Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0152025 (polyneuropathy)
 7,862 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Familial amyloidotic polyneuropathy (FAP) is a dominantly inherited form of amyloidosis usually associated with an abnormal transthyretin (TTR), previously known as prealbumin. Several disease-related variants of the protein, each with a different amino acid substitution and correlating DNA point mutation, have been identified. The TTR gene from a patient suffering from this disorder was asymmetrically amplified and directly sequenced, revealing a cytosine for thymine substitution in the second base of codon 30 and the creation of a novel Cfo I restriction endonuclease site in exon 2. This mutation results in a previously undescribed substitution of an alanine for valine in the final TTR protein. Analysis of the amino acid mutation reveals it to be a hydrophilic substitution at a hydrophobic core position. Alanine at position 30 represents the second FAP-associated mutation at position 30 in TTR.
 ...
PMID:Familial amyloidotic polyneuropathy: a new transthyretin position 30 mutation (alanine for valine) in a family of German descent. 154 14

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.
 ...
PMID:Production and functional analysis of normal and variant recombinant human transthyretin proteins. 164 39

Transthyretin (TTR) is a plasma protein interacting with thyroxine T4 and retinol binding protein (RBP). Several variants of TTR with single amino acid substitutions have been identified as the major components of the amyloid fibrils of familial amyloidotic polyneuropathy (FAP), a fetal, autosomal dominant genetic disease. The elucidation of the molecular nature of the variants distinct from that of the wild-type TTR is crucial for understanding the amyloidogenesis in FAP, but our understanding is very poor mainly because of the unavailability of pure variant TTRs. In the present study, we used an Escherichia coli OmpA secretion vector (Ghrayeb et al., 1984) and achieved an effective production of the variant TTRs related to FAP including Met-30, Ile-33, Ala-60, Tyr-77, Met-111, and Ile-122 types. The variant TTRs produced in this system were efficiently secreted to the culture media. The chemical analysis showed that the secreted TTR (Met-30 type) has the same N-terminus as the native one. IEF analyses also indicated that the secreted product is properly processed as assessed by its pI. Furthermore, the secreted TTR was shown to have biological activities, namely, the thyroxin binding activity and the ability to associate with retinol binding protein, indicating that the secreted TTR polypeptide is properly folded. The present work also demonstrated that the processing/secretion of the recombinant TTR molecules in E. coli was strongly affected by single amino acid substitutions.
 ...
PMID:Production of recombinant human transthyretin with biological activities toward the understanding of the molecular basis of familial amyloidotic polyneuropathy (FAP). 184 97

Familial amyloidotic polyneuropathy (FAP) is associated with the deposition of an abnormal transthyretin (TTR) molecule. We have studied DNA from a family of Greek descent with FAP. The proband's TTR gene was asymmetrically amplified by using PCR and then was sequenced directly, to reveal a cytosine-for-guanine substitution in codon 36. This substitution removes a recognition site for endonuclease Fnu4HI. Allele-specific PCR was employed for diagnosis of the mutation. The predicted amino acid change of alanine to proline at position 36 was confirmed by protein sequencing of the proband's plasma TTR.
 ...
PMID:Proline at position 36: a new transthyretin mutation associated with familial amyloidotic polyneuropathy. 185 Jan 91

Two cases of familial amyloidotic polyneuropathy (FAP) in a French family are reported. Clinical onset was in the fifth and sixth decades with decreased sensation in the lower limbs followed by involvement of the upper extremities. Motor changes appeared later and evolved to restrict ambulation. Cardiac involvement with congestive heart failure and arrhythmias was the cause of death. DNA analysis was performed on ten members of this family. Restriction enzyme analysis of amplification products of exons 2, 3 and 4 of the prealbumin gene were negative for the methionine-30, alanine-60 and serine-84 mutations but positive for the tyrosine-77 mutation. The tyrosine-77 prealbumin mutation was first described in a family from Illinois with origin in Germany. The discovery of the tyrosine-77 gene in the family from Picardy may help to determine the origin of this disease and tell us if one mutation has been spread around the world, as we suspect, with many kindreds having the methionine-30 gene, or whether there have been separate spontaneous mutational events, perhaps a peculiarity of this site in the prealbumin gene.
 ...
PMID:Diagnosis of familial amyloidotic polyneuropathy in France. 198 Nov 82

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.
 ...
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.
 ...
PMID:Familial amyloid polyneuropathy: alanine-for-threonine substitution in the transthyretin (prealbumin) molecule. 212 46

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.
 ...
PMID:Biochemical and molecular genetic characterization of a new variant prealbumin associated with hereditary amyloidosis. 372 85

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.
 ...
PMID:Partial amino acid sequence homology between an heredofamilial amyloid protein and human plasma prealbumin. 678 25

Long-term results of 13 liver transplantations in patients with a previous diagnosis of type I familial amyloid polyneuropathy (FAP) are presented. The diagnosis of type I FAP was based on the presence of a biochemical marker in the plasma (TTR-Met-30 in 11 patients, TTR-Ala-71 in two). Maximum follow-up is 28 months and the survival rate stands at 11 of 13 patients. Two patients died from sepsis at 2 and 6 months. TTR disappeared from plasma in all cases. Neurological status improved in all eight patients undergoing transplantation more than 6 months previously, although electromyographic studies showed a slight improvement only in the six with follow-up of more than 1 year. All 13 patients showed a hyperdynamic haemodynamic pattern with a high incidence (four patients) of the use of venovenous bypass due to haemodynamic intolerance. Two patients also received transplants by the 'piggy-back' technique. In conclusion, liver transplantation may be useful in the treatment of certain patients with FAP to halt and improve the neurological consequences of the disease.
 ...
PMID:Clinical improvement after liver transplantation for type I familial amyloid polyneuropathy. 762 23


1 2 3 Next >>