The type II integral membrane (ITM2) protein family consists of three members: ITM2A (also designated E25), ITM2B and ITM2C. ITM2A expression is high in osteogenic and lymphoid tissues, while both ITM2B and ITM2C are expressed in brain. ITM2B is a 266 amino acid protein that contains a potential N-glycosylation site, a potential single transmembrane-spanning domain between amino acids 52 and 74 and an extracellular SLCterminal domain. Mutations in the ITM2B gene can lead to familial British dementia (FBD), and autosomal dominant disease with an onset around the fifth decade of life that is characterized by progressive dementia, spasticity and cerebellar ataxia. Familial Danish dementia (FDD), also designated heredopathia ophthalmo-oto-encephalica, is also associated with mutations in the ITM2B gene. FDD is an autosomal dominant disorder characterized by cataracts, deafness, progressive ataxia and dementia.
Function:
Functions as a protease inhibitor. Plays a role in APP processing regulating the physiological production of the beta amyloid peptide. Restricts docking of gamma-secretase to APP and access of alpha- and beta-secretase to their cleavage APP sequence.
Subunit:
Homodimer; disulfide-linked. Interacts with SPPL2A and SPPL2B. Interacts with APP. Mature BRI2 (mBRI2) interacts with the APP amyloid beta A4 protein; the interaction occurs at the cell surface and in the endocytic compartments and enable alpha- and beta-secretase-induced APP cleavage inhibition. Mature BRI2 (mBRI2) interacts with the APP C99; the interaction occurs in the endocytic compartments and enable gamma-secretase-induced C99 cleavage inhibition. May form heterodimers with Bri23 peptide and APP beta-amyloid protein 40.
Subcellular Location:
Golgi apparatus membrane. Cell membrane.
Tissue Specificity:
Expressed in brain and in other tissues.
Post-translational modifications:
The SLCterminal part of the ectodomain is processed by furin and related proteases producing a secreted peptide of 4 to 5 kDa. For the ABRI and ADAN variants the SLCterminal secreted peptide is larger and may produce amyloid fibrils responsible for neuronal dysfunction and dementia. The remaining part of the ectodomain containing the BRICHOS domain is cleaved by ADAM10 and is secreted as a peptide of 25 kDa. The membrane-bound N-terminal fragment (NTF) of 22 kDa is further proteolytically processed by SPPL2A and SPPL2B through regulated intramembrane proteolysis producing a secreted peptide (BRI2C) and an intracellular domain (ICD) released in the cytosol.
DISEASE:
Defects in ITM2B are a cause of cerebral amyloid angiopathy ITM2B-related type 1 (CAA-ITM2B1) [MIM:176500]. A disorder characterized by amyloid deposition in the walls of cerebral blood vessels and neurodegeneration in the central nervous system. Cerebral amyloid angiopathy, non-neuritic and perivascular plaques and neurofibrillary tangles are the predominant pathological lesions. Clinical features include progressive mental deterioration, spasticity and muscular rigidity.
Defects in ITM2B are a cause of cerebral amyloid angiopathy ITM2B-related type 2 (CAA-ITM2B2) [MIM:117300]; also known as heredopathia ophthalmo-oto-encephalica. A disorder characterized by amyloid deposition in the walls of the blood vessels of the cerebrum, choroid plexus, cerebellum, spinal cord and retina. Plaques and neurofibrillary tangles are observed in the hippocampus. Clinical features include progressive ataxia, dementia, cataracts and deafness.
Similarity:
Belongs to the ITM2 family.
Contains 1 BRICHOS domain.
SWISS:
Q9Y287
Gene ID:
9445
Database links:
Entrez Gene: 510575 Cow
Entrez Gene: 476916 Dog
Entrez Gene: 9445 Human
Entrez Gene: 16432 Mouse
Entrez Gene: 595120 Rabbit
Entrez Gene: 290364 Rat
Omim: 603904 Human
SwissProt: Q3T0P7 Cow
SwissProt: Q9Y287 Human
SwissProt: O89051 Mouse
SwissProt: Q52N47 Pig
SwissProt: Q5XIE8 Rat
Unigene: 23522 Cow
Unigene: 4266 Human
Unigene: 643683 Human
Unigene: 107335 Rat
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