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Gerhard Schreiber - One of the best experts on this subject based on the ideXlab platform.
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the evolution of the thyroid hormone distributor protein Transthyretin in the order insectivora class mammalia
Molecular Biology and Evolution, 2000Co-Authors: Porntip Prapunpoj, Samantha J Richardson, Luca Fumagalli, Gerhard SchreiberAbstract:Thyroid hormones are involved in the regulation of growth and metabolism in all vertebrates. Transthyretin is one of the extracellular proteins with high affinity for thyroid hormones which determine the partitioning of these hormones between extracellular compartments and intracellular lipids. During vertebrate evolution, both the tissue pattern of expression and the structure of the gene for Transthyretin underwent characteristic changes. The purpose of this study was to characterize the position of Insectivora in the evolution of Transthyretin in eutherians, a subclass of Mammalia. Transthyretin was identified by thyroxine binding and Western analysis in the blood of adult shrews, hedgehogs, and moles. Transthyretin is synthesized in the liver and secreted into the bloodstream, similar to the situation for other adult eutherians, birds, and diprotodont marsupials, but different from that for adult fish, amphibians, reptiles, monotremes, and Australian polyprotodont marsupials. For the characterization of the structure of the gene and the processing of mRNA for Transthyretin, cDNA libraries were prepared from RNA from hedgehog and shrew livers, and full-length cDNA clones were isolated and sequenced. Sections of genomic DNA in the regions coding for the splice sites between exons 1 and 2 were synthesized by polymerase chain reaction and sequenced. The location of splicing was deduced from comparison of genomic with cDNA nucleotide sequences. Changes in the nucleotide sequence of the Transthyretin gene during evolution are most pronounced in the region coding for the N-terminal region of the protein. Both the derived overall amino sequences and the N-terminal regions of the Transthyretins in Insectivora were found to be very similar to those in other eutherians but differed from those found in marsupials, birds, reptiles, amphibians, and fish. Also, the pattern of Transthyretin precursor mRNA splicing in Insectivora was more similar to that in other eutherians than to that in marsupials, reptiles, and birds. Thus, in contrast to the marsupials, with a different pattern of Transthyretin gene expression in the evolutionarily "older" polyprotodonts compared with the evolutionarily "younger" diprotodonts, no separate lineages of Transthyretin evolution could be identified in eutherians. We conclude that Transthyretin gene expression in the liver of adult eutherians probably appeared before the branching of the lineages leading to modern eutherian species.
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Evolution of thyroid hormone binding by Transthyretins in birds and mammals
European journal of biochemistry, 1999Co-Authors: Linus Chang, Samantha J Richardson, Sharon L. A. Munro, Gerhard SchreiberAbstract:Transthyretin, a protein synthesized and secreted by the choroid plexus and liver, binds thyroid hormones in extracellular compartments. This binding prevents accumulation of thyroid hormones in the lipids of membranes, establishing extracellular thyroid hormone pools for the distribution of the hormones throughout the body and brain. The N-termini of the Transthyretin subunits are longer and more hydrophobic in chicken than in eutherian Transthyretins. Here, we show that this is a general structural feature of avian Transthyretins. Systematic changes of protein structure during evolution result from selection pressure leading to changes in function. The evolution of Transthyretin function, namely, the binding of thyroid hormones, was studied in nine vertebrate species. The affinity of thyroxine binding to Transthyretin is lowest in avians (mean Kd of about 30 nm), intermediate in metatherians (mean Kd of about 17 nm) and highest in eutherians (mean Kd of about 11 nm). The affinity for 3,5,3'-triiodothyronine shows an opposite trend, being four times higher for avian Transthyretins than for mammalian Transthyretins.
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Structural characteristics of bullfrog (Rana catesbeiana) Transthyretin and its cDNA
European journal of biochemistry, 1998Co-Authors: Kiyoshi Yamauchi, Sharon L. A. Munro, Hiro-aki Takeuchi, Maree L. Overall, Marie Dziadek, Gerhard SchreiberAbstract:Transthyretin, an extracellular thyroid-hormone-binding protein (THBP) in higher vertebrates, is synthesized and secreted by the choroid plexus of all classes of vertebrates, except fish and amphibians, and synthesized in the liver of endothermic animals. Here, we report the nucleotide sequence of the cDNA for a THBP found in plasma of bullfrog (Rana catesbeiana) tadpoles before the climax of metamorphosis. The amino acid sequence clearly shows this protein to be an amphibian Transthyretin. The three-dimensional structure of bullfrog Transthyretin was derived using homology modeling. Compared with Transthyretins from other vertebrate species, bullfrog Transthyretin is highly conserved at the thyroid hormone-binding sites and other important structural regions of the subunits. Bullfrog Transthyretin mRNA was found in tadpole liver, but not in tadpole choroid plexus. Thus, during evolution, synthesis of Transthyretin in the liver of metamorphosing amphibians preceded that in the choroid plexus of reptiles, birds and mammals. It was previously observed that the protein most abundantly synthesized and secreted by the choroid plexus in adult amphibians is a lipocalin [Achen, M. G., Harms, P. J., Thomas, T., Richardson, S. J., Wettenhall, R. E. H. & Schreiber, G. (1992) J. Biol. Chem. 267, 23 170−23 174], in contrast to Transthyretin being the most abundantly synthesized and secreted protein in the choroid plexus of mammals, birds and reptiles. Lipocalin mRNA was found in large amounts in tadpole choroid plexus, but not livers.
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The Acute Phase Response of Plasma Proteins in the Polyprotodont Marsupial Monodelphis domestica
Comparative biochemistry and physiology. Part B Biochemistry & molecular biology, 1998Co-Authors: Samantha J Richardson, Katarzyna M. Dziegielewska, Na Andersen, Shawn B. Frost, Gerhard SchreiberAbstract:In eutherians, patterns of plasma protein levels in blood change during the acute phase response to trauma and inflammation. Until now, such an acute phase response has not been characterised in a noneutherian species. Here we describe the acute phase response in a marsupial species, the South American polyprotodont marsupial Monodelphis domestica, after brain surgery or injection of lipopolysaccharide. Several days after brain surgery, Transthyretin was not detected in plasma. For 48 hr following injection of lipopolysaccharide, the concentration of haptoglobin in plasma increased, that of Transthyretin decreased, and the concentration of albumin in plasma did not change significantly. The American polyprotodont marsupials are probably more closely related to the common ancestor marsupial than the Australian marsupials are. It is most likely that the Transthyretin gene was not expressed in the liver of this common ancestor. As the Transthyretin gene is expressed in the liver of M. domestica, it seems that as soon as Transthyretin is synthesised by the liver, it is under negative acute phase control.
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The Evolution of Gene Expression, Structure and Function of Transthyretin
Comparative biochemistry and physiology. Part B Biochemistry & molecular biology, 1997Co-Authors: Gerhard Schreiber, Samantha J RichardsonAbstract:Thyroxine, the most abundant thyroid hormone in blood, partitions into lipid membranes. In a network-like system, thyroxine-binding plasma proteins counteract this partitioning and establish intravascular, protein-bound thyroxine pools. These are far larger than the free thyroxine pools. In larger eutherians, proteins specifically binding thyroxine are albumin, Transthyretin, and thyroxine-binding globulin. Some binding of thyroxine can also occur to lipoproteins. During evolution, Transthyretin synthesis first appeared in the choroid plexus of the stem reptiles, about 300 million years ago. Transthretin synthesis in the liver evolved much later, independently, in birds, eutherians and some marsupial species. Analysis of 57 human Transthyretin variants suggests that most mutations in Transthyretin are not compatible with its normal metabolism and lead to its deposition as amyloid. Analysis of Transthyretin or its gene in 20 different species shows that evolutionary changes of Transthyretin predominantly occurred near the N-termini. A change in RNA splicing between exon 1 and exon 2 led to a decrease in hydrophobicity and length of the N-termini. It is proposed that the selection pressure producing these changes was the need for a more effective prevention of thyroxine partitioning into lipids. Lipid pools increased during evolution with the increases in relative sizes of brains and internal organs and changes in lipid composition of membranes in ectothermic and endothermic species.
Samantha J Richardson - One of the best experts on this subject based on the ideXlab platform.
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Evolutionary changes to Transthyretin: evolution of Transthyretin biosynthesis.
The FEBS journal, 2009Co-Authors: Samantha J RichardsonAbstract:Thyroid hormones are involved in growth and development, particularly of the brain. Thus, it is imperative that these hormones get from their site of synthesis to their sites of action throughout the body and the brain. This role is fulfilled by thyroid hormone distributor proteins. Of particular interest is Transthyretin, which in mammals is synthesized in the liver, choroid plexus, meninges, retinal and ciliary pigment epithelia, visceral yolk sac, placenta, pancreas and intestines, whereas the other thyroid hormone distributor proteins are synthesized only in the liver. Transthyretin is synthesized by all classes of vertebrates; however, the tissue specificity of Transthyretin gene expression varies widely between classes. This review summarizes what is currently known about the evolution of Transthyretin synthesis in vertebrates and presents hypotheses regarding tissue-specific synthesis of Transthyretin in each vertebrate class.
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Recent Advances in Transthyretin Evolution, Structure and Biological Functions - Recent advances in Transthyretin evolution, structure, and biological functions /
2009Co-Authors: Samantha J Richardson, Vivian Cody.Abstract:Recent advances in Transthyretin evolution, structure, and biological functions / , Recent advances in Transthyretin evolution, structure, and biological functions / , کتابخانه دیجیتال جندی شاپور اهواز
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the evolution of the thyroid hormone distributor protein Transthyretin in the order insectivora class mammalia
Molecular Biology and Evolution, 2000Co-Authors: Porntip Prapunpoj, Samantha J Richardson, Luca Fumagalli, Gerhard SchreiberAbstract:Thyroid hormones are involved in the regulation of growth and metabolism in all vertebrates. Transthyretin is one of the extracellular proteins with high affinity for thyroid hormones which determine the partitioning of these hormones between extracellular compartments and intracellular lipids. During vertebrate evolution, both the tissue pattern of expression and the structure of the gene for Transthyretin underwent characteristic changes. The purpose of this study was to characterize the position of Insectivora in the evolution of Transthyretin in eutherians, a subclass of Mammalia. Transthyretin was identified by thyroxine binding and Western analysis in the blood of adult shrews, hedgehogs, and moles. Transthyretin is synthesized in the liver and secreted into the bloodstream, similar to the situation for other adult eutherians, birds, and diprotodont marsupials, but different from that for adult fish, amphibians, reptiles, monotremes, and Australian polyprotodont marsupials. For the characterization of the structure of the gene and the processing of mRNA for Transthyretin, cDNA libraries were prepared from RNA from hedgehog and shrew livers, and full-length cDNA clones were isolated and sequenced. Sections of genomic DNA in the regions coding for the splice sites between exons 1 and 2 were synthesized by polymerase chain reaction and sequenced. The location of splicing was deduced from comparison of genomic with cDNA nucleotide sequences. Changes in the nucleotide sequence of the Transthyretin gene during evolution are most pronounced in the region coding for the N-terminal region of the protein. Both the derived overall amino sequences and the N-terminal regions of the Transthyretins in Insectivora were found to be very similar to those in other eutherians but differed from those found in marsupials, birds, reptiles, amphibians, and fish. Also, the pattern of Transthyretin precursor mRNA splicing in Insectivora was more similar to that in other eutherians than to that in marsupials, reptiles, and birds. Thus, in contrast to the marsupials, with a different pattern of Transthyretin gene expression in the evolutionarily "older" polyprotodonts compared with the evolutionarily "younger" diprotodonts, no separate lineages of Transthyretin evolution could be identified in eutherians. We conclude that Transthyretin gene expression in the liver of adult eutherians probably appeared before the branching of the lineages leading to modern eutherian species.
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Evolution of thyroid hormone binding by Transthyretins in birds and mammals
European journal of biochemistry, 1999Co-Authors: Linus Chang, Samantha J Richardson, Sharon L. A. Munro, Gerhard SchreiberAbstract:Transthyretin, a protein synthesized and secreted by the choroid plexus and liver, binds thyroid hormones in extracellular compartments. This binding prevents accumulation of thyroid hormones in the lipids of membranes, establishing extracellular thyroid hormone pools for the distribution of the hormones throughout the body and brain. The N-termini of the Transthyretin subunits are longer and more hydrophobic in chicken than in eutherian Transthyretins. Here, we show that this is a general structural feature of avian Transthyretins. Systematic changes of protein structure during evolution result from selection pressure leading to changes in function. The evolution of Transthyretin function, namely, the binding of thyroid hormones, was studied in nine vertebrate species. The affinity of thyroxine binding to Transthyretin is lowest in avians (mean Kd of about 30 nm), intermediate in metatherians (mean Kd of about 17 nm) and highest in eutherians (mean Kd of about 11 nm). The affinity for 3,5,3'-triiodothyronine shows an opposite trend, being four times higher for avian Transthyretins than for mammalian Transthyretins.
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The Acute Phase Response of Plasma Proteins in the Polyprotodont Marsupial Monodelphis domestica
Comparative biochemistry and physiology. Part B Biochemistry & molecular biology, 1998Co-Authors: Samantha J Richardson, Katarzyna M. Dziegielewska, Na Andersen, Shawn B. Frost, Gerhard SchreiberAbstract:In eutherians, patterns of plasma protein levels in blood change during the acute phase response to trauma and inflammation. Until now, such an acute phase response has not been characterised in a noneutherian species. Here we describe the acute phase response in a marsupial species, the South American polyprotodont marsupial Monodelphis domestica, after brain surgery or injection of lipopolysaccharide. Several days after brain surgery, Transthyretin was not detected in plasma. For 48 hr following injection of lipopolysaccharide, the concentration of haptoglobin in plasma increased, that of Transthyretin decreased, and the concentration of albumin in plasma did not change significantly. The American polyprotodont marsupials are probably more closely related to the common ancestor marsupial than the Australian marsupials are. It is most likely that the Transthyretin gene was not expressed in the liver of this common ancestor. As the Transthyretin gene is expressed in the liver of M. domestica, it seems that as soon as Transthyretin is synthesised by the liver, it is under negative acute phase control.
Mathew S Maurer - One of the best experts on this subject based on the ideXlab platform.
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expert consensus recommendations for the suspicion and diagnosis of Transthyretin cardiac amyloidosis
Circulation-heart Failure, 2019Co-Authors: Mathew S Maurer, Thibaud Damy, Martha Grogan, Arnt V Kristen, Sabahat Bokhari, Sharmila Dorbala, Brian M Drachman, Marianna Fontana, Isabelle Lousada, Jose NativinicolauAbstract:Cardiomyopathy is a manifestation of Transthyretin amyloidosis (ATTR), which is an underrecognized systemic disease whereby the Transthyretin protein misfolds to form fibrils that deposit in variou...
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tafamidis treatment for patients with Transthyretin amyloid cardiomyopathy
The New England Journal of Medicine, 2018Co-Authors: Mathew S Maurer, Giampaolo Merlini, Balarama Gundapaneni, Jeffrey H Schwartz, Perry M Elliott, Martha Grogan, Arnt V Kristen, Ronald M Witteles, Marcia Waddingtoncruz, Thibaud DamyAbstract:Abstract Background Transthyretin amyloid cardiomyopathy is caused by the deposition of Transthyretin amyloid fibrils in the myocardium. The deposition occurs when wild-type or variant Transthyretin becomes unstable and misfolds. Tafamidis binds to Transthyretin, preventing tetramer dissociation and amyloidogenesis. Methods In a multicenter, international, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 441 patients with Transthyretin amyloid cardiomyopathy in a 2:1:2 ratio to receive 80 mg of tafamidis, 20 mg of tafamidis, or placebo for 30 months. In the primary analysis, we hierarchically assessed all-cause mortality, followed by frequency of cardiovascular-related hospitalizations according to the Finkelstein–Schoenfeld method. Key secondary end points were the change from baseline to month 30 for the 6-minute walk test and the score on the Kansas City Cardiomyopathy Questionnaire–Overall Summary (KCCQ-OS), in which higher scores indicate better health status. Results In the prim...
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design and rationale of the phase 3 attr act clinical trial tafamidis in Transthyretin cardiomyopathy clinical trial
Circulation-heart Failure, 2017Co-Authors: Mathew S Maurer, Giampaolo Merlini, Balarama Gundapaneni, Marcia Waddington Cruz, Perry M Elliott, Sanijv J Shah, Alison Flynn, Steven Riley, C. Hahn, Jeffrey H SchwartzAbstract:Transthyretin amyloidosis is a rare, life-threatening disease resulting from aggregation and deposition of Transthyretin amyloid fibrils in various tissues. There are 2 predominate phenotypic presentations of the disease: Transthyretin familial amyloid polyneuropathy, which primarily affects the peripheral nerves, and Transthyretin cardiomyopathy (TTR-CM), which primarily affects the heart. However, there is a wide overlap with symptoms at presentation and disease course being highly variable and influenced by the underlying Transthyretin mutation, age of the affected individual, sex, and geographic location. Treatment of Transthyretin amyloidosis is typically focused on symptom management. Although tafamidis has been shown to delay neurologic progression of Transthyretin familial amyloid polyneuropathy, there are no approved pharmacologic therapies shown to improve survival in TTR-CM. The natural history of TTR-CM is poorly characterized, which presents difficulties for the design of large-scale trials for new treatments. This review provides a brief overview of TTR-CM and the challenges of identifying clinically meaningful end points and study parameters to determine the efficacy of treatments for rare diseases. The design and rationale behind the ongoing phase 3 ATTR-ACT study (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial), an international, multicenter, double-blind, placebo-controlled, randomized clinical trial, is also outlined. The ATTR-ACT study will provide important insight into the efficacy and safety of tafamidis for the treatment of TTR-CM. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01994889.
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Transthyretin Cardiac Amyloidosis in Older Adults: Optimizing Cardiac Imaging to the Corresponding Diagnostic and Management Goal
Current Cardiovascular Risk Reports, 2017Co-Authors: Adam Castaño, Mathew S Maurer, Daniel K. Manson, Sabahat BokhariAbstract:Purpose of Review Transthyretin cardiac amyloidosis is increasingly recognized as an important cause of heart failure in older adults. Many cardiac imaging modalities have evolved to evaluate Transthyretin cardiac amyloidosis and include 2D echocardiography with tissue Doppler and speckle-strain imaging, nuclear scintigraphy, cardiac magnetic resonance imaging, and positron emission tomography. The purpose of this review is to highlight the optimal selection of advanced cardiac imaging techniques with corresponding diagnostic goals including raising suspicion, making an early diagnosis, and subtyping Transthyretin cardiac amyloid, as well as management goals including assessment of ventricular impairment, prognosticating, and monitoring disease progression. Potential benefits of optimizing cardiac imaging in the elderly patient with Transthyretin cardiac amyloidosis may include enhanced and earlier diagnosis and refined long-term management. Recent Findings Advances in cardiac imaging techniques are changing diagnostic and management algorithms for Transthyretin cardiac amyloidosis. Summary With a new era of novel therapeutics, enhanced recognition, and earlier diagnosis approaching, selecting the appropriate non-invasive cardiac imaging modality will be essential for optimal care in the elderly patient with Transthyretin cardiac amyloidosis.
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Differences in Transthyretin Amyloidosis between the United States and the Rest of the World: A Report from the Transthyretin Amyloid Outcome Survey (THAOS)
Journal of Cardiac Failure, 2013Co-Authors: Mathew S Maurer, Thibaud Damy, Arnt V Kristen, Violaine Planté-bordeneuve, Teresa Coelho, Rodney H. Falk, Claudio Rapezzi, Rajiv Mundayat, Ole B SuhrAbstract:Differences in Transthyretin amyloidosis between the United States and the rest of the world : a report from the Transthyretin Amyloid Outcome Survey (THAOS)
Mitsuharu Ueda - One of the best experts on this subject based on the ideXlab platform.
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a statement on the appropriate administration of tafamidis in patients with Transthyretin cardiac amyloidosis
Circulation, 2019Co-Authors: Jin Endo, Mitsuharu Ueda, Takayuki Inomata, Kazufumi Nakamura, Koichiro Kuwahara, Nobuhiro Tahara, Kenichi Tsujita, Yasuhiro Izumiya, Motoaki Sano, Yoshiki SekijimaAbstract:Transthyretin cardiac amyloidosis is a progressive and life-threating disease that is significantly underdiagnosed, and the actual number of patients with the disease is presently unknown. Accumulation of wild-type Transthyretin-derived amyloid in the heart is a common finding in very elderly patients. Recent clinical trials demonstrated that tafamidis reduced all-cause death and the number of cardiovascular hospitalizations when compared with placebo. The Japanese Ministry of Health, Labour and Welfare approved tafamidis (Vyndaqel®, Pfizer Inc.) for the treatment of cardiomyopathy caused by both wild-type and mutated Transthyretin-derived amyloidoses. This scientific statement on Transthyretin-derived cardiac amyloidosis summarizes the conditions for reimbursement of the cost of tafamidis therapy, and the institutional and physician requirements for the introduction of tafamidis.
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Rapid detection of wild-type and mutated Transthyretins.
Annals of Clinical Biochemistry, 2016Co-Authors: Masayoshi Tasaki, Mitsuharu Ueda, Konen Obayashi, Hiroaki Motokawa, Yumiko Kinoshita, Genki Suenaga, Akihiro Yanagisawa, Risa Toyoshima, Yohei Misumi, Teruaki MasudaAbstract:BackgroundFamilial amyloid polyneuropathy is caused by a variant Transthyretin, which is a serum protein secreted by the liver. We previously reported that mutated Transthyretins were detected in s...
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Rapid detection of wild-type and mutated Transthyretins.
Annals of clinical biochemistry, 2015Co-Authors: Masayoshi Tasaki, Mitsuharu Ueda, Konen Obayashi, Hiroaki Motokawa, Yumiko Kinoshita, Genki Suenaga, Akihiro Yanagisawa, Risa Toyoshima, Yohei Misumi, Teruaki MasudaAbstract:Familial amyloid polyneuropathy is caused by a variant Transthyretin, which is a serum protein secreted by the liver. We previously reported that mutated Transthyretins were detected in serum samples by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS). The aim of this study was to evaluate the clinical usefulness of SELDI-TOF MS for diagnosis of Transthyretin-related amyloidosis. We used 106 serum samples obtained from patients who were clinically suspected of having amyloidosis between February 2011 and April 2014. SELDI-TOF MS allowed analysis for Transthyretin via a 3-h one-step procedure. Of the 106 patients, 51 are Transthyretin amyloidosis. Mutated Transthyretins were detected in serum samples from 30 of 51 patients with Transthyretin amyloidosis. The results of genetic analysis showed that all of those patients had mutations in the Transthyretin gene. For all 18 patients with senile systemic amyloidosis of 51 patients with Transthyretin amyloidosis, SELDI-TOF MS detected only wild-type Transthyretin peaks, not mutated Transthyretin peaks. SELDI-TOF MS is a clinically useful tool for diagnosis of Transthyretin-related amyloidosis. © The Author(s) 2015.
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amyloid deposits derived from Transthyretin in the ligamentum flavum as related to lumbar spinal canal stenosis
Modern Pathology, 2015Co-Authors: Akihiro Yanagisawa, Mitsuharu Ueda, Masayoshi Tasaki, Yohei Misumi, Takanao Sueyoshi, Tatsuya Okada, Toru Fujimoto, Keisuke Kitagawa, Toshinori Oshima, Hirofumi JonoAbstract:Amyloidosis is a protein conformational disorder with the distinctive feature of extracellular accumulation of amyloid fibrils that come from different proteins. In the ligamentum flavum of the lumbar spine, amyloid deposits were frequently found in elderly patients with lumbar spinal canal stenosis and were at least partially formed by wild-type Transthyretin. However, how amyloid deposits in the ligamentum flavum affect lumbar spinal canal stenosis has remained unclear. In this study, we analyzed clinical, pathologic, and radiologic findings of patients with lumbar spinal canal stenosis who had amyloid deposits in the ligamentum flavum. We studied 95 ligamentum flavum specimens obtained from 56 patients with lumbar spinal canal stenosis and 21 ligamentum flavum specimens obtained from 19 patients with lumbar disk herniation. We evaluated histopathologic findings and clinicoradiologic manifestations, such as thickness of the ligamentum flavum and lumbar spinal segmental instability. We found that all 95 ligamentum flavum specimens resected from patients with lumbar spinal canal stenosis had amyloid deposits, which we classified into two types, Transthyretin-positive and Transthyretin-negative, and that Transthyretin amyloid formation in the ligamentum flavum of patients with lumbar spinal canal stenosis was an age-associated phenomenon. The amount of amyloid in the ligamentum flavum was related to clinical manifestations of lumbar spinal canal stenosis, such as thickness of the ligamentum flavum and lumbar spinal segmental instability, in the patients with lumbar spinal canal stenosis with Transthyretin-positive amyloid deposits. To our knowledge, this report is the first to show clinicopathologic correlations in Transthyretin amyloid deposits of the ligamentum flavum. In conclusion, Transthyretin amyloid deposits in the ligamentum flavum may be related to the pathogenesis of lumbar spinal canal stenosis in elderly patients.
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wild type Transthyretin derived amyloidosis in various ligaments and tendons
Human Pathology, 2011Co-Authors: Takanao Sueyoshi, Mitsuharu Ueda, Yukio Ando, Hirofumi Jono, Hiroki Irie, Akira Sei, Junji Ide, Hiroshi MizutaAbstract:Transthyretin-derived amyloid deposition is commonly found in intercarpal ligaments of patients with senile systemic amyloidosis. However, the frequency of Transthyretin-derived amyloid deposits in ligaments of other tissues remains to be elucidated. This study aimed to determine the frequency of amyloid deposition and the precursor proteins of amyloid found in orthopedic disorders. We studied 111 specimens from patients with carpal tunnel syndrome (flexor tenosynovium specimens), rotator cuff tears (rotator cuff tendon specimens), and lumbar canal stenosis (yellow ligament specimens). To identify amyloid precursor proteins, we used immunohistochemical staining with antibodies that react with Transthyretin, immunoglobulin light chain, amyloid A protein, and β(2)-microglobulin. By means of Congo red staining, we identified 47 (42.3%) amyloid-positive samples, 39 of which contained Transthyretin-derived amyloid (18 flexor tenosynovium specimens, 5 rotator cuff tendon specimens, and 16 yellow ligament specimens). Genetic testing and/or clinical findings suggested that all patients with Transthyretin amyloid deposits did not have familial amyloidotic polyneuropathy. The occurrence of amyloid deposition in those tissues depended on age. These results suggest that Transthyretin-derived amyloid deposits may occur more frequently in various ligaments and tendons than originally expected. In the future, such amyloid deposits may aid determination of the pathogenesis of ligament and tendon disorders in older patients.
Per Westermark - One of the best experts on this subject based on the ideXlab platform.
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Transthyretin and amyloid in the islets of Langerhans in type-2 diabetes
Experimental Diabetes Research, 2008Co-Authors: Gunilla T. Westermark, Per WestermarkAbstract:Transthyretin (TTR) is a major amyloid fibril protein in certain systemic forms of amyloidosis. It is a plasma protein, mainly synthesized by the liver but expression occurs also at certain minor locations, including the endocrine cells in the islets of Langerhans. With the use of immunohistochemistry and in situ hybridization, we have studied the distribution of Transthyretin-containing cells in islets of Langerhans in type-2 diabetic and nondiabetic individuals. TTR expression was particularly seen in alpha (glucagon) cells. Islets from type-2 diabetic patients had proportionally more Transthyretin-reactive islet cells, including beta cells. A weak Transthyretin immunoreaction in IAPP-derived amyloid occurred in some specimens. In seeding experiments in vitro, we found that TTR fibrils did not seed IAPP while IAPP fibrils seeded TTR. It is suggested that islet expression of Transthyretin may be altered in type-2 diabetes.
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Purification of Transthyretin and Transthyretin fragments from amyloid-rich human tissues.
Methods in molecular biology (Clifton N.J.), 2005Co-Authors: Per Westermark, Gunilla T. WestermarkAbstract:Transthyretin is the major amyloid fibril protein in many forms of familial systemic amyloidosis where a missense mutation creates an amyloidogenic protein, and in senile systemic amyloidosis in which wild-type Transthyretin aggregates into amyloid fibrils. The amyloid deposits may consist of full-length Transthyretin but is very often, in senile systemic amyloidosis always, a mixture of full-length Transthyretin and C-terminal Transthyretin fragments. The amyloid fibril protein mixture can be purified by extraction of fibrils followed by sequential gel filtration after solubilization in a solution of guanidine hydrochloride. Since the C-terminal Transthyretin fragments lack cysteine residues, a method to separate full-length Transthyretin from fragments by covalent chromatography has been developed.
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Amyloid deposits in Transthyretin-derived amyloidosis: cleaved Transthyretin is associated with distinct amyloid morphology.
The Journal of pathology, 2005Co-Authors: Joakim Bergström, Knut Sletten, Åsa Gustavsson, Ulf Hellman, Charles L. Murphy, Deborah T. Weiss, Alan Solomon, Bert Ove Olofsson, Per WestermarkAbstract:Amyloid deposits in Transthyretin-derived amyloidosis : cleaved Transthyretin is associated with distinct amyloid morphology.
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The Transthyretin cDNA sequence is normal in Transthyretin‐derived senile systemic amyloidosis
FEBS letters, 1991Co-Authors: Lars Christmanson, Christer Betsholtz, Å. Gustavsson, B. Johansson, Knut Sletten, Per WestermarkAbstract:A variety of mutations leading to amino acid substitutions have been described in the Transthyretin gene in association with different familial amyloidoses and have been implicated to be involved in the pathogenesis of amyloid deposits. However, there has been disagreement whether or not a Transthyretin mutation is present in the most common form of Transthyretin-derived amyloid, namely senile systemic amyloidosis. Therefore, the cDNA sequence of liver Transthyretin was determined in a 91-year-old patient with typical senile systemic amyloidosis. This sequence was completely normal and lacked any variation. We conclude that in senile systemic amyloidosis factors other than the presence of a sequentially variant Transthyretin must determine the amyloid fibril formation.
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Normal Transthyretin and synthetic Transthyretin fragments from amyloid-like fibrils in vitro
Biochemical and biophysical research communications, 1991Co-Authors: Åsa Gustavsson, Ulla Engström, Per WestermarkAbstract:In two general forms of amyloidosis, senile systemic amyloidosis and several familial amyloidoses the amyloid fibrils are built up by Transthyretin and fragments of the molecule. It has previously been demonstrated that other amyloid fibril proteins e.g. atrial natriuretic factor and islet amyloid polypeptide form amyloid-like fibrils in vitro. In this study we used normal Transthyretin and synthetic polypeptides corresponding to segments of the Transthyretin molecule. We show that normal Transthyretin and two of our tested polypeptides, which corresponded to the beta-strands A and G, easily form amyloid-like fibrils in vitro.
