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A stop-codon mutation in the BRI gene associated with familial British dementia

Abstract

Familial British dementia (FBD), previously designated familial cerebral amyloid angiopathy–British type1, is an autosomal dominant disorder of undetermined origin characterized by progressive dementia, spasticity, and cerebellar ataxia, with onset at around the fifth decade of life. Cerebral amyloid angiopathy, non-neuritic and perivascular plaques and neurofibrillary tangles are the predominant pathological lesions1,2,3,4,. Here we report the identification of a unique 4K protein subunit named ABri from isolated amyloid fibrils. This highly insoluble peptide is a fragment of a putative type-II single-spanning transmembrane precursor that is encoded by a novel gene, BRI, located on chromosome 13. A single base substitution at the stop codon of this gene generates a longer open reading frame, resulting in a larger, 277-residue precursor. Release of the 34 carboxy-terminal amino acids from the mutated precursor generates the ABri amyloid subunit. The mutation creates a cutting site for the restriction enzyme Xba I, which is useful for detecting asymptomatic carriers. Antibodies against the amyloid or homologous synthetic peptides recognize both parenchymal and vascular lesions in FBD patients. A point mutation at the stop codon of BRI therefore results in the generation of the ABri peptide, which is deposited as amyloid fibrils causing neuronal disfunction and dementia.

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Figure 1: Nucleotide sequence and predicted amino-acid sequence of a cDNA clone encoding the precursor of the ABri amyloid protein.
Figure 2: Model of the ABri precursor molecule as a cell-surface glycoprotein.
Figure 3: Chromosomal localization of BRI.
Figure 4: Expression of the ABri precursor protein.
Figure 5: Analysis of nucleotide substitutions in the gene encoding the ABri precursor protein.
Figure 6: Immunohistochemical analysis.

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Acknowledgements

This work was supported by the NIA LEAD award Alzheimer's disease and amyloid proteins (B.F.). J.G. is the recipient of the NIDA from AHA (NYC affiliate).

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Correspondence to Jorge Ghiso.

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Vidal, R., Frangione, B., Rostagno, A. et al. A stop-codon mutation in the BRI gene associated with familial British dementia. Nature 399, 776–781 (1999). https://doi.org/10.1038/21637

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