A decamer duplication in the 3 ' region of the BRI gene originates an amyloid peptide that is associated with dementia in a Danish kindred

Familiar Danish dementia (FDD), also known as heredopathia ophthalmo-oto-en cephalica. is an autosomal dominant disorder characterized by cataracts, de afness, progressive ataxia, and dementia, Neuropathological findings includ e severe widespread cerebral amyloid angiopathy, hippocampal plaques, and n eurofibrillary tangles, similar to Alzheimer's disease. N-terminal sequence analysis of isolated leptomeningeal amyloid fibrils revealed homology to A Bri, the peptide originated by a point mutation at the stop codon of gene B RI in familial British dementia. Molecular genetic analysis of the BRI gene in the Danish kindred showed a different defect, namely the presence of a 10-nt duplication (795-796insTTTAATTTGT) between codons 265 and 266, one co don before the normal stop codon 267. The decamer duplication mutation prod uces a frame-shift in the BRI sequence generating a larger-than-normal prec ursor protein, of which the amyloid subunit (designated ADan) comprises the last 34 C-terminal amino acids. This de novo-created amyloidogenic peptide , associated with a genetic defect in the Danish kindred, stresses the impo rtance of amyloid formation as a causative factor in neurodegeneration and dementia.