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)

The most common form of hereditary systemic amyloidosis is familial amyloidotic polyneuropathy associated with single amino acid changes in the plasma protein, transthyretin. In addition, there are two variants of transthyretin (Ser6 and Thr109) not associated with familial amyloidotic polyneuropathy but with familial euthyroid hyperthyroxinemia, also an autosomal dominant disorder. In these autosomal dominant diseases, most affected individuals are heterozygous and therefore have hybrid forms of the tetrameric plasma transthyretin. In order to study the structure/function relationships of homozygous variant transthyretins, normal human transthyretin and five variant transthyretins (Gly6----Ser, Leu58----His, Thr60----Ala, Ile84----Ser, and Ala109----Thr) were produced in Escherichia coli using the expression vector, pCZ11, and site-directed mutagenesis. These recombinant transthyretin (r-TTR) proteins showed the correct size (14 kilodaltons) on sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western analysis and self-associated into tetramers as determined by size exclusion chromatography. Recombinant normal, Ser6, and Ala60 r-TTRs had an affinity for thyroxine indistinguishable from normal human TTR purified from plasma, whereas His58 and Ser84 r-TTRs had significantly reduced affinity. On the other hand, Thr109 r-TTR had a much higher affinity, probably due to its position within the thyroxine-binding pocket. Expression of mutant transthyretins in E. coli provides the opportunity to study structure/function relationships and amyloid-forming capabilities induced by single amino acid substitutions in the transthyretin molecule.
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PMID:Production and functional analysis of normal and variant recombinant human transthyretin proteins. 164 39

We analyzed 11 consecutive unrelated cases of polyneuropathy due to transthyretin amyloidosis. Direct sequencing of the promoter region, exons, and splice junctions revealed that each patient was heterozygous for a mutation: six patients had valine 30 substituted by methionine (V30----M; Portuguese-Japanese type), one had threonine 60 substituted by alanine (T60----A; Appalachian type), and two had serine 77 substituted by tyrosine (S77----Y; Illinois type). In addition, two patients had previously undescribed mutation: phenylalanine 33 substituted by leucine (F33----L) and phenylalanine 64 substituted by leucine (F64----L). From present information, the probands of these novel mutations do not exhibit any pathology that clearly distinguishes them from individuals with the other mutations. The mutations extend the range of mutations associated with amyloidotic polyneuropathy. In our 11 patients, the different mutations did not seem to correlate with distinct clinical phenotypes. We developed PASA assays (PCR amplification of specific alleles) for each of the five mutations. PASA can be used by any diagnostic laboratory that can perform PCR to rapidly detect any of the known mutations. The minority of samples with an undescribed mutation can be sent to a specialty laboratory for delineation of the mutation by direct genomic sequencing. The presently described combination of methods may have widespread utility in the diagnosis of genetic disease.
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PMID:Two-tiered DNA-based diagnosis of transthyretin amyloidosis reveals two novel point mutations. 204 36

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

Transthyretin isolated from amyloid fibrils from an Israeli patient with Familial Amyloidotic Polyneuropathy was sequenced by two research groups. One laboratory reported a position 49 Thr----Gly substitution, while the other noted a Phe for Ile interchange at amino acid 33. We used a transthyretin cDNA probe to study DNA from this patient by Southern blotting. The DNA displayed the unique Bcl I restriction site predicted by the mutation in codon 33. Because of the close size of the normal (6.40 kb), and variant (6.27 kb) fragments, the variant was more easily demonstrated after digestion with both Bcl I and Sph I, which generated two easily resolvable fragments of 2.39 and 2.27 kb.
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PMID:Restriction fragment analysis confirms the position 33 mutation in transthyretin from an Israeli patient (SKO) with familial amyloidotic polyneuropathy. 289 49

Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant late-onset disorder characterized by the extracellular deposition of amyloid fibrils. In all cases studied these fibrils have been found to be composed of plasma prealbumin (transthyretin) containing a single amino acid substitution. Biochemical studies were conducted on amyloid from one patient and plasma prealbumin from his affected brother, both part of a large kindred from the Appalachian region of the United States. Sequence analysis of the amyloid subunit protein showed it to be prealbumin with about two-thirds of the molecules containing a substitution of alanine for threonine at position 60. Studies of the plasma prealbumin showed that the same substitution was present in 40-45% of the protein. Based on this substitution and the prealbumin cDNA sequence, a Pvu II restriction fragment length DNA polymorphism (RFLP) was predicted and demonstrated in DNA of both patients as well as other family members. This RFLP confirms the predicted DNA mutation responsible for the protein variant, and represents an accurate method for detection of this gene.
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PMID:Biochemical and molecular genetic characterization of a new variant prealbumin associated with hereditary amyloidosis. 372 85

The first instance of familial amyloidotic polyneuropathy affecting a Jewish family is reported. Vitreous opacities were its presenting feature in the father at age 30 and the son at 25. Severe autonomic dysfunction and progressive peripheral neuropathy affecting initially the lower extremities soon followed. Death, suicidal in the son, occurred after seven and four years of illness. Their amyloid contained three proteins-an entire variant monomer of prealbumin, glycine replacing threonine as residue 49, and both products of its cleavage at the point of substitution. Lower limb familial amyloidotic polyneuropathy has been recorded in many families in Portugal, Sweden and Japan and occasionally in families of various ethnic stocks. This ethnic diversity prompts consideration of genetic heterogeneity. Differentiation on a genetic basis is forestalled since all pedigrees are compatible with autosomal dominant transmission and clinical data are marred by observer variance, even regarding vitreous opacities. Notwithstanding, an isolated British family is unique in the frequent occurrence of intractable peptic ulceration, cataracts, deafness and renal disease not attributable to amyloidosis and a striking predominance of males afflicted. Biochemically, monomeric prealbumin has been demonstrated by electrophoretic and immunologic techniques as the single protein constituent of amyloids isolated from Portuguese, Japanese and Swedish patients. The variant prealbumin of Japanese amyloid is characterised by methionine replacing valine as residue 30 and is identical to that found in plasma (but not as yet in amyloid) of affected Swedes. These limited data suggest that: (a) derivation of their amyloids from prealbumin is the biochemical common denominator of lower limb familial amyloidotic neuropathies regardless of the ethnic derivation of the afflicted; (b) to the extent that ethnic diversity reflects genetic heterogeneity, this will be demonstrable in the amyloid (and hopefully in the plasma) of the afflicted as entity-specific variant prealbumin monomers distinguished by different single amino acid substitutions; (c) on clinical and biochemical grounds, lower limb familial amyloidotic neuropathies include at least three genetic entities. In the upper limb and facial forms of familial amyloidotic polyneuropathy first recorded in Swiss and Finns respectively, the differences in their patterns of neurological disease and ocular lesions could be the result of their amyloids deriving from proteins other than prealbumin.
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PMID:Amyloidotic polyneuropathy in a Jewish family. Evidence for the genetic heterogeneity of the lower limb familial amyloidotic neuropathies. 385 86

Amyloid fibrils were isolated from spleen and thyroid obtained at autopsy from one patient (S.K.O.) of Jewish origin with familial amyloidotic polyneuropathy. Gel filtration on Sephadex G100 after solubilization in 5 M guanidine HCl yielded three major components with 14,000, 9,000, and 5,000 mol wt, respectively. The two larger components shared antigenic determinants with human prealbumin. Amino acid analysis and amino terminal sequence studies revealed the 14,000-mol wt protein to be an intact prealbumin subunit. The 9,000-mol wt fragment obtained in highest yield encompassed the region from position 49-127 and the 5,000 mol wt fraction encompassed the amino terminal of prealbumin (position 1-48). An amino acid substitution (Gly/Thr) was detected at position 49, where enzymatic cleavage occurred. Thus, several prealbumin-derived fragments, predominantly the carboxyl end, constitute the amyloid fibrils in a heredofamilial amyloidosis syndrome of dominant inheritance.
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PMID:A variant of prealbumin from amyloid fibrils in familial polyneuropathy of Jewish origin. 616 26

Amyloid fibril protein (SKO-III) of 14K daltons associated with familial amyloidotic polyneuropathy of Jewish type was identified by Pras et al. as a prealbumin variant with a single amino acid substitution of a glycine for a threonine at position 49, mainly based on data obtained by automated sequence analyses. Structural re-investigation of SKO-III was performed by comparing tryptic peptide maps of SKO-III and normal human prealbumin. The present analysis reveals that the reported replacement at position 49 is not present in the molecule of SKO-III. SKO-III should be revised to be a prealbumin variant with one amino acid substitution of an isoleucine for a phenylalanine at position 33.
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PMID:Revised analysis of amino acid replacement in a prealbumin variant (SKO-III) associated with familial amyloidotic polyneuropathy of Jewish origin. 648 35

Amyloid fibril protein has been isolated from the tissues of a patient of Swedish ancestry with autosomal dominant heredofamilial amyloidosis. After solubilization in guanidine HCl, a significant amount of the protein was contained in a homogeneous low molecular weight fraction. Molecular weight of approximately 14,000, amino acid analysis, double immunodiffusion analysis and immunoelectrophoresis all supported this material being a prealbumin-related protein. Automated sequence analysis gave a mixture of amino acids at each step, suggesting an heterogeneous NH2-terminus. After cleavage of the protein with cyanogen bromide, a homogeneous peptide was obtained with the sequence Val-Val-Val-Leu-Asp-Ala-Val-Arg-Gly-Thr-Pro- corresponding in 9 of the 11 positions analyzed with the known sequence of human prealbumin, starting with position 14. Antiserum raised to the amyloid protein reacted with normal human prealbumin. After absorption with normal human serum, this antiserum continued to detect a determinant in the amyloid patient's serum, suggesting an abnormal serum prealbumin, which may be the precursor of the fibril protein in this type of heredo-familial amyloidosis. Indirect immunohistochemical studies on kidney tissue from the patient with amyloidosis showed marked staining with anti-prealbumin and anti-heredofamilial amyloid protein, but not with anti-AA or anti-kappa antisera. No genetic association between this family and amyloidosis and Portuguese families with familial amyloid polyneuropathy is known.
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PMID:Partial amino acid sequence homology between an heredofamilial amyloid protein and human plasma prealbumin. 678 25

The role that transthyretin (TTR) mutations play in the amyloid disease familial amyloid polyneuropathy (FAP) has been probed by comparing the biophysical properties of several TTR variants as a function of pH. We have previously demonstrated that the partial acid denaturation of TTR is sufficient to effect amyloid fibril formation by self-assembly of a denaturation intermediate which appears to be monomeric. Earlier studies on the most pathogenic FAP variant known, Leu-55-Pro, revealed that this variant is much less stable toward acid denaturation than wild-type TTR, apparently explaining why this variant can form amyloid fibrils under mildly acidic conditions where wild-type TTR remains nonamyloidogenic. The hypothesis that FAP mutations destabilize the TTR tetramer in favor of a monomeric amyloidogenic intermediate under lysosomal (acidic) conditions is further supported by the data described here. We compare the acid stability and amyloidogenicity of the most prevalent FAP variant, Val-30-Met, along with the double mutant, Val-30-Met/Thr-119-Met, which serves to model the effects of these mutations in heterozygous patients where the mutations are in different subunits. In addition, we have characterized the Thr-119-Met TTR variant, which is a common nonpathogenic variant in the Portuguese population, to further investigate the role that this mutation plays in protecting individuals who also carry the Val-30-Met mutation against the classically severe FAP pathology. This biophysical study demonstrates that Val-30-Met TTR is significantly less stable toward acid denaturation and more amyloidogenic than wild-type TTR, which in turn is less stable and more amyloidogenic than Thr-119-Met TTR. Interestingly, the double mutant Val-30-Met/Thr-119-Met is very similar to wild-type TTR in terms of its stability toward acid denaturation and its amyloidogenicity. The data suggest that the Thr-119-Met mutation confers decreased amyloidogenicity by stabilizing tetrameric TTR toward acid denaturation. In addition, fluorescence studies monitoring the acid-mediated denaturation pathways of several TTR variants reveal that the majority exhibit a plateau in the relative fluorescence intensity over the amyloid-forming pH range, i.e., ca. pH 4.3-3.3. This intensity plateau suggests that the amyloidogenic intermediate(s) is (are) being observed over this pH range. The Thr-119-Met variant does not exhibit this plateau presumably because the amyloidogenic intermediate(s) do(es) not build up in concentration in this variant. The intermediate is undoubtedly forming in the Thr-119-Met variant, as it will form amyloid fibrils at high concentrations; however, the intermediate is only present at a low steady-state concentration which makes it difficult to detect.
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PMID:Comparison of lethal and nonlethal transthyretin variants and their relationship to amyloid disease. 757 41


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