Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0152025 (polyneuropathy)
7,862 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nineteen patients with overt hypothyroidism were examined for the prevalence of myocardial disfunction, respiratory disturbances, peripheral neuropathy, and visual failure due to pituitary enlargement. Prevalences of pericardial effusion and myocardial disfunction (decrease PEP/LVET) were 50% and 75%, respectively. The degree of decreased myocardial function did not parallel with the grade of pericardial effusion. Arterial blood analysis indicated a frequent incidence of hypoxia in hypothyroidism. The incidence of hypoxia was 69%. The hypoxia was improved by thyroxine replacement therapy. In 6 patients examined for the ventilatory control, all had the index for hypercapnic ventilatory drive lower than normal control. It was suggested that the hypoxia in hypothyroidism was caused by a depression of the respiratory center in the brain and by anemia. Sensory nerve conduction was diminished in 6 of 11 hypothyroid patients and motor conduction in 6 of 15 was studied. In distal segments of sensory nerves, the abnormality frequently appeared before clinical symptoms of polyneuropathy. Visual field defect was detected in 71% of patients suffering of primary hypothyroidism. The most common characteristic change was the defect in the central visual field. All cases of visual field defect were cured by thyroid hormone replacement therapy. Two cases with deteriorated visual failure who did not improve during physiological replacement, were successively treated with over dosage of thyroid hormone.
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PMID:Unusual manifestations in primary hypothyroidism. 622 84

In plasma the thyroid hormone-binding protein transthyretin (TTR) forms a tight complex with the specific retinol carrier retinol-binding protein (RBP). The Ile-84-->Ser mutation and several other point mutations in TTR are associated with familial amyloidotic polyneuropathy, which is characterized by extracellular depositions of amyloid fibrils mainly consisting of mutated TTRs. The interactions with human RBP of recombinant human normal and Ser-84 TTRs were investigated by monitoring the fluorescence anisotropy of RBP-bound retinol. A nearly negligible affinity of the recombinant Ser-84 TTR for RBP was found. This result indicates the participation of a region on the outer surface of TTR that comprises Ile-84 in the recognition of RBP. In preliminary studies the Ser-84 TTR was the only one among several amyloidogenic variant TTRs to display negligible interaction with RBP. Therefore, in general a substantially altered binding of TTR to RBP is not associated with familial amyloidotic polyneuropathy. Instead, the altered binding of Ser-84 TTR to RBP appears to be responsible for an abnormal plasma transport of RBP. The recombinant normal TTR exhibits binding properties, in its interaction with human RBP, approximately similar to those of TTR purified from human plasma. Two independent and equivalent RBP binding sites on recombinant normal TTR are characterized by a dissociation constant of about 0.4 microM.
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PMID:The Ile-84-->Ser amino acid substitution in transthyretin interferes with the interaction with plasma retinol-binding protein. 808 2

Recently, a transthyretin variant, TTR Met 119, in which methionine substitutes for threonine 119, a component of the protein's iodothyronine binding site, was identified in individuals with transient euthyroid hyperthyroxinemia. Healthy carriers of Met 119 have normal serum thyroid hormone concentrations, but two studies of Met 119 carriers have differed as to whether T4 binding to TTR is increased. An additional kindred has been identified by hybrid isoelectric focusing in an ongoing screening program for TTR variants in the Portuguese population with TTR Met 30 associated familial amyloidotic polyneuropathy. Cyanogen bromide peptide mapping and DNA restriction length polymorphism analyses showed that the propositus was a compound heterozygote for two TTR variants: Asn 90 and Met 119. Family analysis revealed that he inherited the TTR Met 119 variant from the mother and the TTR Asn 90 variant from the father. Neither the compound heterozygote nor his parents had symptoms of familial amyloidotic polyneuropathy. Serum dialysis with stepwise saturation of iodothyronine binding sites confirmed that TTR binding of T4 is increased in TTR Met 119. The increased binding is due to a higher TTR concentration rather than an increased association constant for T4. Because of the small proportion of serum T4 bound by TTR, increased T4 binding by TTR did not affect the ratio of free to bound T4 or T4 concentrations. In contrast, plasma retinol binding protein, almost all of which is bound by TTR, was elevated. The Asn 90 mutation does not affect either the concentration or the hormone binding characteristics of the protein. Possible long-term effects of these mutations and the combined heterozygotic state remain to be determined.
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PMID:Thyroxine binding in a TTR Met 119 kindred. 810 46

Serum transthyretin (TTR) is a protein of liver origin that under normal conditions transports approximately 20% T4. Missense mutations of the TTR gene produce familial amyloidotic polyneuropathy and rarely, euthyroid hyperthyroxinemia (EHT). Of the 3 TTR variants so far identified with increased affinity for T4, Ser6, Thr109, and Met119, only TTR-Thr109 has high enough affinity for T4 to produce consistent hyperthyroxinemia in the heterozygous individuals. Because the mutation GCC-->ACC in codon 109 results in the loss of one Bso FI site in exon 4 of the TTR gene, the use of this enzyme was suggested to screen for TR-Thr109 in subjects with EHT. We investigated a family with dominantly inherited EHT, in which two of eight affected members received ablative thyroid treatment for presumed thyrotoxicosis, and one was misdiagnosed as having resistance to thyroid hormone. All affected individuals had serum reverse T3 concentrations above normal and average T4 50% above the mean of unaffected relatives. Total T3 and TSH levels were within the normal range. Although loss of the Bso FI site in one allele of the two TTR suggested the presence of Thr109, gene sequencing revealed a different mutation in the same codon (GCC-->GTC) producing TTR-Val109. T4-binding to TTR-Val109 was compared to that of the normal TTR-Ala109 and the formerly identified variant TTR-Thr109. Association constants were 1.3, 9.5, and 13.6 X 10(7) M-1 for TTR-Ala109, Val109, and Thr109, respectively. Thus, for equally expressed mutant and normal allele and 20% of serum T4 bound to TTR, the calculated mean serum T4 concentration of heterozygotes for TTR-Val109 should be 50% above the normal mean; the observed value being 55%. These results are in agreement with the observations based on the crystallographic structure of TTR-Thr109 indicating that the extra atoms in Val as in Thr, which are absent in the Ala of the wild type TTR, widen the ligand binding site.
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PMID:A new family with hyperthyroxinemia caused by transthyretin Val109 misdiagnosed as thyrotoxicosis and resistance to thyroid hormone--a clinical research center study. 878 93

In the Western world, diabetes is the biggest cause of peripheral neuropathy, usually distal symmetric polyneuropathy but some times another polyneuropathy or a focal neuropathy. In addition, hypothyroidism and acromegaly can cause carpal tunnel syndrome and other sensory complaints. A complete blood cell count, nerve-conduction tests, thyroid-function tests (needed in all patients with carpal tunnel syndrome), and when necessary, needle electromyography can help confirm the diagnosis. Treatment of underlying disease is the most successful management approach: Tight glucose control in diabetic patients, thyroid hormone replacement therapy in patients with hypothyroidism, and removal of the pituitary adenoma in patients with acromegaly are of proven benefit. Significant symptomatic relief of dysesthesias can be obtained with use of capsaicin cream, tricyclic antidepresants, anticonvulsant agents, or an antiarrhythmic drug.
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PMID:Endocrinologic causes of peripheral neuropathy. Pins and needles in a stocking-and-glove pattern and other symptoms. 930 20

The Ile-->Ser84 substitution in the thyroid hormone transport protein transthyretin is one of over 50 variations found to be associated with familial amyloid polyneuropathy, a hereditary type of lethal amyloidosis. Using a peptide analogue of the loop containing residue 84 in transthyretin, we have examined the putative local structural effects of this substitution using 1H-NMR spectroscopy. The peptide, containing residues 71-93 of transthyretin with its termini linked via a disulfide bond, was found to possess the same helix-turn motif as in the corresponding region of the crystallographically derived structure of transthyretin in 20% trifluoroethanol (TFE) solution. It therefore, represents a useful model with which to examine the effects of amyloidogenic substitutions. In a peptide analogue containing the Ile84-->Ser substitution it was found that the substitution does not greatly disrupt the overall three-dimensional structure, but leads to minor local differences at the turn in which residue 84 is involved. Coupling constant and NOE measurements indicate that the helix-turn motif is still present, but differences in chemical shifts and amide-exchange rates reflect a small distortion. This is in keeping with observations that several other mutant forms of transthyretin display similar subunit interactions and those that have been structurally analysed possess a near native structure. We propose that the Ser84 mutation induces only subtle perturbations to the transthyretin structure which predisposes the protein to amyloid formation.
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PMID:1H-NMR structural studies of a cystine-linked peptide containing residues 71-93 of transthyretin and effects of a Ser84 substitution implicated in familial amyloidotic polyneuropathy. 1033 46

Transthyretin is an essential protein responsible for the transport of thyroid hormones and retinol in human serum and is also implicated in the amyloid diseases familial amyloidotic polyneuropathy and senile systemic amyloidosis. Its folding properties and stabilization by ligands are of current interest due to their importance in understanding and combating these diseases. Here we report the solid phase synthesis of the monomeric unit of a transthyretin analog (equivalent to 127 amino acids) using t-Boc chemistry and peptide ligation and its folding to form a functional 54-kDa tetramer. The monomeric unit of the protein was chemically synthesized in three parts (positions 1--51, 54--99, and 102--127) and ligated using a chemoselective thioether ligation chemistry. The synthetic protein was folded and assembled to a tetrameric structure in the presence of transthyretin's native ligand, thyroxine, as shown by gel filtration chromatography, native gel electrophoresis, transthyretin antibody recognition, and thyroid hormone binding. Other folding products included a high molecular weight aggregate as well as a transient dimeric species. This represents one of the largest macromolecules chemically synthesized to date and demonstrates the potential of protein chemical synthesis for investigations of protein-ligand interactions.
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PMID:Synthesis of an analog of the thyroid hormone-binding protein transthyretin via regioselective chemical ligation. 1135 12

Transthyretin (TTR) is a plasma protein that transports thyroid hormone and retinol binding protein-vitamin A complex. Eighty-four variants of TTR have been identified and seventy-four are associated with familial amyloidotic polyneuropathy. Normal TTR is the major protein found in the fibrillar deposits in the heart at time of autopsy of individuals with senile systemic amyloidosis. The mechanism by which normally soluble TTR deposits as organ-damaging, insoluble, pathological fibrils late in life is unknown. Understanding the mechanism of fibrillogenesis of normal TTR is critical to the design of clinical treatments aimed at retardation, prevention, or reversal of fibril deposition. We have employed a biophysical approach to explore the hypothesis that an instability in a particular secondary or tertiary structure plays a role in the ability of normal TTR to form fibrils at physiological pH. Using far UV circular dichroic (CD) spectroscopy as a function of temperature we have identified simultaneous, cooperative, reversible structural changes in the beta-sheet and alpha-helical regions. The flexible short, surface-located loops undergo an irreversible conformational change at a lower temperature. Spectra before and after heating are different, particularly in the wavelength region associated with these loops, strongly suggesting that the major portion of TTR returns to its initial conformation while the loops do not. Near UV CD reveals partially reversible and irreversible changes in tertiary structure. Using calorimetry to directly measure the enthalpy associated with these changes, two peaks are observed, with further analysis suggesting conformational intermediates. Precipitates from heated samples reveal pre-fibrillar morphology by negative stain electron microscopy. These biophysical studies suggest that heat-induced conformational rearrangements enable normal TTR to assemble into pre-fibrils at physiological pH.
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PMID:Biophysical analysis of normal transthyretin: implications for fibril formation in senile systemic amyloidosis. 1140 37

As introduction to the First International Congress on Transthyretin in Health and Disease, this lecture traces the origin of the subjectfrom the discovery in the 1950s that a serum protein migrating ahead of albumin in an electrical field binds the thyroid hormone, thyroxine. Early work defined the molecular and biological properties of thyroxine-binding prealbumin (TBPA). Its tetrameric structure, first recognized from a polymorphism in monkeys, was later elaborated by crystallographic studies, and the very different affinity of its two identical thyroxine-binding sites was explained by an allosteric effect upon occupation of the first site. The far higher concentration of TBPA in cerebrospinal fluid compared to blood was explained by the discovery, 30 years later, that TBPA is synthesized by cells of the choroid plexus, and its rapid turnover in the body made TBPA a convenient marker of malnutrition and chronic disease. Late in the 1960s it was learned that TBPA also carries vitamin A in the circulation by interacting with retinol-binding protein (RBP). TBPA then was renamed transthyretin (TTR), in recognition of its dual transport function, and it was shown that retinol-RBP-TTR interactions are mutually enhancing. Investigation of the molecular genetics of TTR began in 1980 and a large number of inherited variants were discovered in the ensuing years. Some affect thyroxine and/or RBP binding but the majority are associated with familial amyloidotic polyneuropathy. Seizing on this discovery, structural biologists are now investigating why mutated TTR changes from a compact, soluble molecule into a fibrillar, insoluble polymer, and how this pathological transformation might be prevented.
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PMID:Transthyretin from discovery to now. 1255 18

Transthyretin (TTR) is a 55 kDa protein responsible for the transport of thyroid hormones and retinol in human serum. Misfolded forms of the protein are implicated in the amyloid diseases familial amyloidotic polyneuropathy and senile systemic amyloidosis. Its folding properties and stabilization by ligands are of current interest due to their importance in understanding and combating these diseases. To assist in such studies we developed a method for the solid phase synthesis of the monomeric unit of a TTR analogue and its folding to form a functional 55 kDa tetramer. The monomeric unit of the protein was chemically synthesized in three parts, comprising amino acid residues 1-51, 54-99 and 102-127, and ligated using chemoselective thioether ligation chemistry. The synthetic protein was folded and assembled to a tetrameric structure in the presence of the TTR's native ligand, thyroxine, as shown by gel filtration chromatography, native gel electrophoresis, TTR antibody recognition and thyroid hormone binding. In the current study the solution structure of the first of these fragment peptides, TTR(1-51) is examined to determine its intrinsic propensity to form beta-sheet structure, potentially involved in amyloid fibril formation by TTR. Despite the presence of extensive beta-structure in the native form of the protein, the N-terminal fragment adopts an essentially random coil conformation in solution.
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PMID:Synthesis and structural analysis of the N-terminal domain of the thyroid hormone-binding protein transthyretin. 1255 22


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