A stop-codon mutation in the BRI gene associated with familial British dementia

Familial British dementia (FBD), previously designated familial cerebral am yloid angiopathy-British type(1), is an autosomal dominant disorder of unde termined origin characterized by progressive dementia, spasticity, and cere bellar ataxia, with onset at around the fifth decade of life. Cerebral amyl oid angiopathy, non-neuritic and perivascular plaques and neurofibrillary t angles are the predominant pathological lesions(1-4). Here we report the id entification of a unique 4K protein subunit named ABri from isolated amyloi d fibrils. This highly insoluble peptide is a fragment of a putative type-I I single-spanning transmembrane precursor that is encoded by a novel gene, BRI; located on chromosome 13. A single base substitution at the scop 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 cre ates a cutting site for the restriction enzyme XbaI, which is useful for de tecting asymptomatic carriers. Antibodies against the amyloid or homologous synthetic peptides recognize both parenchymal and vascular lesions in FED patients. A point mutation at the stop codon of BRI therefore results in th e generation of the ABri peptide, which is deposited as amyloid fibrils cau sing neuronal disfunction and dementia.