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)

A previously reported family with amyloid polyneuropathy (FAP) was reinvestigated to determine the type of mutation in the transthyretin (prealbumin) molecule. Transthyretin was isolated from amyloid-laden myocardium and serum, and tryptic peptides were resolved by high-performance liquid chromatography. Amino acid sequencing of an anomalous peptide revealed an alanine-for-threonine substitution corresponding to position No. 60 of the transthyretin monomer. Detection of the FAP gene in asymptomatic carriers was accomplished by hybrid isoelectric focusing of transthyretin in the presence of dithiothreitol and high concentrations of urea, and by Southern blotting of Pvull-digested leukocyte deoxyribonucleic acid. This type of FAP was found to be identical to the previously described Appalachian amyloid. Patients with FAP and their asymptomatic gene-carrying offspring had significantly reduced levels of serum transthyretin and retinol-binding protein.
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PMID:Familial amyloid polyneuropathy: alanine-for-threonine substitution in the transthyretin (prealbumin) molecule. 212 46

Immunocytochemical methods were used to study the nature of the amyloid deposits in the Finnish type-familial amyloid polyneuropathy (FAP) type IV, which is characterized by cranial neuropathy and corneal lattice dystrophy. Commercial antisera to human plasma transthyretin (prealbumin) did not stain the amyloid deposits, but in every case a positive staining was obtained with antibodies raised against transthyretin-related amyloid fibril whole protein isolated from the myocardium of a patient with familial amyloid polyneuropathy from the state of New York. The FAP type IV amyloid deposits stained also with antiserum to serum amyloid P component, but did not stain with antisera to retinol-binding protein, amyloid A protein, gamma-trace protein, beta 2-microglobulin, or immunoglobulin light chains. The serum level of serum transthyretin was significantly decreased in FAP type IV patients (256 +/- 75 (SD) mg/L, n = 15) as compared with Finnish control subjects (360 +/- 56 mg/L, n = 30, P less than 0.001), whereas the level of retinol-binding protein was within the normal range. The results of this study strongly suggest that the amyloid fibril protein in FAP type IV amyloidosis is related to transthyretin.
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PMID:Amyloid fibril protein in familial amyloidosis with cranial neuropathy and corneal lattice dystrophy (FAP type IV) is related to transthyretin. 325 17

Serum concentrations of prealbumin and retinol-binding protein were measured in 28 patients with Japanese-type familial amyloid polyneuropathy, 46 relatives and normal controls. Both the serum prealbumin and retinol-binding protein concentrations were significantly decreased in the patients when compared with normal controls. The mean serum levels of these proteins in the asymptomatic relatives were intermediate between controls and patients.
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PMID:Serum prealbumin and retinol-binding protein concentrations in Japanese-type familial amyloid polyneuropathy. 341 86

Amyloid fibrils were isolated from cardiac tissue of two brothers who died from familial amyloidotic polyneuropathy (FAP) type II. Sequence analysis on peptides derived from proteolytic cleavage with trypsin and fragmentation with cyanogen bromide reveal that the fibril subunit protein is derived from plasma transthyretin (prealbumin). About two-thirds of the fibril subunit protein was found to contain an amino acid substitution at position 84 where the normal isoleucine residue has been replaced by serine. Sequence analysis of the plasma transthyretin (prealbumin) from the two brothers as well as two clinically diagnosed FAP type II family members and two of four children of affected individuals showed the presence of serine at position 84. The presence of this substitution also correlates with low serum levels of retinol-binding protein and thus transthyretin (prealbumin) position 84 may be involved with the interaction of these two proteins.
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PMID:Characterization of a transthyretin (prealbumin) variant associated with familial amyloidotic polyneuropathy type II (Indiana/Swiss). 376 Jan 89

Amyloid deposits in several heredofamilial forms of amyloidosis are chemically related to transthyretin (TTR, the protein usually referred to as prealbumin). A genetically abnormal TTR may be involved. Studies were conducted on TTR isolated from sera of patients with familial amyloidotic polyneuropathy (FAP), and on amyloid fibril protein (AFp) isolated from tissues of two Portuguese patients who died with FAP. AFp, purified by affinity chromatography on retinol-binding protein (RBP), resembled plasma TTR in forming a stable tetrameric structure, and in its binding affinities for both thyroxine and RBP. Purified AFp was found to comprise a TTR variant with a methionine for valine substitution at position 30. This conclusion was based upon studies that included: (i) comparative peptide mapping by reverse-phase high-performance liquid chromatography after trypsin digestion; (ii) cyanogen bromide (CNBr) cleavage studies; and (iii) amino acid microsequence analysis of selected tryptic and CNBr peptides. The variant TTR was also found to be present in serum samples from FAP patients, along with larger amounts of normal TTR. An effective, small-scale procedure was developed to determine whether or not the variant TTR was present in the plasma of an individual subject. This procedure involved isolation of TTR by affinity chromatography on RBP, followed by CNBr cleavage, and analysis for the presence of specific aberrant CNBr peptides. Studies with six kindreds, including 21 asymptomatic children of 6 patients with FAP, showed that the "abnormal" TTR can be detected and used as a preclinical marker of the disease in affected children of patients with FAP. It is likely that the variant TTR represents a point mutation within the TTR structural gene, and that the normal and mutant genes act as co-dominant alleles at a single locus in FAP. The distribution of the mutant TTR within the six families was consistent with the autosomal dominant mode of inheritance of FAP. The mutant TTR apparently selectively deposits in tissues as the amyloid characteristic of the disease.
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PMID:Family studies of the genetic abnormality in transthyretin (prealbumin) in Portuguese patients with familial amyloidotic polyneuropathy. 609 6

Amyloid fibril protein was purified from postmortem organs of patients with familial amyloid polyneuropathy. In immunodiffusion tests, the protein reacted with antihuman prealbumin antibody but not with antihuman retinol-binding protein or antihuman immunoglobulin G (IgG). In immunoelectrophoresis, the amyloid fibril protein gave a single line with a slightly faster mobility than prealbumin. Immunohistochemical analysis, using fluorescent and peroxidase-antiperoxidase methods, showed that the amyloid deposits contained antigenic determinants of human retinol-binding protein and IgG but not prealbumin.
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PMID:Immunologic and immunohistochemical study of familial amyloid polyneuropathy. 617 55

Amyloid deposits in several heredofamilial forms of amyloidosis are known to be chemically related to transthyretin (TTR, the plasma protein usually referred to as prealbumin). A genetic mutation, leading to an abnormal TTR, may be involved. Studies were conducted to investigate whether or not Portuguese patients with familial amyloidotic polyneuropathy (FAP) have an abnormal species of TTR circulating in their plasma and, if so, whether this might have any impact on vitamin A transport and retinol-binding protein (RBP) metabolism in these patients. The initial studies examined the plasma concentrations of TTR, RBP, and retinol in patients with FAP. Significantly reduced (p less than 0.005) levels of TTR were found in patients with FAP. The TTR levels in 24 FAP patients were approximately two thirds of those of a group of 18 control subjects from the same geographic area. In contrast, RBP levels were not reduced, nor was there an abnormality in the ratio of retinol to RBP, in the patients with FAP. Thus there does not appear to be an abnormality in vitamin A transport in Portuguese patients with FAP. There does, however, appear to be an abnormality of TTR metabolism, accounting for the reduced plasma levels of TTR. TTR was isolated from pooled sera of the FAP patients and was characterized in detail. FAP-TTR was indistinguishable from normal TTR with regard to a variety of parameters, including (1) electrophoretic mobility, (2) chromatographic behavior, (3) molecular weight, (4) stability of the TTR tetramer, (5) immunoreactivity in TTR radioimmunoassays using antisera prepared against both normal and FAP-TTR, (6) ability to form a protein-protein complex with RBP and affinity for RBP as assessed by polarization of fluorescence, and (7) overall amino acid composition. The possible explanations are as follows: (1) an abnormal TTR molecule is not produced in this form of FAP; (2) the abnormal molecule is present in only trace amounts (not detectable in the present study) in FAP plasma; or (3) the abnormal TTR is structurally almost identical to normal TTR and does not differ from normal TTR with regard to the various physical and chemical properties investigated in this study. Preliminary observations suggest that FAP patients do produce an abnormal form of TTR that selectively deposits in tissues as amyloid protein.
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PMID:Studies on plasma transthyretin (prealbumin) in familial amyloidotic polyneuropathy, Portuguese type. 631 26

Amyloid fibril protein in patients with familial amyloidotic polyneuropathy is known to be chemically related to transthyretin (TTR), the plasma protein that is usually referred to as prealbumin. A genetically abnormal TTR may be involved in this disease. Studies were conducted on amyloid fibril protein (AFp) isolated from tissues of two Portuguese patients who died with familial amyloidosis, and on TTR isolated from sera of patients with this disease. AFp, purified by affinity chromatography on retinol-binding protein linked to Sepharose, resembled plasma TTR in forming a stable tetrameric structure, and in its binding affinities for both thyroxine and retinol-binding protein. The structural studies included: (a) comparative peptide mappings by reverse-phase high performance liquid chromatography (HPLC) after trypsin digestion; (b) cyanogen bromide cleavage studies; and (c) amino acid microsequence analysis of selected tryptic and CNBr peptides. On the basis of the known amino acid sequence of TTR, comparative tryptic peptide maps showed the presence of a single aberrant tryptic peptide (peptide 4, residues 22-34) in AFp as compared with TTR. This aberrant peptide contained a methionine residue, not present in normal tryptic peptide 4. CNBr cleavage of AFp produced two extra peptide fragments, which were demonstrated, respectively, by HPLC analysis and by sodium dodecyl sulfate-gel electrophoresis. Sequence analyses indicated the presence of a methionine-for-valine substitution at position 30 in AFp as compared with TTR. Thus, the purified amyloid fibril protein comprised a TTR variant with a methionine-forvaline substitution at position 30. A single nucleotide change in a possible codon for valine 30 could explain the substitution. The variant TTR was also present in the TTR isolated from the pooled sera of amyloidoses patients, together with larger (four- to six-fold) amounts of the normal TTR. Thus, in these patients, the variant TTR was circulating in plasma, along with larger amounts of normal TTR. We suggest that the variant TTR represents the specific biochemical cause of the disease, and that this abnormal form of TTR selectively deposits in tissues as the amyloid characteristic of the disease.
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PMID:Amyloid fibril protein in familial amyloidotic polyneuropathy, Portuguese type. Definition of molecular abnormality in transthyretin (prealbumin). 673 44

In patients on regular dialysis treatment, uremic symptoms (anemia, osteopathy, myopathy, neuropathy, and disorders of carbohydrate, fat, and protein metabolism) may be partly due to an accumulation of low molecular weight (MW) proteins (10,000 to 60,000 daltons). We tested this hypothesis using membranes with a higher permeability than conventional Cuprophan membranes. The primary aim of the study was to test the cutoff of various hemofilters (Cuprophan [Highflux], polyamide [FH 20], cellulose acetate [Duoflux], and polyacrylonitrile [Hospal RP 7 + 8 and Asahi PAN]) under in vivo conditions. In addition the effects of hemofiltration on plasma low molecular weight protein concentrations, polyneuropathy, and autonomic insufficiency were also tested in a long-term (six-month) study using the membrane with the highest cutoff and most constant sieving coefficient, i.e., Highflux. Low MW proteins with a defined MW were used as marker substances. Sieving coefficients of beta 2-microglobulin, lysozyme, retinol-binding protein, alpha 1-glycoprotein, alpha 1-antitrypsin, prealbumin, albumin, and transferrin were determined during a four-hour hemofiltration (20 L ultrafiltrate). Proteins were analyzed using an immunodiffusion technique. In the long-term study, motor nerve conduction velocity, the Schellong test, and Valsalva maneuver were tested prior to and three and six months after hemofiltration therapy. Highflux, Duoflux, and FH 202 membranes were permeable to proteins with molecular weights up to 15,000 daltons, and the Highflux module had the most constant sieving coefficient during hemofiltration. In the six-month hemofiltration study with the Highflux filter, plasma beta 2-microglobulin and lysozyme decreased significantly as expected. Parameters of polyneuropathy and autonomic insufficiency were slightly improved.
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PMID:Elimination of low molecular weight proteins during hemofiltration. 681 37

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


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