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

Ruben Vidal, Tamas Révész, Agueda Rostagno, Eugene Kim, Janice L. Holton, Toke Bek, Marie Bojsen-Møller, Hans Braendgaard, Gordon Plant, Jorge Ghiso, Blas Frangione

Research output: Contribution to journalArticle

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Abstract

Familial Danish dementia (FDD), also known as heredopathia ophthalmo-oto-encephalica, is an autosomal dominant disorder characterized by cataracts, deafness, progressive ataxia, and dementia. Neuropathological findings include severe widespread cerebral amyloid angiopathy, hippocampal plaques, and neurofibrillary tangles, similar to Alzheimer's disease. N-terminal sequence analysis of isolated leptomeningeal amyloid fibrils revealed homology to ABri, the peptide originated by a point mutation at the stop codon of gene BRI 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 codon before the normal stop codon 267. The decamer duplication mutation produces a frame-shift in the BRI sequence generating a larger-than-normal precursor 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 importance of amyloid formation as a causative factor in neurodegeneration and dementia.

Original languageEnglish (US)
Pages (from-to)4920-4925
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number9
DOIs
StatePublished - Apr 25 2000
Externally publishedYes

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