The ITM2B gene (Integral Membrane Protein 2B), also known as BRI2, encodes a type II transmembrane protein that undergoes proteolytic processing to generate a soluble peptide. Mutations in ITM2B cause familial British dementia (FBD) and Danish dementia (FDD). ITM2B also modulates amyloid-beta metabolism in Alzheimer's disease.
ITM2B/BRI2 is a transmembrane protein that undergoes constitutive processing by furin-like proprotein convertases, releasing a soluble BRI2 peptide. The BRICHOS domain has anti-amyloidogenic properties and can interact with amyloid-beta to regulate its aggregation. BRI2 also plays roles in neuronal survival, synaptic function, and iron homeostasis.
Dominant mutations in ITM2B cause familial British dementia (FBD) and familial Danish dementia (FDD), characterized by cerebral amyloid angiopathy and progressive dementia. These mutations create amyloidogenic peptides (ABri, ADan) that accumulate as amyloid deposits. Common variants in ITM2B are associated with sporadic Alzheimer's disease risk. ITM2B modulates Aβ metabolism.
ITM2B is widely expressed with highest levels in brain, heart, and skeletal muscle. In brain, it is expressed in neurons throughout cortex, hippocampus, and cerebellum. The protein localizes to neuronal processes and synapses.