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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Plant, G. T., Révész, T., Barnard, R. O., Harding, A. E. & Gautier-Smith, P. C. Familial cerebral amyloid angiopathy with nonneuritic plaque formation. Brain 113, 721–747 (1990).
Worster-Drought, C., Hill, T. R. & McMenemey, W. H. Familial presenile dementia with spastic paralysis. J. Neurol. Psychopathol. 14, 27–34 (1933).
Worster-Drought, C., Greenfield, J. G. & McMenemey, W. H. Aform of familial presenile dementia with spastic paralysis (including the pathological examination of a case). Brain 63, 237–254 (1940).
Worster-Drought, C., Greenfield, J. G. & McMenemey, W. H. Aform of presenile dementia with spastic paralysis. Brain 67, 38–43 (1944).
Corsellis, J. & Brierley, J. B. An unusual type of presenile dementia: (atypical Alzheimer's disease with amyloid vascular change). Brain 77, 571–587 (1954).
Aikawa, H., Suzuki, K., Iwasaki, Y. & Iizuka, R. Atypical Alzheimer's disease with spastic paresis and ataxia. Ann. Neurol. 17, 297–300 (1985).
Masters, C., Gajdusek, C. & Gibbs, C. J. The familial occurrence of Creutzfeldt-Jakob disease and Alzheimer's disease. Brain 104, 535–558 (1981).
Keohane, C., Peatfield, R. & Duchen, L. W. Subacute spongiform encephalopathy (Creutzfeldt-Jakob disease) with amyloid angiopathy. J. Neurol. Neurosurg. Psych. 48, 1175–1178 (1985).
Courten-Myers, G. & Mandybur, T. I. Atypical Gerstmann-Straüssler syndrome or familial spinocerebellar ataxia and Alzheimer's disease? Neurology 37, 269–275 (1987).
Pearlman, R. L., Towfight, J., Pezeshkpour, G. H., Tenser, R. B. & Turel, A. P. Clinical significance of types of cerebellar amyloid plaques in human spongiform encephalopathies. Neurology 38, 1249–1254 (1988).
Vinters, H. Cerebral amyloid angiopathy: a critical review. Stroke 18, 311–324 (1987).
Ghiso, J., Plant, G. T., Révész, T., Wisniewski, T. & Frangione, B. Familial cerebral amyloid angiopathy (British type) with nonneuritic amyloid plaque formation may be due to a novel amyloid protein. J. Neurol. Sci. 129, 74–75 (1995).
Baumann, M. H., Wisniewski, T., Levy, E., Plant, G. T. & Ghiso, J. C-terminal fragments of α- and β-tubulin form amyloid fibrils in vitro and associate with amyloid deposits of familial amyloid angiopathy, British type. Biochem. Biophys. Res. Commun. 219, 238–242 (1996).
Révész, T. et al. Cytoskeletal pathology in familial amyloid angiopathy (British type) with non-neuritic plaque formation. Acta Neuropath. 97, 170–176 (1999).
Altschul, S. F. et al. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 25, 3389–3402 (1997).
Kozak, M. An analysis of 5′-noncoding sequences from 699 vertebrate messenger RNA. Nucleic Acids Res. 15, 8125–8148 (1987).
Kyte, J. & Doolittle, R. F. Asimple method for displaying the hydropathic character of a protein. J. Mol. Biol. 157, 105–132 (1982).
Sonnhammer, E. L., von Heijne, G. & Krogh, A. Ahidden Markov model for predicting transmembrane helices in protein sequences. I.S.M.B., 6, 175–182 (1998).
Deleersnijder, W. et al. Isolation of markers for chondro-osteogenic differentiation using cDNA library subtraction. J. Biol. Chem. 271, 19475–19482 (1996).
Ghiso, J., Wisniewski, T. & Frangione, B. Unifying features of systemic and cerebral amyloidosis. Mol. Neurobiol. 8, 49–64 (1994).
Vidal, R. et al. Meningocerebrovascular amyloidosis associated with a novel transthyretin mis-sense mutation at codon 18 (TTRD18G). Am. J. Pathol. 148, 361–366 (1996).
Crook, R. et al. Avariant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1. Nature Med. 4, 452–455 (1998).
Ghetti, B. et al. Vascular variant of prion protein cerebral amyloidosis with tau-positive neurofibrillary tangles: the phenotype of the stop codon 145 mutation in PRNP. Proc. Natl Acad. Sci. USA 93, 744–748 (1996).
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).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/21637
This article is cited by
-
The emerging role of furin in neurodegenerative and neuropsychiatric diseases
Translational Neurodegeneration (2022)
-
Alzheimer’s disease – the journey of a healthy brain into organ failure
Molecular Neurodegeneration (2022)
-
Familial British dementia: a clinical and multi-modal imaging case study
Journal of Neurology (2022)
-
Immune infiltration landscape and immune-marker molecular typing of pulmonary fibrosis with pulmonary hypertension
BMC Pulmonary Medicine (2021)
-
Expression of the human molecular chaperone domain Bri2 BRICHOS on a gram per liter scale with an E. coli fed-batch culture
Microbial Cell Factories (2021)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.