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Abstract
The disease phenotype of transthyretin (TTR) is dramatically influenced by single point mutations in the TTR gene. Herein, we report on a novel mutation D99N (Asp99Asn) in TTR found in a Danish kindred. None of the family members carrying this mutation have so far shown any clinical signs of amyloidosis. One carrier found compound heterozygous for TTR D99N and L111M (Leu111Met) associated with cardiac amyloid is asymptomatic (42 years). Disease severity can often be linked to both the kinetics of fibril formation and the degree of destabilisation of the native state. In this study, we show that the thermodynamic stability and rate of tetramer dissociation of the variant TTR D99N is unchanged or slightly more stable than wild type (WT) TTR. Furthermore, the in vitro fibrillation kinetics of the variant reveals an unchanged or slightly suppressed tendency to form fibrils compared to WT. Thus, the in vitro experiments support the lack of clinical symptoms observed so far for the TTR D99N carriers. In line with this, studies on kinetic stability and fibrillation kinetics reveal indistinguishable stability of TTR heterotetramers D99N/L111M compared to the heterotetramers WT/L111M. In conclusion, TTR D99N is predicted to be a non-pathogenic benign mutation with WT properties.
| Abbreviations | ||
| CNS | = | central nervous system |
| FAC | = | familial amyloid cardiomyopathy |
| FAP | = | familial amyloid polyneuropathy |
| IPTGP | = | isopropyl β-D-1-thiogalactopyranoside |
| PCR | = | polymer chain reaction |
| OD | = | optical density |
| TEM | = | transmission electron microscopy |
| ThT | = | Thioflavin T |
| Trp | = | tryptophan |
| SDS-PAGE | = | sodium dodecyl sulfate polyacrylamide gel electrophoresis |
| SSA | = | senile systemic amyloidosis |
| WT | = | wild type |
| Abbreviations | ||
| CNS | = | central nervous system |
| FAC | = | familial amyloid cardiomyopathy |
| FAP | = | familial amyloid polyneuropathy |
| IPTGP | = | isopropyl β-D-1-thiogalactopyranoside |
| PCR | = | polymer chain reaction |
| OD | = | optical density |
| TEM | = | transmission electron microscopy |
| ThT | = | Thioflavin T |
| Trp | = | tryptophan |
| SDS-PAGE | = | sodium dodecyl sulfate polyacrylamide gel electrophoresis |
| SSA | = | senile systemic amyloidosis |
| WT | = | wild type |
Acknowledgements
The authors would like to express their gratitude for the cooperation of the Danish family presenting with the TTR mutations. This work was supported by the Danish Medical Research Council (MG), Novo Nordisk A/S (MG), the Drug Research Academy (MG), the Swedish Research Council (PH), Knut and Alice Wallenberg Foundation (PH), and the Swedish Foundation for Strategic Research (PH). PH is a Swedish Royal Academy of Science Research Fellows sponsored by a grant from the Knut and Alice Wallenberg Foundation. The pmmHα plasmid containing the TTR gene was a kind gift from Jeff Kelly and David Wemmer.
Declaration of interest:
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.