Alternative titles; symbols
HGNC Approved Gene Symbol: CHMP2B
SNOMEDCT: 702393003;
Cytogenetic location: 3p11.2 Genomic coordinates (GRCh38) : 3:87,227,309-87,255,556 (from NCBI)
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
---|---|---|---|---|
3p11.2 | Frontotemporal dementia and/or amyotrophic lateral sclerosis 7 | 600795 | Autosomal dominant | 3 |
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 (164010), is required for both MVB formation and regulation of cell cycle progression (summary by Tsang et al., 2006).
Skibinski et al. (2005) identified the human CHMP2B gene by positional cloning of a candidate gene region identified for frontotemporal dementia linked to a 15.5-Mb region on chromosome 3 (FTD3; 600795). The deduced 213-amino acid protein contains coiled-coil, Snf-7, and acidic C-terminal domains. Northern blot analysis identified a major 2.4-kb mRNA transcript in multiple human tissues and all major regions of the brain. Two minor transcripts of approximately 1.9 and 1.35 kb were also identified, suggestive of alternative 5-prime and 3-prime untranslated regions.
Skibinski et al. (2005) determined that the CHMP2B gene contains 6 exons.
By in situ hybridization of mouse brain, Skibinski et al. (2005) found widespread Chmp2b expression in all neuronal populations, especially in the hippocampus, frontal and temporal lobes, and cerebellum. No astrocytes or oligodendrocytes were labeled.
The yeast ortholog of CHMP2B, Vps2, was initially identified in a mutagenesis screen for unusual vacuolar protein sorting (vps) phenotypes in S. cerevisiae, and was found to be part of the ESCRTIII complex (endosomal secretory complex required for transport), which participates in endosomal trafficking (Babst et al., 2002).
Urwin et al. (2010) 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 (602298), that are necessary for fusion to occur.
In 11 affected members of a large Danish family with frontotemporal dementia linked to chromosome 3 (FTDALS7; 600795) reported by Brown et al. (1995) and Gydesen et al. (2002), Skibinski et al. (2005) identified a heterozygous mutation in the CHMPB2 gene (609512.0001). The authors identified a different CHMPB2 mutation (609512.0002) in a single unrelated patient with nonspecific dementia.
Parkinson et al. (2006) identified a heterozygous CHMPB2 mutation (609512.0003) in a patient with rapidly progressive motor deterioration consistent with a diagnosis of amyotrophic lateral sclerosis. No dementia was present in this patient. A second unrelated man with FTD and ALS had a different heterozygous mutation (I29V; 609512.0005).
Van der Zee et al. (2008) identified a truncating mutation in the CHMPB2 gene (609512.0004) in a Belgian patient with autosomal dominant frontotemporal lobar degeneration.
Cox et al. (2010) identified heterozygous mutations in the CHMP2B gene (see, e.g., 609512.0003, 609512.0005, and 609512.0006) in 4 (1%) of 433 patients with ALS17. However, CHMP2B mutations were found in 10% of those with the specific lower motor neuron variant of ALS. Microarray analysis of motor neurons with CHMP2B mutations showed downregulation of genes involved in axonal transport, autophagy induction, protein translation, and certain signaling pathways, such as MAPK-related pathways (see, e.g., 600289). Transfection of mutant CHMP2B into HEK293 and COS-7 cells resulted in the formation of large cytoplasmic vacuoles, aberrant lysosomal localization, and impaired autophagy. Cox et al. (2010) hypothesized that CHMP2B mutations may contribute to motor neuron injury through dysfunction of the autophagic clearance of cellular proteins.
Exclusion Studies
Momeni et al. (2006) did not identify pathogenic mutations in the CHMPB2 gene in 128 probands with frontotemporal dementia in whom MAPT mutations had been excluded. A truncating mutation in the CHMPB2 gene was identified in 2 middle-aged unaffected Afrikaner individuals from a large affected family; however, their affected father and 5 affected paternal relatives did not have the mutation. The maternal side of the family had no reported dementia. Momeni et al. (2006) noted that the large Danish family reported by Skibinski et al. (2005) had a similar truncating mutation in the CHMPB2 gene, which resulted from a different nucleotide change. The findings raised questions about the pathogenicity of the CHMPB2 mutation identified by Skibinski et al. (2005) and suggested that CHMPB2 mutations are not a common cause of frontotemporal dementia.
Cannon et al. (2006) did not identify pathogenic CHMPB2 mutations in 141 familial frontotemporal probands from the U.S. and U.K.
In 11 affected members from a large Danish family with frontotemporal dementia (FTDALS7; 600795), Skibinski et al. (2005) identified a heterozygous G-to-C transversion in the acceptor splice site of exon 6 of the CHMP2B gene. RT-PCR analysis showed that the mutation resulted in either inclusion of the 201-bp intronic sequence spanning exons 5 and 6 or a short deletion resulting from the use of a cryptic splice site mapping 10 bp from the 5-prime end of exon 6. Evidence suggested the presence of a third abnormal product which may have resulted from a heteroduplex formed between wildtype and mutant CHMP2B. The G-to-C transversion was not identified in 14 unaffected family members or 220 control DNA samples. In vitro functional expression studies in rat PC12 cells showed that the mutant proteins accumulated on the outer membrane of large aberrant cytoplasmic bodies, consistent with the formation of dysmorphic organelles of the late endosomal pathway.
Cannon et al. (2006) did not identify the splice site mutation reported by Skibinski et al. (2005) in 450 control individuals.
In a patient with frontotemporal dementia (FTDALS7; 600795), Skibinski et al. (2005) identified a 442G-T transversion in exon 5 of the CHMP2B gene, resulting in an asp148-to-tyr (D148Y) substitution in the conserved Snf-7 domain. The patient was 1 of 400 unrelated European patients studied.
In a 75-year-old man with rapidly progressive amyotrophic lateral sclerosis (FTDALS7; 600795), Parkinson et al. (2006) identified a heterozygous 694A-C transversion in exon 6 of the CHMP2B gene, resulting in a gln206-to-his (Q206H) substitution in a highly conserved residue. The mutation was not identified in 640 control samples. At age 74 years, the patient developed bulbar-onset weakness with flaccid dysarthria and tongue fasciculations. He later developed weakness and wasting of the intrinsic hand muscles and respiratory weakness. Although he had a previous right leg amputation from trauma, neurophysiologic testing showed neurogenic changes in all 4 limbs. He had depressed reflexes and flexor plantar responses, consistent with lower motor neuron involvement. He died of respiratory failure 15 months after symptom onset. There was no evidence of dementia or extramotor neurologic involvement. A cousin reportedly had died of ALS. Neuropathologic examination showed a predominantly lower motor neuron disease with intraneuronal inclusions immunopositive for ubiquitin (UBB; 191339) and p62/sequestosome (SQSTM1; 601530). SQSTM1-reactive inclusions were also detected within oligodendroglia in the cerebral motor cortex.
By in vitro functional studies in HEK293 and COS-7 cells, Cox et al. (2010) showed that cells expressing the Q206H mutant protein had large cytoplasmic vacuoles with an accumulation of mutant CHMP2B on the outer membrane, termed halos. Cells with the mutant protein also had aberrant localization of CD63 (155740) and an increase in LC3-II (601242), overall indicating a defect in the autophagic pathway.
In a Belgian woman with onset of frontotemporal dementia (FTDALS7; 600795) at age 58, van der Zee et al. (2008) identified a heterozygous 493C-T transition in exon 5 of the CHMP2B gene, resulting in a gln165-to-ter (Q165X) substitution. Her mother and maternal aunt were reportedly similarly affected. RT-PCR studies confirmed the presence of a mutant transcript in patient cells. The mutation was not found in 459 Belgian control individuals. Overexpression of the Q165X mutant in human neuroblastoma cells resulted in accumulation of truncated protein in enlarged vesicular structures. Normally, the C terminal of CHMP2B functions as an autoinhibitor, allowing the protein to shuttle between the inactive and active states. The truncation eliminates this inhibitory effect, resulting in constitutive activation and involvement in the endosomal complex and accumulation on the endosomal membrane.
In a man with onset of progressive frontotemporal dementia (FTDALS7; 600795) in his late sixties followed by amyotrophic lateral sclerosis, Parkinson et al. (2006) identified a heterozygous 161A-G transition in the CHMP3B gene, resulting in an ile29-to-val (I29V) substitution located between 2 conserved regions of the protein. The mutation was not found in 640 controls or in 400 FTD samples. However, Parkinson et al. (2006) noted that Cannon et al. (2006) found the I29V variant in 1 of 141 probands with frontotemporal dementia and at a frequency of 0.5% among 200 control chromosomes, thus suggesting that it may be a benign variant. The patient reported by Parkinson et al. (2006) had brisk tendon reflexes and extensor plantar responses. His father reportedly had motor disturbances and frontal lobe dysfunction.
Cox et al. (2010) identified a heterozygous I29V substitution, which they stated resulted from an 85A-G transition, in 2 unrelated patients with onset of amyotrophic lateral sclerosis at ages 64 and 49 years, respectively. The mutation was not found in 1,000 control chromosomes. Both patients had involvement of the upper and lower limbs, as well as bulbar symptoms, but no signs of upper motor neuron involvement. In vitro functional studies in HEK293 and COS-7 cells showed that cells expressing the mutant protein had large cytoplasmic vacuoles with an accumulation of mutant CHMP2B on the outer membrane, termed halos. Cells with the mutant protein also had aberrant localization of CD63 (155740) and an increase in LC3-II (601242), overall indicating a defect in the autophagic pathway.
In a 54-year-old man with amyotrophic lateral sclerosis (FTDALS7; 600795), Cox et al. (2010) identified a heterozygous 311C-A transversion in exon 3 of the CHMP2B gene, resulting in a thr104-to-asn (T104N) substitution at a highly conserved residue. The mutation was not found in 1,000 control chromosomes. The patient presented with bulbar and respiratory dysfunction and later developed wasting and fasciculation in the upper and lower limbs. Reflexes were normal, suggesting only lower motor neuron involvement. In vitro functional studies in HEK293 and COS-7 cells showed that cells expressing the mutant protein had large cytoplasmic vacuoles with an accumulation of mutant CHMP2B on the outer membrane, termed halos. Cells with the mutant protein also had aberrant localization of CD63 (155740) and an increase in LC3-II (601242), overall indicating a defect in the autophagic pathway.
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Gydesen, S., Brown, J. M., Brun, A., Chakrabarti, L., Gade, A., Johannsen, P., Rossor, M., Thusgaard, T., Grove, A., Yancopoulou, D., Spillantini, M. G., Fisher, E. M. C., Collinge, J., Sorensen, S. A. Chromosome 3 linked frontotemporal dementia (FTD-3). Neurology 59: 1585-1594, 2002. [PubMed: 12451202] [Full Text: https://doi.org/10.1212/01.wnl.0000034763.54161.1f]
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Tsang, H. T. H., Connell, J. W., Brown, S. E., Thompson, A., Reid, E., Sanderson, C. M. A systematic analysis of human CHMP protein interactions: additional MIT domain-containing proteins bind to multiple components of the human ESCRT III complex. Genomics 88: 333-346, 2006. [PubMed: 16730941] [Full Text: https://doi.org/10.1016/j.ygeno.2006.04.003]
Urwin, H., Authier, A., Nielsen, J. E., Metcalf, D., Powell, C., Froud, K., Malcolm, D. S., Holm, I., Johannsen, P., Brown, J., Fisher, E. M. C., van der Zee, J., Bruyland, M., the FReJA Consortium, Collinge, J., Brandner, S., Futter, C., Isaacs, A. M. Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B mutations. Hum. Molec. Genet. 19: 2228-2238, 2010. [PubMed: 20223751] [Full Text: https://doi.org/10.1093/hmg/ddq100]
van der Zee, J., Urwin, H., Engelborghs, S., Bruyland, M., Vandenberghe, R., Dermaut, B., De Pooter, T., Peeters, K., Santens, P., De Deyn, P. P., Fisher, E. M., Collinge, J., Isaacs, A. M., Van Broeckhoven, C. CHMP2B C-truncating mutations in frontotemporal lobar degeneration are associated with an aberrant endosomal phenotype in vitro. Hum. Molec. Genet. 17: 313-322, 2008. [PubMed: 17956895] [Full Text: https://doi.org/10.1093/hmg/ddm309]