| Gene (symbol, name) | Inheritance | Key pathogenic variant | Variant type / mechanism | Pathogenic product | Processing enzyme / cleavage | Key evidence / PMID |
|---|---|---|---|---|---|---|
| **ITM2B** (*integral membrane protein 2B*; also **BRI2**) | Autosomal dominant | **NM_021999.4(ITM2B):c.787_796dup** (reported in review as **787_796dupTTTAATTTGT**); protein consequence **p.Ser266PhefsTer11** / **p.Ser266PhefsX11** (pqac-00000001, pqac-00000004) | 10-nt duplication immediately before the normal stop codon; creates a frameshift/stop-loss–like C-terminal extension, producing a **277-aa mutant precursor** instead of the normal 266-aa protein (pqac-00000001, pqac-00000004, pqac-00000003) | Mutant precursor **ADanPP / mutant BRI2-277**; proteolytic release of **ADan**, a **34-aa amyloidogenic peptide**; deposits in parenchyma and vasculature (CAA), often with Aβ co-deposition (pqac-00000001, pqac-00000004, pqac-00000006) | **Furin-like convertase** cleavage at **Arg243–Glu244** / **...KGIQKR243↓E244...** releases the C-terminal peptide that becomes ADan (pqac-00000001, pqac-00000004, pqac-00000008) | Primary review evidence cites original disease-gene papers including **PMID: 10391242** and **PMID: 10781099** via curated disease-target association (pqac-00000000); supporting mechanistic reviews/details (pqac-00000001, pqac-00000004, pqac-00000008) |
| **ITM2B** (*integral membrane protein 2B*; BRI2) | Autosomal dominant | Same Danish mutation above; human FDD brain data also support pathogenic effect through reduced mature BRI2 levels (pqac-00000007) | Dual mechanism proposed: **toxic gain of function** from amyloidogenic ADan generation **plus loss of normal BRI2 function**, including impaired inhibition of APP processing and altered synaptic physiology (pqac-00000007, pqac-00000031, pqac-00000009) | Increased APP-derived metabolites/Aβ in human FDD brain; ADan/Aβ co-accumulation; reduced functional mature BRI2 at synapses in KI models (pqac-00000007, pqac-00000031) | BRI2 normally undergoes furin cleavage; disease mutation alters downstream peptide composition and is also associated with reduced mature BRI2 stability/maturation (pqac-00000008, pqac-00000031) | Human FDD brain: soluble **Aβ42 11-fold**, insoluble **Aβ42 125-fold**, soluble **Aβ40 27-fold**, insoluble **Aβ40 38-fold** vs control in one analyzed case (pqac-00000007); synaptic LOF model support (pqac-00000031) |


*Table: This table summarizes the currently supported genetic cause and pathogenic mechanism of ADan amyloidosis/familial Danish dementia from the retrieved evidence. It highlights the ITM2B Danish duplication, its processing into ADan, and the evidence for both toxic peptide accumulation and BRI2 loss-of-function.*