A stop-codon mutation in the BRI gene associated with familial British dementia (original) (raw)

Nature volume 399, pages 776–781 (1999)Cite this article

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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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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Authors and Affiliations

  1. Department of Pathology, New York University School of Medicine, 550 First Avenue, 10016, New York, USA
    Ruben Vidal, Blas Frangione, Agueda Rostagno & Jorge Ghiso
  2. The National Hospital for Neurology and Neurosurgery, Queen Square, WC1N 3BG, London, UK
    Simon Mead & Gordon Plant
  3. The Department of Neuropathology, Institute of Neurology, Queen Square, London, WC1N 3BG, UK
    Tamas Révész & Gordon Plant

Authors

  1. Ruben Vidal
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  2. Blas Frangione
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  3. Agueda Rostagno
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  4. Simon Mead
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  5. Tamas Révész
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  6. Gordon Plant
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  7. Jorge Ghiso
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Correspondence toJorge 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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