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We found a novel possible pathogenic variant in the ITM2B gene in one amyotrophic lateral sclerosis patient with a complex phenotype, associating movement disorders, psychiatric and cognitive features, deafness, and optic atrophy.
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Bri2 BRICHOS monomers potently prevent neuronal network toxicity of amyloid-beta peptide (A-beta), while dimers strongly suppress A-beta fibril formation.
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Bri2 BRICHOS domain is a potent inhibitor of IAPP fibril formation.Bri2 is highly expressed in human pancreatic islets and beta cells and colocalizes with IAPP both intracellularly and in islet amyloid deposits.
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ITM2B is expressed in most cortical neurons, neurons of the hippocampus and dentate nucleus, cerebellar Purkinje and granule cells, and (newly described here) in focal neurons in the basal ganglia, many neurons of the thalamus and brainstem, many cells in the ependyma and choroid plexus, and in the smooth muscle of blood vessels. ITM2B expression is prominent in plaques in AD-containing dystrophic neurites
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by modulating BRI2 processing using an ADAM10 inhibitor, a dual role for BRI2 in neurite outgrowth is suggested: phosphorylated full-length BRI2 appears to be important for the formation of neuritic processes, and BRI2 NTF promotes neurite elongation.
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Familial British dementia (FBD) and familial Danish dementia (FDD) are caused by mutations in the BRI2 gene.
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when BRI2 is phosphorylated a significant increase in neuronal outgrowth and differentiation is evident
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familial Danish dementia mutation and pE posttranslational modification are primary elements driving intact ADan into an amyloidogenic/neurotoxic pathway while truncations at the C-terminus eliminate the pro-amyloidogenic characteristics of the molecule
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Data depict roles for Bri2 and apolipoprotein E4 (ApoE4) proteins in a long-term memory regulation pathway. A single mutation in one Itm2b/Bri2 allele can affect both long-term and working memory, while ApoE4 seems to regulate short-term/working memory.
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Cystine-linked oligomers of ABri are toxic to neurons and block long-term potentiation.
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Data indicate integral membrane 2B (ITM2B) as a target of B-cell CLL/lymphoma 6 protein (BCL6) repression in lymphoma.
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Data indicate that the mutation originates the highly amyloidogenic molecule integral membrane protein 2B ABri.
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This review support the hypothesis that BRI2 change during disease devel-opment, and thus may have a role in Alzheimer disease.
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It binds amyloid precursor protein to halt amyloid-b production and inhibits amyloid-b aggregation via its BRICHOS-domain suggesting a link between BRI2 and Alzheimer's disease (AD)
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Findings highlight pathogenic mechanism(s) associated with ITM2B mutations underlying dementia or retinal disease and add a new candidate to the list of genes involved in inherited retinal dystrophies.
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Structural modeling of transmembrane (BRICHOS) domains of BRI2/ITM2B and SFTPC (pulmonary surfactant protein C) precursor identifies conserved region structurally complementary to beta-sheet/amyloid-prone region in BRICHOS domain-containing proteins.
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These results suggest that BRI2 may prevent access of BACE1 to APP and the BRI2/BACE1 interaction may mediate the reduction in BACE1 levels.
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Similarities of ABri and ADan to Abeta in Alzheimer's disease suggest that posttranslational pGlu-modification of amyloid peptides might represent general pathological mechanism leading to increased aggregation and toxicity forms of degenerative dementias.
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Data indicate that double transgenic (Tg-FDD-Tau) mice showed a significant decrease in synaptophysin levels.
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Neurological effects of the Danish form of BRI2 dementia caused by toxic amyloid Abeta protein precursor metabolites suggest that familial Danish and Alzheimer's dementias share common pathogenic mechanisms.
