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Inherited Abnormalities in Thyroid Hormone Transport Proteins
Published in Geraldo Medeiros-Neto, John Bruton Stanbury, Inherited Disorders of the Thyroid System, 2019
Geraldo Medeiros-Neto, John Bruton Stanbury
The variant TTR called type I, associated with FAP, is characterized by the replacement of valine at position 30 by methionine. It is not only present in the amyloid fibril protein but also in the serum of affected individuals. The variant TTR has a reduced affinity for T4. The so-called Indiana variant or type II has a serine for isoleucine replacement at position 84. Types ΠΙ and IV, have other mutations, as shown in Tables 2 and 3. Genetic abnormalities of TTR can be accompanied by altered affinity for T4but the thyroid status of the affected person is normal. Three other mutant TTRs have been identified recently either anoliated with FAP50a,50bor familial amyloid cardiomyopathy.50c
Amyloidosis and Aging
Published in Alvaro Macieira-Coelho, Molecular Basis of Aging, 2017
Per Westermark, Kenneth H. Johnson
TTR, which has substantial beta pleated-sheet structure,72 also is the major protein precursor for several heredofamilial forms of predominantly late-onset amyloidosis (e.g., familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), and isolated vitreous amyloid (IVA) that affects individuals within certain Swedish, Portuguese, Japanese, Jewish, German, Swiss, Danish, Greek, or Italian kindreds. Investigations of these autosomal-dominant forms of amyloidosis have shown that specific point mutations in the TTR gene lead to single amino acid substitutions in TTR which are characteristic for each of the affected kindreds. To date more than 40 point mutations, distributed throughout the TTR-molecule, have been found in association with familial TTR-derived amyloidosis.73 Although these mutations are generally considered to be importantly linked to the development of amyloidosis in affected individuals, there still is not a clear understanding of how these mutations are specifically related to fibrillogenesis. Furthermore, factors other than the presence of point mutations must also be of importance. For example, some individuals never develop amyloidosis although they synthesize a mutant TTR that is amyloidogenic in other individuals.74
Relationship of binding-site occupancy, transthyretin stabilisation and disease modification in patients with tafamidis-treated transthyretin amyloid cardiomyopathy
Published in Amyloid, 2023
David A. Tess, Tristan S. Maurer, Zhenhong Li, Christine Bulawa, James Fleming, Amy T. Moody
Transthyretin-mediated amyloidosis (ATTR amyloidosis) is caused when circulating TTR dissociates to monomer, misfolds and abnormally deposits in tissues. Amyloid deposition occurs in a variety of tissues and organs throughout the body including peripheral nerves and the heart, resulting in the two main presentations of disease [2]: transthyretin amyloid polyneuropathy (ATTR-PN, formerly called familial amyloid polyneuropathy) and transthyretin amyloid cardiomyopathy (ATTR-CM). ATTR-CM can be caused by wild-type TTR (formerly called senile systemic amyloidosis) or variant TTR [2] (formerly called familial amyloid cardiomyopathy). Inheritance of variant TTR is autosomal dominant. ATTR-PN is always hereditary while ATTR-CM has both hereditary and non-hereditary origins. The most common variant causing hereditary ATTR-CM is Val122Ile, which is present in 3.4% of African Americans [3]. The non-hereditary form of ATTR-CM is caused by the deposition of wild-type TTR that presents predominantly as heart failure with preserved ejection fraction in the elderly. Symptoms include shortness of breath, fatigue, heart failure, loss of consciousness and abnormal heart rhythms. Median survival for untreated ATTR-CM is ∼3–5 years after diagnosis [4,5]. Prevalence in the US is ∼120,000, of which only ∼4% of patients are diagnosed [6].
Natural compounds as inhibitors of transthyretin amyloidosis and neuroprotective agents: analysis of structural data for future drug design
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Lidia Ciccone, Nicoló Tonali, Susanna Nencetti, Elisabetta Orlandini
Due to high β-strands content TTR is intrinsically amyloidogenic. Under physiological condition, wt-TTR circulates as a soluble protein, but in some elderly or, in patients with TTR single point mutations, it is able to form amyloid fibrils, responsible of neurotoxicity and organ dysfunction. Senile systemic amyloidosis (SSA) is related to wt-TTR deposition and it is has be estimated that ∼25% of individuals over the age of 80 may be affected with SSA33. TTR variants34 are responsible for more aggressive hereditary TTR amyloidosis (ATTR) in which heart and peripheral nervous system are largely compromised, as in familial Amyloid cardiomyopathy (FAC) and familial amyloid polyneuropathy (FAP), respectively35,36. The most spread mutations are Val30Met which is associated to FAP, Val122Ile that leads to FAC, and Asp18Gly and Ala23Thr which are involved in some central nervous system damaging37,38. Native TTR is more stable and less prone to dissociation compare to TTR mutants in which the tetramer stability decreases, with the exception of some point mutations that are considered non-amyloidogenic variants34.
Targeting transthyretin amyloidosis in the eye with next-generation stabilizers: AT40 displays potent TTR stabilization in the human vitreous
Published in Amyloid, 2019
Filipa Bezerra, Carlos J. V. Simões, João M. Beirão, Maria João Saraiva, Rui M. M. Brito, Maria Rosário Almeida
Transthyretin amyloidoses (ATTR) are characterized by extracellular deposition of insoluble amyloid fibrils in several tissues, being polyneuropathy and cardiomyopathy the major clinical manifestations, respectively, in familial amyloid polyneuropathy (TTR-FAP) and familial amyloid cardiomyopathy (TTR-FAC) [1]. However, the ocular and cerebral manifestations are increasingly frequent due to amyloid deposition in different structures in the eye and central nervous system [2]. These include amyloid deposition on the anterior surface of the lens and on the pupil border, abnormal conjunctiva vessels, retinal amyloid microangiopathy, dry eye, scalloped pupil, glaucoma and vitreous opacities [2]. TTR-FAP therapies in current use show efficacy in slowing down or halting the progression of peripheral nervous system symptoms, yet with no signs of improvement of ATTR-related oculopathy [3]. Tafamidis has been detected in 10 vitreous samples extracted from treated patients in an average concentration of 54.2 ± 20.8 nM [4], which is significantly inferior to TTR concentration (≈300 nM) in the vitreous body [4]. This work is part of an ongoing effort to discover potent TTR stabilizers capable of reaching the eye’s aqueous humour and vitreous an, thus, inhibiting amyloid formation in the surrounding ocular structures.