Researchers supported by the National Institute on Aging (NIA) have discovered a novel gene, which when mutated is responsible for familial British dementia (FBD), a rare inherited disease that causes progressive dementia like that seen in patients with Alzheimer’s disease (AD) and severe movement disorders. This finding provides an exciting new clue to abnormal changes in the brain that lead to dementia. FBD, previously called familial cerebral amyloid angiopathy, was first reported in the 1940s. This autosomal dominant disorder has since been described in a large British family of more than 300 members spanning 9 generations. The most common symptoms of this devastating disease which usually develops in patients in their 40s and 50s are dementia and spasticity. A distinct feature of FBD is the development of Alzheimer’s disease-like dementia instead of stroke, which is common in other inherited forms of cerebral angiopathy. Researchers at the New York University School of Medicine in collaboration with scientists at the National Hospital for Neurology and Neurosurgery and the Institute of Neurology, both in London, England, discovered a novel gene, BRI, located on chromosome 13. A point mutation at the stop codon of this gene results in the production of a longer-than-normal BRI precursor protein. A peptide (ABri peptide) snipped from the mutated end of the BRI precursor protein is deposited as amyloid fibrils, which are thought to contribute to neuronal dysfunction and dementia. The research is reported in the June 24, 1999, issue of Nature (Vidal, R; Frangione, B; Rostagno, A; Mead, S; Revesz, T; Plant, G and Ghiso, J “A stop-codon mutation in the BRI gene associated with familial British dementia,” Nature June 24, 1999). The research group identified the mutated gene in a female FBD family member, who developed the disease at age 56 and died at age 65. They also found the mutation in 7 affected FBD family members, but not in unaffected family members, individuals with unrelated neurologic disorders, or normal controls from comparable ethnic origins. “Our hope is that this genetic mutation, which causes a disease as devastating as Alzheimer’s, will lead to a better understanding of how neurons actually are lost in the brain,” says Jorge Ghiso, Ph.D., associate professor of pathology at NYU School of Medicine, one of the authors of the study. “This is an important finding because it gives us another window into the brain diseases associated with amyloid.” FBD is similar to AD both disorders have in common the production of neurofibrillary tangles and amyloid deposits, although these amyloid deposits are derived from the processing of different cell membrane precursor proteins coded by genes located on different chromosomes; FBD amyloid is produced by chromosome 13 and AD amyloid is produced by chromosome 21. This study further supports the notion that aggregation of amyloid proteins plays an important role in the initiation of neuronal dysfunction. Amyloid is a generic name for protein fragments that clump together in a specific way to form insoluble deposits.
These fragments can arise from different proteins and have different amino acid sequences. Up until now, the identity of the major component of the amyloid deposits seen in FBD remained unknown. The present report details the biochemical analysis of the isolated amyloid fibrils revealing a unique protein fragment named ABri and leading to the identification and analysis of the BRI gene. Examples of mutations that lead to a shorter protein are common in the literature, but it is unusual to see a mutation that extends the length of a protein. According to Creighton H. Phelps, Ph.D., director of NIA’s Alzheimer’s Disease Centers Program, “Comparing the similarities and differences of these two related neurological diseases may provide clues to how AD develops. A number of different routes lead to dementia. This exciting discovery points to one that we didn’t know about before.” FBD may prove to be an ideal model to study the role of a different amyloid in the development of a dementia similar to AD, as well as in dementias occurring in other neurological disorders. Insights into the pathogenesis of movement disorders, which are common in older people, also may emerge when FBD pathogenesis is more fully understood.
Dr. Blas Frangione is the recipient of an NIA Leadership and Excellence in Alzheimer’s Disease (LEAD) award, which supported this research.
National Institute of Aging