This report describes frontotemporal dementia and/or amytrophic lateral sclerosis 7 (FTDALS7); FTDALS7 exhibits autosomal dominant inheritance. The human gene implicated in this disease is CHMP2B, which is a component of the human ESCRT-III (endosomal sorting complex required for transport III) complex. There is a single fly ortholog, CHMP2B, for which RNAi-targeting constructs and over-expression constructs have been generated.
OMIM includes this disease in two phenotypic series: Amyotrophic lateral sclerosis (PS105400, see below) and Frontotemporal dementia and/or Amyotrophic Lateral Sclerosis (PS105550).
Multiple UAS constructs of the human Hsap\CHMP2B gene have been introduced into flies, including wild-type CHMP2B and genes carrying mutational lesions. Variant(s) implicated in human disease tested (as transgenic human gene, CHMP2B): the IVS5AS, G-C variant splicing form of the human gene, which results in truncation of 35 aa at the carboxyl terminus of the protein, has been introduced into flies. Phenotypic assays using the human gene have allowed characterization of genetic interactions.
The Dmel\CHMP2B gene has not been genetically characterized. Physical interactions of the CHMP2B protein product have been described; see below and in the CHMP2B gene report.
See also the FlyBase gene group report ESCRT-III COMPLEX (FBgg0000057).
[updated Feb. 2021 by FlyBase; FBrf0222196]
Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. ALS usually begins with asymmetric involvement of the muscles in middle adult life. Approximately 10% of ALS cases are familial (Siddique and Deng, 1996, pubmed:8875253). ALS is sometimes referred to as 'Lou Gehrig disease' after the famous American baseball player who was diagnosed with the disorder. [from MIM:105400, 2015.02.11]
[FRONTOTEMPORAL DEMENTIA AND/OR AMYOTROPHIC LATERAL SCLEROSIS 7; FTDALS7](https://omim.org/entry/600795)
[CHARGED MULTIVESICULAR BODY PROTEIN 2B; CHMP2B](https://omim.org/entry/609512)
Chromosome 3-linked frontotemporal dementia (FTD3) has been described in a single family from Denmark and in one individual with familial FTD3 from Belgium. It typically starts between ages 46 and 65 years with subtle personality changes and slowly progressive behavioral changes, dyscalculia, and language disturbances. Disinhibition or loss of initiative is the most common presenting symptom. The disease progresses over a few years into profound dementia with mutism. Several individuals have developed an asymmetric akinetic rigid syndrome with arm and gait dystonia and pyramidal signs that may be related to treatment with neuroleptic drugs. Disease duration may be as short as three years or longer than 20 years. [from GeneReviews, Frontotemporal Dementia, Chromosome 3-Linked, pubmed:20301378 2016.04.14]
Frontotemporal dementia mapping to chromosome 3 is caused by heterozygous mutation in the CHMP2B gene. [from MIM:600795, 2016.04.12]
Urwin et al. (2010, pubmed:20223751) described endosomal pathology in CHMP2B mutation-positive patient brains and also identified and characterized abnormal endosomes in patient fibroblasts. Functional studies demonstrated a specific disruption of endosome-lysosome fusion but not protein sorting by the multivesicular body (MVB). The authors proposed a mechanism for impaired endosome-lysosome fusion whereby mutant CHMP2B constitutively binds to MVBs and prevents recruitment of proteins, such as Rab7 (MIM:602298), that are necessary for fusion to occur. [from MIM:609512, 2016.04.12]
CHMP2B belongs to the chromatin-modifying protein/charged multivesicular body protein (CHMP) family. These proteins are components of ESCRT-III (endosomal sorting complex required for transport III), a complex involved in degradation of surface receptor proteins and formation of endocytic multivesicular bodies (MVBs). Some CHMPs have both nuclear and cytoplasmic/vesicular distributions, and one such CHMP, CHMP1A, is required for both MVB formation and regulation of cell cycle progression. (summary by Tsang et al., 2006, pubmed:16730941). [from MIM:609512, 2016.04.12]
One to one: 1 human to 1 Drosophila.
Ortholog of human CHMP2B (1 Drosophila to 1 human).
Dmel\CHMP2B shares 50% identity and 70% similarity with human CHMP2B.
