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)

Familial amyloidotic polyneuropathy (FAP) is a genetic disorder showing autosomal dominant inheritance. Amyloid fibrils of FAP patients from various origins have been shown to contain a prealbumin variant with Val30----Met30 substitution as a major component. However, the structure of the prealbumin gene responsible for the variation has not been characterized. We determined the complete nucleotide sequence of the prealbumin gene from a patient with the Japanese type of FAP. In comparison with a normal prealbumin gene sequence, the patient's gene was found to be carrying seven base substitutions. The substitution responsible for the Val----Met change was found in exon 2, as expected, and the others were in introns. Hybridization analyses of normal and FAP patient DNAs showed that the base substitution in exon 2 was specific for FAP but the others were polymorphic changes. It was concluded that the mutation responsible for the Val----Met change is the only base change specific for FAP in the prealbumin gene.
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PMID:Structure of the mutant prealbumin gene responsible for familial amyloidotic polyneuropathy. 302 7

We have cloned a chromosomal DNA segment that covers the entire sequence for the mutant prealbumin gene associated with familial amyloidotic polyneuropathy, and determined the sequence of the gene including 581 base-pairs of the 5'-flanking region and 95 base-pairs of the 3'-flanking region, except for the internal portions of the second and third introns. This sequence was aligned with that of the previously determined normal prealbumin gene and both sequences matched perfectly except for a single-base substitution present in the second exon. This substitution is responsible for the transition from valine (GTG) to methionine (ATG) in the mutant prealbumin and creates NsiI and BalI restriction sites in the mutant prealbumin gene. We also analysed prealbumin mRNAs in the livers of a disease-free individual and one with familial amyloidotic polyneuropathy and confirmed that there is no difference in the levels and sizes of the prealbumin mRNAs between the two. As we have demonstrated already that individuals with familial amyloidotic polyneuropathy are heterozygous for the prealbumin gene, carrying one normal and one mutant gene, levels of the two different mRNAs within the liver of an individual with familial amyloidotic polyneuropathy were separately estimated and were demonstrated to be approximately equal.
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PMID:Structure and expression of the mutant prealbumin gene associated with familial amyloidotic polyneuropathy. 302 8

Type I familial amyloidotic polyneuropathy is an autosomal dominant, inherited systemic amyloidosis characterized initially by dissociated sensory disturbance and autonomic dysfunction. The amyloid fibril protein seen in patients of Portuguese, Japanese, and Swedish descent in the U.S. mainly consists of a variant form of transthyretin (also called prealbumin) with the substitution of methionine for valine at position 30. Methods have been developed to detect this variant transthyretin in the serum, and to detect a base change in a mutated transthyretin gene. The biochemical and genetic abnormalities in transthyretin are completely linked to the clinical diagnosis of type I familial amyloidotic polyneuropathy. These diagnostic methods may allow early diagnosis and genetic counseling to avoid transmission of this intractable disorder to the next generation.
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PMID:Biochemical and genetic characterization of type I familial amyloidotic polyneuropathy. 303 92

Structurally abnormal transthyretin is a precursor protein of amyloid fibrils in type I familial amyloidotic polyneuropathy (FAP). This variant transthyretin has an amino acid substitution of methionine for valine at position 30. The purpose of this study was to clarify whether this variant transthyretin also circulates in the cerebrospinal fluid (CSF) of patients with type I FAP. CSF transthyretin of the patients was purified and its primary structure determined. Sequence determination indicated that transthyretin consisted of a mixture of normal and variant transthyretin. Variant transthyretin was present in the CSF of all 5 Japanese FAP patients studied. The CSF concentration of variant transthyretin was high (0.72 +/- 0.15 mg/dl, mean +/- S.D.), suggesting that variant transthyretin is synthesized in the choroid plexus. Variant transthyretin was not present in any of 20 controls. The CSF concentration of total transthyretin in FAP patients was 1.74 +/- 0.42 mg/dl, which was not significantly different from controls.
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PMID:Variant transthyretin in cerebrospinal fluid in familial amyloidotic polyneuropathy. 303 62

The purpose of this study is to disclose the molecular basis of type I familial amyloidotic polyneuropathy (FAP) in Japan. Amyloid fibril protein of type I FAP consists of a variant transthyretin (also called prealbumin) with one amino acid substitution of methionine-for-valine at position 30. This variant transthyretin is present in the serum as a precursor protein of amyloid. A radioimmunoassay (RIA) has been established to detect the variant transthyretin. All the 94 patients with FAP who originate from various districts in Japan have the variant transthyretin, but any one of 78 healthy adults of families with FAP do not have it. Half of the symptom-free children of FAP patients have the variant transthyretin even before clinical manifestations appear. The RIA is widely applicable for early diagnosis. The methionine-for-valine substitution is due to a base change from guanine to adenine at the first letter of the valine codon at position 30. Type I FAP in Japan is considered to be a molecular disorder of transthyretin. Since the age of onset ranges from twenties to forties, genetic counseling is recommended to prevent the transmission of this intractable disorder to the next generation.
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PMID:Biochemical characterization of familial amyloidotic polyneuropathy in various districts of Japan. 304 Oct 83

Amino-acid sequence analysis of an amyloid fibril protein from a patient with Swedish familial amyloidotic polyneuropathy showed homology with prealbumin but with heterogeneous N-terminal deletions. One-third of the molecules had the same amino acid substitution, methionine for valine in position 30, as in familial amyloidosis of Portuguese, Japanese and Swedish-American type. A protein with the same antigenic properties and size was found in the fibrils of two other patients with Swedish FAP while the amyloid fibrils in two further patients predominantly contained a smaller prealbumin-derived protein. Cyanogen bromide cleavage of this protein revealed no evidence for a methionine residue in position 30.
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PMID:Prealbumin variants in the amyloid fibrils of Swedish familial amyloidotic polyneuropathy. 311 63

Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant inherited disorder. Recent biochemical studies have revealed that amyloid protein in FAP of Japanese, Swedish and Portuguese origin mainly consists of a variant transthyretin (TTR) (formerly called prealbumin) with one amino acid substitution of methionine for valine at position 30. In a 56-year-old man with typical polyneuropathy, gastrointestinal problems and vitreous amyloid, we diagnosed homozygosity for the TTR-met30-gene using RFLP analysis. In a family study, a sister presented the same homozygous RFLP pattern; however, in a careful clinical investigation we were not able to demonstrate any of the typical symptoms of FAP, nor could we demonstrate amyloid deposits in a biopsy skin specimen. This is the first report of homozygosity for the TTR-met30-gene, and it shows that the mutation of the protein involved in amyloid formation may be necessary but is clearly not sufficient for the clinical symptoms.
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PMID:Homozygosity for the transthyretin-met30-gene in two Swedish sibs with familial amyloidotic polyneuropathy. 322 2

The purpose of this study is to develop an early diagnostic method for familial amyloidotic polyneuropathy (FAP) before clinical manifestations appear around the age of 30 yr. Amyloid fibrils isolated from type I FAP (FAP1) of Portuguese, Swedish, and Japanese origins consist of a variant transthyretin (TTR) that contains a methionine-for-valine substitution at position 30 or a mixture of normal TTR and this variant form. The variant TTR is present in the serum of FAP1 patients and can be measured by a radioimmunoassay (RIA) based on a nonapeptide (positions 22-30) derived from the variant TTR. Serum levels of the variant TTR in 45 Japanese FAP1 patients range from 4.71 to 17.61 mg/dl with a mean value of 9.18 mg/dl. The variant TTR is not present in the serum of 100 normal individuals, in four cases of primary and six cases of secondary amyloidosis, nor in 26 non-inheriting members of families with FAP1. The variant TTR level is measured in 24 children of 15 FAP1 patients as well. The variant TTR is already present in nine symptom-free children with the mean serum level of 11.90 mg/dl, but it is not present in 15 other children. FAP1 patients can be differentiated from non-FAP by this noninvasive diagnostic method even within families. The RIA can be applied worldwide to this intractable disorder for early diagnosis during childhood and for appropriate genetic counseling.
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PMID:Diagnostic radioimmunoassay for familial amyloidotic polyneuropathy before clinical onset. 345 2

A simple and quantitative method for detecting the variant prealbumin associated with familial amyloidotic polyneuropathy has been developed. This method is based on (1) a rapid and simple high performance liquid chromatographic method for the purification of prealbumin, using an immunoadsorbent-affinity column with bound monospecific prealbumin antibody, (2) the presence of an extra methionine in the variant prealbumin at position 30, detected by cyanogen bromide cleavage, and (3) sensitive and quantitative detection of cleaved peptides by reversed phase high performance liquid chromatography. This non-radioisotopic method gives quantitatively reliable results on serum samples as small as 0.5 ml. This method is not only useful for the detection of patients and carriers of familial amyloidotic polyneuropathy, but also for determination of the ratio of normal to variant prealbumin in the serum samples.
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PMID:Quantitative detection of a variant prealbumin associated with type 1 familial amyloidotic polyneuropathy (Japanese type) by high performance liquid chromatography. 347 58

A Japanese family with atypical type I familial amyloidotic polyneuropathy (FAP) in Iiyama, Japan was studied. Most of the family members have dysfunctions in the central nervous system, in addition to typical symptoms of type I FAP. The transthyretin (TTR, also called prealbumin) gene of the atypical FAP(FAP-IY) was analyzed with recombinant DNA techniques and a RIA method. FAP-IY was found to have the mutation responsible for the methionine-for-valine substitution at position 30 of TTR, as in the case of typical type I FAP. However, analysis of DNA polymorphisms in the TTR locus showed that FAP-IY has a genetic background differing from that of the typical type I FAP. These observations lead to the consideration that a genetic factor(s) involved in the dysfunction of the central nervous system may locate in a chromosome region in close proximity to the TTR gene.
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PMID:Molecular analysis of a variant type of familial amyloidotic polyneuropathy showing cerebellar ataxia and pyramidal tract signs. 347 41


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