CHMP2B

Several changes in the CHMP2B gene have been identified in people with frontotemporal dementia. At least two of these genetic changes are thought to be mutations that cause the disease. It is unclear whether the other genetic changes also cause disease; they may be rare variations that are unrelated to the development of frontotemporal dementia.

Most people with CHMP2B-related frontotemporal dementia are members of a single, large Danish family. Affected individuals in this family have a particular mutation, written as 532-1G>C, that changes a single DNA building block (base pair) in the CHMP2B gene. This mutation leads to the production of two abnormal versions of charged multivesicular body protein 2B, both of which are missing the C-terminal domain.

Without the C-terminal domain, charged multivesicular body protein 2B is constantly turned on (active) as part of the ESCRT-III complex. It cannot interact with Vps4, so the complex cannot be disassembled when it is no longer needed. As a result, the ESCRT-III complex builds up within cells and disrupts the transport and degradation of other proteins. These abnormalities ultimately lead to the death of neurons in the brain.

A gradual loss of neurons throughout the brain is characteristic of CHMP2B-related frontotemporal dementia. Many of the features of this disease result from neuronal death in regions near the front of the brain called the frontal and temporal lobes. The frontal lobes are involved in reasoning, planning, judgment, and problem-solving, while the temporal lobes help process hearing, speech, memory, and emotion. It is unclear why the signs and symptoms of this disease are related primarily to the frontal and temporal lobes.

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