title: A decamer duplication in the 3' region of the BRI gene originates an amyloid peptide that is associated with dementia in a Danish kindred.
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.
authors.affiliation: Department of Pathology, New York University School of Medicine, New York 10016, USA. vidalr01@popmail.med.nyu.edu
authors.forename: R
authors.initials: R
authors.lastname: Vidal
authors.forename: T
authors.initials: T
authors.lastname: Revesz
authors.forename: A
authors.initials: A
authors.lastname: Rostagno
authors.forename: E
authors.initials: E
authors.lastname: Kim
authors.forename: J L
authors.initials: JL
authors.lastname: Holton
authors.forename: T
authors.initials: T
authors.lastname: Bek
authors.forename: M
authors.initials: M
authors.lastname: Bojsen-Møller
authors.forename: H
authors.initials: H
authors.lastname: Braendgaard
authors.forename: G
authors.initials: G
authors.lastname: Plant
authors.forename: J
authors.initials: J
authors.lastname: Ghiso
authors.forename: B
authors.initials: B
authors.lastname: Frangione
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics*; D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000682:Amyloid / Q000032:analysis / Q000235:genetics*; D001483:Base Sequence; D003704:Dementia / Q000235:genetics* / Q000473:pathology; D003718:Denmark; D005260:Female; D020440:Gene Duplication; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D010375:Pedigree; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013702:Temporal Lobe / Q000098:blood supply* / Q000473:pathology; D044465:White People
chemical_list: D020413:3' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing; D000682:Amyloid; C120083:ITM2B protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins