A Novel Compound Heterozygote (FAP ATTR Arg104His/ATTR Val30Met) with High Serum Transthyretin (TTR) and Retinol Binding Protein (RBP) Levels

Terazaki, Hisayasu; Ando, Yukio; Misumi, Shogo; Nakamura, Masaaki; Ando, Eiko; Matsunaga, Noriko; Shoji, Shuichi; Okuyama, M; Ideta, H.; Nakagawa, Kazuko; Ishizaki, Takashi; Ando, Masayuki; Saraiva, Maria João

doi:10.1006/bbrc.1999.1514

Cited by 56 publications

(43 citation statements)

References 31 publications

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“…Nevertheless, large studies of other ethnic groups are needed to address this issue. Finally, R104H, a genetic variant previously identified in Asians, 18,22 was not detected in our study, but may have similar protective effects as T119M in Asian populations.…”

Section: Discussioncontrasting

confidence: 39%

“…Genotype distribution did not deviate from the HardyWeinberg equilibrium (P=0.54). R104H, a stabilizing genetic variant previously identified in Asians, 18,22 was not detected. Neither risk factors for ischemic vascular disease (Table) …”

Section: Characteristicsmentioning

confidence: 82%

“…14,18 Finally, some family studies have suggested increased thyroxine binding or increased levels of thyroxine or transthyretin in carriers of these 2 stabilizing variants. 14,[18][19][20][21] Whether any of these variants are common in the general population, whether they associate with increased thyroxine and transthyretin levels as markers of increased transthyretin tetramer stabilization, and whether they associate with reduced risk of vascular disease and increased life expectancy in the general population is currently unknown. We tested these hypotheses by genotyping for R104H and T119M in 2 similar studies of the Danish general population, the Copenhagen General Population Study and the Copenhagen City Heart Study, totalling 68 602 participants, of which 10 636 participants developed vascular disease.…”

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confidence: 99%

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Genetic Stabilization of Transthyretin, Cerebrovascular Disease, and Life Expectancy

Hornstrup

Frikke‐Schmidt

Nordestgaard

et al. 2013

ATVB

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Objective-Transthyretin can cause amyloidosis attributable to destabilization of transthyretin tetramers in plasma. We tested the hypothesis that genetic stabilization of transthyretin associates with reduced risk of vascular disease and increased life expectancy. Approach and Results-We included 68 602 participants from 2 prospective studies of the general population. We genotyped for 2 stabilizing genetic variants in the transthyretin gene (TTR), R104H and T119M, and determined the association of genotypes with plasma levels of transthyretin, measures of thyroid function, risk of vascular disease, and life expectancy. During a mean follow-up of 32 years, 10 636 participants developed vascular disease. We identified 321 heterozygotes for T119M (frequency, 0.47%); R104H was not detected. First, mean plasma transthyretin and thyroxine levels were increased by 17% (26 µg/mL) and 20% (19 nmol/L), respectively, in heterozygotes versus noncarriers (P=0.007 and P<0.0001), demonstrating functionality of this variant in the general population. Second, corresponding hazard ratios were 0.70 (95% confidence interval, 0.51-0.97) for all vascular diseases, 0.85 (0.59-1.23) for cardiovascular disease, 0.45 (0.25-0.81) for cerebrovascular disease, 0.47 (0.25-0.88) for ischemic cerebrovascular disease, and 0.31 (0.04-2.22) for hemorrhagic stroke. The cumulative incidence of cerebrovascular disease as a function of age was decreased in heterozygotes versus noncarriers (P=0.005). Third, median age at death from all causes, from vascular and cerebrovascular diseases, and after diagnosis of vascular disease, and median age at diagnosis of vascular disease, was increased by 5 to 10 years in heterozygotes versus noncarriers (P=0.002-0.05). Conclusions-These results are compatible with an association between genetic stabilization of transthyretin and decreased risk of cerebrovascular disease, and with increased life expectancy in the general population.

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Section: Discussioncontrasting

confidence: 39%

Section: Characteristicsmentioning

confidence: 82%

mentioning

confidence: 99%

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Genetic Stabilization of Transthyretin, Cerebrovascular Disease, and Life Expectancy

Hornstrup

Frikke‐Schmidt

Nordestgaard

et al. 2013

ATVB

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“…Eight healthy volunteers (5 males and 3 females) were selected as controls. Blood samples from the sub-jects were obtained after identification as wild-type TTR using matrix-assisted laser desorption/ ionization (MALDI)/time-of-flight/mass-mass spectrometry (TOF-MS) (Terazaki et al, 1999).…”

Section: Research Subjectsmentioning

confidence: 99%

Effect of MPO/H2O2/NO- system on nitric oxide-mediated modification of TTR amyloid and serum TTR in FAP ATTR Val30Met patients

et al. 2014

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ABSTRACT. Amyloid deposits consist of protein fibrils and amorphous material, and this deposition is related to oxidative stress. Previously, we demonstrated the presence of high-density lipoproteins and/or lipids in amyloid deposits of familial amyloid polyneuropathy patients. In this study, the presence of myeloperoxidase (MPO) in amyloid deposits was demonstrated using immunohistochemical staining. In contrast, normal surrounding tissues were consistently negative for MPO. Nitrotyrosine was present in amyloid deposits after being exposed to the MPO/H 2 O 2 / NO -system by immunohistochemical staining, and the oxide mediated modification of serum transthyretin (TTR) was observed upon exposure to the MPO/H 2 O 2 system using two-dimensional gel electrophoresis and TTR Western blotting. This observation revealed that the TTR amyloid deposits and serum TTR were oxidized by the MPO/H 2 O 2 /NO -system. Nitric oxide-mediated modification of TTR may play a role in

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“…Of particular significance is the existence of heterozygous individuals with amyloidogenic and nonamyloidogenic mutations, usually in different alleles. At least in two such cases (Thr119Met/Val30Met and Arg104His/Val30Met) the non-amyloidogenic mutation gives some protection against the disease, with the subjects presenting close to normal phenotypes [28][29][30]. Interestingly, it was recently identified a compound heterozygous TTR (Thr59Lys/Arg104His) in a patient of Chinese ancestry, who was diagnosed with ATTR [31].…”

Section: Introductionmentioning

confidence: 99%

Amyloid Formation by Transthyretin: From Protein Stability to Protein Aggregation

Brito¹,

Damas²,

Saraiva

2003

CMCIEMA

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Abstract:In recent years the issues of protein stability, folding and aggregation have become central in several pathological conditions and in particular in amyloid diseases. Here, we review the recent developments on the molecular mechanisms of amyloid formation by transthyretin (TTR), in particular, in what concerns to protein conformational stability, protein folding and aggregation.Transthyretin has been implicated in pathologies such as senile systemic amyloidosis (SSA), familial amyloid polyneuropathy (FAP) and familial amyloid cardiomyopathy (FAC) which are characterized by extracellular deposition of insoluble amyloid fibrils. SSA is generally a mild disorder and affects predominantly individuals over 80 years of age. In contrast, FAP is an autossomal dominant lethal disease, characterized by peripheral neuropathy, which may affect individuals from their twenties. While in SSA WT-TTR and its fragments are the major constituents of the amyloid fibrils, in FAP and FAC the amyloid fibrils are mostly constituted by variants of TTR. Today, more than 80 amyloidogenic TTR mutations throughout the TTR sequence are known.Transthyretin is a homotetrameric protein found in the plasma and in the cerebral-spinal fluid, it is synthesized in the liver and in the choroid plexus of the brain, it has a total molecular mass of 55kDa and a high percentage of β-sheet. Current views on amyloid fibril formation by TTR state that, depending on the protein variant or solution conditions, the native tetrameric protein might dissociate to non-native or partially unfolded monomeric (or even dimeric) species with a high tendency for ordered aggregation into soluble oligomers which grow into insoluble oligomers and eventually mature amyloid fibrils. Thus, issues such as dissociation thermodynamics and dissociation kinetics of the native tetrameric TTR and thermodynamic stability and conformational fluctuations of the non-native TTR molecular species are essential in determining the amyloidogenic potential of different TTR variants. In addition, several other cellular and tissue factors must be involved in modulating the penetrance and age of onset of amyloid pathologies by TTR.

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A Novel Compound Heterozygote (FAP ATTR Arg104His/ATTR Val30Met) with High Serum Transthyretin (TTR) and Retinol Binding Protein (RBP) Levels

Cited by 56 publications

References 31 publications

Genetic Stabilization of Transthyretin, Cerebrovascular Disease, and Life Expectancy

Genetic Stabilization of Transthyretin, Cerebrovascular Disease, and Life Expectancy

Effect of MPO/H2O2/NO- system on nitric oxide-mediated modification of TTR amyloid and serum TTR in FAP ATTR Val30Met patients

Amyloid Formation by Transthyretin: From Protein Stability to Protein Aggregation

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