122I and provide evidence supporting the amyloidogenecity of T60I.

Methods

A 63-year-old African American female presented with atrial fibrillation, congestive heart failure, autonomic and peripheral neuropathy. In vitro studies of TTR T60I and V122I were undertaken to compare the biophysical properties of the proteins.

Results

Congophilic deposits in a rectal biopsy were immunohistochemically positive for TTR. Serum screening by isoelectric focussing revealed two TTR variants in the absence of wild-type protein. DNA sequencing identified compound heterozygous TTR gene mutations, c.239C > T and c.424G > A. Adipose amyloid deposits were composed of both T60I and V122I. While kinetic stabilities of T60I and V122I variants were similar, distinct thermodynamic stabilities and amyloid growth kinetics were observed.

Conclusions

This report provides clinical and experimental results supporting the amyloidogenic nature of a novel TTR T60I variant. In vitro data indicate that the destabilising effect of individual T60I and V122I variants appears to be additive rather than synergistic.

Keywords:

• Amyloid-forming propensity
• ATTRv amyloidosis
• T60I and V122I variants
• TTR gene mutation

Acknowledgement

We acknowledge all members of the Amyloidosis Center clinical team who took care of patient included into the study and the patient who provided serum and tissue samples for this study.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work has been supported by the following funding: Wildflower Foundation to TP, EK and LHC; Boston University Amyloid Research Fund to TP and EK; Young Family Amyloid Research Fund to LHC. The funding organisations had no role in study design; data collection; results interpretation; writing the manuscript; and decision to submit.