title: A stop-codon mutation in the BRI gene associated with familial British dementia.
abstract: 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.
authors.affiliation: Department of Pathology, New York University School of Medicine, New York 10016, USA.
authors.forename: R
authors.initials: R
authors.lastname: Vidal
authors.forename: B
authors.initials: B
authors.lastname: Frangione
authors.forename: A
authors.initials: A
authors.lastname: Rostagno
authors.forename: S
authors.initials: S
authors.lastname: Mead
authors.forename: T
authors.initials: T
authors.lastname: Révész
authors.forename: G
authors.initials: G
authors.lastname: Plant
authors.forename: J
authors.initials: J
authors.lastname: Ghiso
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D000595:Amino Acid Sequence; D000682:Amyloid / Q000032:analysis / Q000737:chemistry / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D016657:Cerebral Amyloid Angiopathy / Q000235:genetics*; D002882:Chromosomes, Human, Pair 13; D003001:Cloning, Molecular; D018388:Codon, Terminator / Q000235:genetics*; D003704:Dementia / Q000235:genetics*; D005260:Female; D006801:Humans; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D011498:Protein Precursors / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D006113:United Kingdom
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000682:Amyloid; D018388:Codon, Terminator; C120083:ITM2B protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011498:Protein Precursors