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

Ruben Vidal, Blas Frangione, Agueda Rostagno, Simon Mead, Tamas Révész, Gordon Plant and Jorge Ghiso ()
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Ruben Vidal: New York University School of Medicine
Blas Frangione: New York University School of Medicine
Agueda Rostagno: New York University School of Medicine
Simon Mead: The National Hospital for Neurology and Neurosurgery
Tamas Révész: Institute of Neurology
Gordon Plant: The National Hospital for Neurology and Neurosurgery
Jorge Ghiso: New York University School of Medicine

Nature, 1999, vol. 399, issue 6738, 776-781

Abstract: 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.

Date: 1999
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DOI: 10.1038/21637

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