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

摘要

Familial Danish dementia (FDD), also known as heredopathia ophthalmo-oto-encephalica, is an autosomal dominant disorder characterized by cataracts, deafness, progressive ataxia, and de- mentia. Neuropathological findings include severe widespread cerebral amyloid angiopathy, hippocampal plaques, and neurofi- brillary tangles, similar to Alzheimer's disease. N-terminal se- quence analysis of isolated leptomeningeal amyloid fibrils re- vealed 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 dupli- cation (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 sub- unit (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 impor- tance of amyloid formation as a causative factor in neurodegen- eration and dementia.