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)

We report familial amyloidotic polyneuropathy in a pedigree of German ancestry residing in New Jersey. Eight affected subjects presented in the third to seventh decade with carpal tunnel syndrome (CTS) and one subject presented with vitreous opacification. Transmission was autosomal dominant and survival was prolonged. Affected subjects were heterozygous for a novel mutation in serum transthyretin (TTR), resulting in an asparagine for lysine substitution at residue 70 of the TTR monomer. We report two methods for rapid identification of the mutation based on the polymerase chain reaction. This pedigree further emphasizes the evolving phenotypic and genotypic heterogeneity of the transthyretinopathies. Familial or sporadic CTS or unexplained vitreous opacification suggest the possibility of TTR amyloidosis and should prompt a search for TTR mutations.
 ...
PMID:Familial amyloidotic polyneuropathy presenting with carpal tunnel syndrome and a new transthyretin mutation, asparagine 70. 143 17

Familial amyloidosis of Finnish type (FAF) is one of the familial amyloidotic polyneuropathy (FAP) syndromes, a group of inherited disorders characterized by extracellular accumulation of amyloid and by clinical symptoms and signs of polyneuropathy. FAF, an autosomal dominant trait, belongs to those rare monogenic disorders which occur with increased frequency in the Finnish population: only single FAF cases have been reported from other populations. In most types of FAP syndromes the accumulating protein is a transthyretin variant. However, recent evidence has suggested that the amyloid peptides in FAF are related to gelsolin, an actin modulating protein. The gelsolin fragments isolated from at least one patient with amyloidosis have been reported to have an amino acid substitution, with asparagine replacing aspartic acid at position 187 of the plasma gelsolin. In this study allele-specific oligonucleotides were used to analyze three large FAF families with multiple affected individuals as well as healthy family members. We found the corresponding G-A mutation in nucleotide 654 of the plasma gelsolin gene to cosegregate with the disease. The result was confirmed by sequencing and strongly suggests that the mutation has caused all the FAF cases of these families. Since the disease is clustered in restricted areas on the southern coast of Finland, this mutation most probably causes the majority, if not all, of FAF cases in Finland.
 ...
PMID:Finnish type of familial amyloidosis: cosegregation of Asp187----Asn mutation of gelsolin with the disease in three large families. 183 58

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.
 ...
PMID:Molecular analyses of an acidic transthyretin Asn 90 variant. 185 Jan 90

A new transthyretin variant which lost an Sph I cleavage site within exon 3 has been characterized. A 260 bp sequence containing exon 3 was amplified using the polymerase chain reaction, and the variant was found to possess a Bsm I cleavage site not present in normal transthyretin. This led to the conclusion that the histidine at position 90 was replaced by asparagine, and amino acid analysis supported the conclusion. The discovery of this mutation suggests that intermolecular binding between hydrophobic polypeptide loops on the surface of transthyretin can lead to familial amyloidotic polyneuropathy.
 ...
PMID:A new transthyretin variant from a patient with familial amyloidotic polyneuropathy has asparagine substituted for histidine at position 90. 199 17

Familial amyloidosis, Finnish type (FAF), is an autosomal dominant form of familial amyloid polyneuropathy. The novel amyloid fibril protein found in these patients is a degradation fragment of gelsolin, an actin-binding protein. We found a mutation (adenine for guanine) at nucleotide 654 of the gelsolin gene in genomic DNA isolated from five FAF patients. This site is polymorphic since the normal allele was also present in all the patients tested. This mutation was not found in two unaffected family members and 11 normal controls. The A for G transition causes an amino acid substitution (asparagine for aspartic acid) that was found at position 15 of the amyloid protein. The mutation and consequent amino acid substitution may lead to the development of FAF.
 ...
PMID:Mutation in gelsolin gene in Finnish hereditary amyloidosis. 217 44

Amyloid subunit protein was isolated from familial amyloid polyneuropathy type IV (Finnish type) cardiac tissue and purified to homogeneity. N-terminal amino acid sequence analysis shows that the amyloid protein is a fragment of the inner region of human gelsolin. When compared with the predicted sequence of human plasma gelsolin, the amyloid protein contains an asparagine-for-aspartic acid substitution at position 15 corresponding to residue 187 of the secreted protein. Antibodies raised against the amyloidogenic region of gelsolin specifically stained the amyloid deposited in tissues in familial amyloidosis type IV. The results show that the subunit amyloid protein in familial amyloid polyneuropathy type IV represents a unique type of amyloid derived from a variant (Asn-187) gelsolin molecule by limited proteolysis.
 ...
PMID:Isolation and characterization of cardiac amyloid in familial amyloid polyneuropathy type IV (Finnish): relation of the amyloid protein to variant gelsolin. 217 50

Gelsolin-related amyloidosis, also called familial amyloidosis, Finnish type (FAF) is an autosomal dominantly inherited disorder characterized by progressive polyneuropathy and corneal lattice dystrophy. All the analyzed patients are found to carry a nucleotide substitution of A or T for G654 in their gelsolin gene, which at the protein level results in the conversion of the 187 amino acid residue, aspartic acid, to asparagine or tyrosine, respectively. In this study, we transfected mammalian mesenchymal COS-1 cells with a derivative of the expression vector pCD-X containing cDNA coding for the wild-type (D187) and mutant forms (N187 and Y187) of plasma gelsolin. Both disease-associated mutant forms of gelsolin were found to be abnormally processed, which led to the secretion of an aberrant 68 kDa gelsolin fragment into the culture media. This fragment most probably represents a carboxy-terminal part of the protein and contains the suggested amyloid-forming sequence. Initial data were also obtained for involvement of a metalloendoprotease in the pathologic processing. This aberrant proteolysis is likely to represent a crucial initiator step in the cascade resulting in amyloid accumulation in patients' tissues.
 ...
PMID:Toward understanding the pathogenic mechanisms in gelsolin-related amyloidosis: in vitro expression reveals an abnormal gelsolin fragment. 788 24

A family with familial amyloidotic polyneuropathy (FAP) was previously found to have a substitution of asparagine for histidine at position 90 of transthyretin. Members with his90asn developed FAP. However, close examination of the transthyretin gene revealed that glu42gly is coinherited with his90asn in this family. Since glu42gly has already been seen in Japanese FAP patients, and his90asn has been found in Portuguese and German individuals without FAP, we conclude that his90asn is a nonpathogenic variant.
 ...
PMID:Two transthyretin mutations (glu42gly, his90asn) in an Italian family with amyloidosis. 792 55

Major advances of the past year in the amyloidoses include a better understanding of the polymorphism of the acute-phase reactant serum amyloid A protein and the appearance of a new mouse model for primary amyloidosis. The list of single point mutations in transthyretin in different families with slightly varied clinical manifestations of the disease continues to grow. Gelsolin, with its asparagine 187 mutation, was found to cause amyloidosis beyond the borders of Finland, where it has been extensively evaluated. The incredible range of osteoarticular lesions due to beta 2-microglobulin in hemodialysis amyloidosis continues to expand and includes severe manifestations of spondyloarthropathy. The greatest number of papers in the amyloid literature have involved amyloid beta protein, amyloid beta protein precursor associated with Alzheimer's disease, and prion protein associated with the spongiform encephalopathies. The widespread systemic involvement of amyloidosis has led to the appearance of a host of manifestations, some common and some rare. Treatment advances focus on the use of liver transplantation in familial amyloid polyneuropathy to remove the source of mutant protein synthesis.
 ...
PMID:Advances in amyloidosis. 843 91

Familial amyloidosis, Finnish type (FAF), is a gelsolin-related systemic amyloidosis that has an autosomal-dominant inheritance pattern and is clinically characterized by progressive cranial neuropathy, corneal lattice dystrophy and skin changes such as cutis laxa, blepharochalasis, and lichen amyloidosis. A 70-year-old Japanese male proband, who was believed to be originally from Fukuoka Prefecture, showed signs and symptoms characteristic of FAF. In addition, he complained of progressive anhidrosis and heat intolerance during the daytime in summer. On examination, perspiration was absent on the almost entire body surface. Molecular genetic studies showed a G-to-A transversion that resulted in the substitution of asparagine for aspartic acid 187 in the gelsolin gene, a mutation found in most patients with FAF. Skin biopsy revealed marked deposition of amyloid, which was positive with anti-gelsolin antibody staining, around eccrine sweat glands and ducts, and around sebaceous glands, outside the basal lamina; slight to mild deposition around small vessels and small nerve fascicles; and very slight deposition in the perineurium and endoneurium. Morphometric evaluation of the nerve terminals and axons of eccrine sweat glands revealed a significant decrease in the number of nerve terminals per transverse profile of the sweat gland. Compared with controls, nerve terminals were further from the secretory epithelial cell owing to deposition of amyloid outside its basal lamina. The proband's sister had almost identical, although much less severe, clinical signs and symptoms with the same mutation of the gelsolin gene. Autonomic signs and symptoms in FAF are reported to be less frequent and less severe than those in familial amyloid polyneuropathy of Andrade type. Findings in our proband suggest that perspiration may be markedly decreased in FAF owing to marked deposition of amyloid around the eccrine sweat gland which causes degeneration of the nerve terminals and disturbs access of the neurotransmitter to the secretory epithelial cell.
 ...
PMID:[Familial amyloidosis, Finnish type with marked anhidrosis]. 874 46


1 2 Next >>