Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026838 (spasticity)
 6,471 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Familial British dementia (FBD), previously designated familial cerebral amyloid angiopathy-British type, is an autosomal dominant disorder of undetermined origin characterized by progressive dementia, spasticity, and cerebellar ataxia, with onset at around the fifth decade of life. Cerebral amyloid angiopathy, non-neuritic and perivascular plaques and neurofibrillary tangles are the predominant pathological lesions. Here we report the identification of a unique 4K protein subunit named ABri from isolated amyloid fibrils. This highly insoluble peptide is a fragment of a putative type-II single-spanning transmembrane precursor that is encoded by a novel gene, BRI, located on chromosome 13. A single base substitution at the stop codon of this gene generates a longer open reading frame, resulting in a larger, 277-residue precursor. Release of the 34 carboxy-terminal amino acids from the mutated precursor generates the ABri amyloid subunit. The mutation creates a cutting site for the restriction enzyme XbaI, which is useful for detecting asymptomatic carriers. Antibodies against the amyloid or homologous synthetic peptides recognize both parenchymal and vascular lesions in FBD patients. A point mutation at the stop codon of BRI therefore results in the generation of the ABri peptide, which is deposited as amyloid fibrils causing neuronal disfunction and dementia.
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PMID:A stop-codon mutation in the BRI gene associated with familial British dementia. 1039 Dec 42

Familial British dementia (FBD) is an early-onset autosomal dominant disorder characterized by progressive cognitive impairment, spasticity, and cerebellar ataxia. Hippocampal neurofibrillar degeneration and widespread parenchymal and vascular amyloid deposits are the main neuropathological lesions. Amyloid fibrils are composed of a novel 34 amino acid subunit (ABri) with no sequence identity to any known amyloid molecule. The peptide derives from a larger precursor protein codified by a single gene BRI on chromosome 13. Affected family members have a single base substitution at the stop codon of the BRI gene that generates a longer open-reading frame resulting in a larger precursor protein. The release of the 34 C-terminal amino acids from the mutated precursor originates the ABri amyloid subunit. Our discovery of a new amyloid associated with the development of dementia supports the concept that amyloid peptides may be of primary importance in the initiation of neurodegeneration.
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PMID:A newly formed amyloidogenic fragment due to a stop codon mutation causes familial British dementia. 1081 98

Mutations in the BRI gene are thought to cause dementias in members of families. The clinical symptoms are similar to those of Alzheimer's disease, but with additional ocular and hearing deficits, and spasticity. The mutations lead to the release of the 34-residue peptides, ABri and ADan, in the brains of afflicted individuals. We have synthesized the peptides in their straight-chain and oxidized cyclic forms and shown that the oxidized form of ABri and reduced form of ADan are toxic to human neuronal cell lines in culture. Neurotoxicity correlates with the extent of formation of SDS-stable non-fibrillar low-molecular-mass oligomers (SSNFOs).
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PMID:Properties of neurotoxic peptides related to the BRI gene. 1219 36