British amyloid dementia
Mutations in the BRI gene are thought to cause dementias in
members of families. The clinical symptoms are similar to those of Alzheimer's
disease, but with additional ocular and hearing deficits, and spasticity.
The mutations lead to the release of the 34-residue peptides, ABri and ADan,
in the brains of afflicted individuals.
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
Vidal, R., T. Revesz, et al. (2000). "A decamer duplication in the 3' region
of the BRI gene originates an amyloid peptide that is associated with dementia
in a danish kindred ." Proc Natl Acad Sci U S A 97(9): 4920-5.