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)

We studied 107 cases and 64 carriers of type I familial amyloidotic polyneuropathy (FAP) residing in 16 districts in Japan. The age of onset of illness ranged from 20 to 71 years old, with a mean of 40.1 +/- 12.8 years (SD). One quarter of the cases were late-onset patients who developed the disorder after age 50. Asymptomatic carriers older than age 50 accounted for 20% of total carriers, with the oldest carrier being a 94-year-old woman. All the patients had a variant transthyretin with a methionine-for-valine substitution at position 30 with a mean serum level of 9.78 +/- 3.27 (SD) mg/dl. The serum level did not significantly differ by gender in either patients or carriers, nor between patients and carriers. Incomplete penetrance of clinical expression was shown in eight cases. This study indicates that there is a considerable variety in age of onset, progression and geographic distribution of type I FAP in Japan.
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PMID:Type I familial amyloidotic polyneuropathy in Japan. 130 Jan 67

Familial amyloidotic polyneuropathy (FAP) with a mutation in position 30 of transthyretin (TTR) (previously called prealbumin) is an autosomal dominant inherited disorder characterized by varying degrees of peripheral neuropathy, nephropathy, gastrointestinal problems, and vitreous amyloid. We have earlier diagnosed homozygosity for the TTR-Met30-gene using Southern analysis in four Swedish individuals. We have found it possible to detect homozygosity for the Met-30 mutation by amplifying discrete regions of the TTR-gene using polymerase chain reaction (PCR), and the amplification products restricted with NsiI analysed by gel electrophoresis. Clinical data on seven homozygous individuals, including three new cases, are presented.
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PMID:Homozygosity for the transthyretin-Met30-gene in seven individuals with familial amyloidosis with polyneuropathy detected by restriction enzyme analysis of amplified genomic DNA sequences. 135 8

Type I familial amyloid polyneuropathy (FAP) is a molecular disorder with a mutation of the transthyretin (TTR) gene, and most patients previously examined were reported to be heterozygous for this mutant gene. In the present study a rapid and easy DNA diagnostic method employing the polymerase chain reaction revealed an asymptomatic homozygous TTR gene carrier in a Japanese family with type I FAP. The level of the variant TTR (methionine instead of valine at position 30) in his serum was much higher than that usually found in type I FAP patients. However, the histological findings of the biopsied rectum and abdominal fat tissues failed to demonstrate amyloid deposits, and the autonomic nerves from his rectal mucosa were normally preserved. Moreover, his 72-year-old mother (a TTR gene heterozygote) was supposed to start amyloid deposition in her late sixties. It is suggested that in addition to the mutant TTR gene some other factors control the development of the disease.
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PMID:Asymptomatic homozygous gene carrier in a family with type I familial amyloid polyneuropathy. 149 Apr 95

Recently, it has been reported that transthyretin (TTR)-immunoreactive amyloid deposition with cerebral amyloid angiopathy in central nervous system is a common pathological finding in type I familial amyloid polyneuropathy (FAP). In the present study, we performed isolation and sequence analysis of TTR-related amyloid fibril protein from the meninges of a patient with type I FAP. Purified major amyloid fibril protein had a molecular weight of 15 kDa. Complete sequence analysis revealed that this amyloid fibril protein was a variant TTR with a single amino acid substitution of methionine for valine at position 30. This variant TTR is a previously unrecognized as cerebrovascular amyloid fibril protein. Furthermore, the patients with type I FAP are well known to have the variant TTR in the serum. These suggest that cerebrovascular amyloid fibril protein in type I FAP may derive from a serum precursor.
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PMID:Characterization of a transthyretin-related amyloid fibril protein from cerebral amyloid angiopathy in type I familial amyloid polyneuropathy. 151 49

The structure of a variant transthyretin has been determined by X-ray crystallography at 2.3 A resolution in order to investigate those changes which lead to amyloid formation. This variant transthyretin, in which the internal valyl residue at position 30 is replaced by methionyl, is associated with the most common form of familial amyloidotic polyneuropathy (FAP). Comparison to the known structure of the normal transthyretin tetramer shows that the bulkier methionine residue 30 which lies between the nearly orthogonal beta sheets of the dimer, results in the sheets being displaced an average of 0.4 A. The internal structure of the sheets and of the monomer-monomer interface is maintained. Such global changes may affect the metabolic properties and the tendency towards polymerization of the mutant protein. These findings may form a basis for understanding other amyloid-deposition diseases.
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PMID:Alteration in molecular structure which results in disease: the Met-30 variant of human plasma transthyretin. 161 Sep 22

Type I familial amyloid polyneuropathy (FAP) is an autosomal dominant hereditary generalized amyloidosis characterized by polyneuropathy and autonomic nerve failure. The main component of the amyloid fibril protein in this disorder has been shown to be a variant prealbumin with a single substitution of a methionine residue for valine at position 30. In the present study we have investigated 19 patients with FAP aged 31 to 67 and an asymptomatic family member using gene analysis with primer-directed enzymatic amplification (PCR) of DNA, isolation of plasma variant prealbumin and immunohistochemical identification of tissue amyloid protein. All patients and a symptom-free boy in the affected family had the mutant prealbumin gene showing abnormal DNA fragments by treatment with restriction endonuclease Bal I, and plasma variant prealbumin was also detected in all of them by reverse-phase high performance liquid chromatography. Rectum biopsies obtained from 9 patients showed amyloid deposits which were specifically immunostained by anti-human prealbumin antiserum. However, an asymptomatic carrier at the age of 16 showed no rectal amyloid deposition. Recent studies of FAP have disclosed that the expression of type I FAP is closely associated with the gene mutation of prealbumin. Accordingly, a simple and rapid method to detect this gene abnormality using PCR technique is considered to be very useful for diagnosis of type I FAP and can also provide valuable information for the genetic counselling of the family members at risk.
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PMID:[Diagnosis of familial amyloid polyneuropathy--gene analysis with primer-directed enzymatic amplification of DNA, isolation of plasma variant prealbumin and immunohistochemical identification of tissue amyloid protein]. 165 25

Traditionally, clinical research has sought to determine the molecular basis of clinical signs and symptoms. Increasingly, the traditional process will be reversed, as many structural protein variants are elucidated as a result of powerful PCR-based methods. Herein we describe a variant of transthyretin (TTR) found by direct genomic sequencing and illustrate the utility of PASA (PCR amplification of specific alleles) in the initial characterization of such variants. TTR is an intriguing protein of unknown function, but deposition of mutant TTR produces familial amyloidotic polyneuropathy (FAP). We identify a carrier of a variant TTR in which threonine119 is changed to methionine (T119----M). T119 is invariant in five mammalian species, suggesting that this residue is important for normal protein function. To determine the frequency of the M119 variant, individuals of northern- and western-European descent were rapidly screened by generating a PASA assay for the sequence change. Four additional individuals were found to be heterozygous for the mutation, for a total of five M119 alleles in 1,666 genes (1/333). Clinical records, initial clinical interviews, and family history of these patients hint at a high frequency of early-onset venous insufficiency and perhaps mild renal dysfunction. Haplotype analysis on the heterozygotes could be performed, despite the absence of samples from relatives, by performing "double PASA." The haplotype data suggest that the M119 variant derives from a common ancestor. The putative functional deficiency caused by TTR M119 should be most marked in the homozygotes, who can be calculated to occur in 1/100,000 conceptions. If viable, these individuals may provide important clues about the physiological role of TTR. Although the nature (if any) of disease caused by TTR M119 remains to be defined, the genetic and clinical data indicate that this mutation does not cause FAP. Future family studies can determine whether the heterozygous state for TTR M119 cosegregates with a disease or trait.
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PMID:From molecular variant to disease: initial steps in evaluating the association of transthyretin M119 with disease. 172 93

Vitreous amyloidosis is often the presenting clinical manifestation of type I, type II or Jewish-type familial amyloid polyneuropathy (FAP). FAP is an autosomal dominant inherited disorder. It is caused by systemic deposition of variants of transthyretin (TTR), formerly called prealbumin. TTR is a tetrameric protein with beta pleated sheets (mol wt = 56,000 dalton). In two cases we were able to confirm the clinical diagnosis of vitreous amyloidosis. Immunohistochemistry revealed TTR in vitreous samples after therapeutic pp vitrectomy for vitreous opacity. The same result was found in samples of rectal mucosa. Amyloid was not found in skin. Isoelectrical focusing disclosed that TTR in the serum was the Portuguese (TTR-Met 30) variant. Together with polyneuropathy of the lower limbs, a diagnosis of FAB type I was made. In the second generation of the first patient's family the normal variant was found (the pathologic gene was not inherited). In the second case the pathologic variant was detected in the second generation, but without any pathologic clinical features. The third generation showed the normal variant. The disorder was detectable before any clinical signs were present. These findings are also important for genetic counseling.
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PMID:[Amyloidosis of the vitreous body. Possibilities of diagnosis]. 178 32

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.
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PMID:Production of recombinant human transthyretin with biological activities toward the understanding of the molecular basis of familial amyloidotic polyneuropathy (FAP). 184 97

A mutation in transthyretin (TTR Asn 90) has been identified in the Portuguese and German populations. This variant has a lower pI and was found by screening analyses in 2/4,000 German subjects and in 4/1,200 Portuguese by using either double one-dimensional (D1-D) electrophoresis with isoelectric focusing (IEF) or hybrid isoelectric focusing in immobilized pH gradient (HIEF) as the final separation step. The Portuguese population sample was from the area where TTR Met 30-associated familial amyloidotic polyneuropathy (FAP) prevails, and it was divided into (a) a group of 500 individuals belonging to FAP kindreds and (b) a group of 700 collected at random. HIEF showed two particular situations: (1) one case, from an FAP kindred, was simultaneously carrier of the Met 30 substitution and the acidic variant, and (2) one individual, from the randomly selected Portuguese sample, had only the acidic monomer. Comparative peptide mapping, by HPLC, of the acidic variant carriers and of normal TTR showed the presence of an abnormal tryptic peptide, not present in the normal TTR digests, with an asparagine-for-histidine substitution at position 90 explained by a single base change of adenine for cytosine in the histidine codon. This was confirmed at the DNA level by RFLP analyses of PCR-amplified material after digestion with SphI and BsmI. In all carriers of the Asn 90 substitution, no indicators were found for an association with traits characteristic for FAP.
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PMID:Molecular analyses of an acidic transthyretin Asn 90 variant. 185 Jan 90


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