Abstract
ObjectiveAla97Ser (A97S) is the major transthyretin (TTR) mutation in Taiwanese patients of familial amyloid polyneuropathy (FAP), characterized by a late‐onset but rapidly deteriorated neuropathy. Tafamidis can restore the stability of some mutant TTR tetramers and slow down the progression of TTR‐FAP. However, there is little understanding of the biophysical features of A97S‐TTR mutant and the pharmacological modulation effect of tafamidis on it. This study aims to delineate the biophysical characteristics of A97S‐TTR and the pharmacological modulation effect of tafamidis on this mutant.MethodThe stability of TTR tetramers was assessed by urea denaturation and differential scanning calorimetry. Isothermal titration calorimetry (ITC) was used to measure the binding constant of tafamidis to TTR. Nuclear magnetic resonance spectroscopy (NMR) titration experiment was used to map out the tafamidis binding site.ResultsChemical and thermal denaturation confirmed the destabilization effect of A97S. Consistent with other the amyloidogenic mutant, A97S‐TTR has slightly lower conformational stability. NMR revealed the binding site of A97S‐TTR with tafamidis is at the thyroxine binding pocket. The ITC experiments documented the high affinity of the binding which can effectively stabilize the A97S‐TTR tetramer.InterpretationThis study confirmed the structural modulation effect of tafamidis on A97S‐TTR and implied the potential therapeutic benefit of tafamidis for A97S TTR‐FAP. This approach can be applied to investigate the modulation effect of tafamidis on other rare TTR variants and help to make individualized choices of available treatments for FAP patients.
Highlights
Familial amyloid polyneuropathy (FAP) is the most common hereditary amyloid diseases
V30M-TTR is the most prevalent disease-causing variant worldwide[2,3] and L55P-TTR is well recognized for its high amyloidogenic potential.[24,25,26]
The advancement of genetic diagnosis has greatly expanded our knowledge of Transthyretin-related FAP (TTR-FAP) and facilitated the development of mechanism-driven therapies targeting to different stages of TTR amyloid formation and deposition, including liver transplantation, TTR stabilizers, gene modifiers like silencing RNA and antisense oligonucleotide therapies.[32,33,34]
Summary
Familial amyloid polyneuropathy (FAP) is the most common hereditary amyloid diseases. Transthyretin-related FAP (TTR-FAP) is the most prevalent genetic subtype characterized by debilitating polyneuropathy and life-threatening cardiomyopathy.[1,2] The disease-causing gene is TTR (NM_000371). Cardiac manifestations usually occur in the later stage of the disease.[4,5,6,7] The overall survival rate could stay around 80% after 10 years of follow-up.[4] It has been reported that Ala97Ser (A97S) is the major TTR mutation, accounting for 91.2% of the hereditary transthyretin amyloidosis (ATTR) pedigrees.[8,9,10] Contrary to the classical early-onset V30M TTR-FAP, the patients with A97S TTR-FAP have a much later onset with the mean age of onset of 58.2 years but would become bed ridden or wheel-chair dependent within 8.4 years of the onset on average.[8,9,10] The rapidly deteriorative course may be partially due to severe cardiac dysfunction. Life-threatening cardiac arrhythmia (15.1%) and heart failure (16.4%) are prevalent in the A97S patients and might become severe before the full brown of peripheral neuropathy.[8,10] only a limited number of cases were available to provide a longitudinal follow-up information, unfavorable events like syncope/cardiac arrest/ cardiopulmonary-cerebral resuscitation tended to occur approximately 4 years after the appearance of the initial neurological symptoms and up to half died within 11 years after the first symptom or event.[9]
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