Alternative titles; symbols
HGNC Approved Gene Symbol: CHMP4B
Cytogenetic location: 20q11.22 Genomic coordinates (GRCh38): 20:33,811,348-33,854,366 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q11.22 | Cataract 31, multiple types | 605387 | Autosomal dominant | 3 |
CHMP4B 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 (Tsang et al., 2006).
Using the N-terminal region of ALIX (PDCD6IP; 608074) as bait in a yeast 2-hybrid screen of a HeLa cell cDNA library, Katoh et al. (2003) cloned CHMP4B. The deduced 224-amino acid protein has 3 coiled-coil regions, a basic N-terminal half, and an acidic C-terminal half. Fluorescence microscopy revealed a diffuse cytoplasmic distribution of CHMP4B following stable expression in HEK293 cells. CHMP4B transiently overexpressed in HeLa cells exhibited a punctate distribution in the perinuclear area that partly overlapped the distributions of early and late endosomal markers.
Using Northern blot analysis, Katoh et al. (2004) detected expression of 1.2- and 1.8-kb CHMP4B transcripts in all tissues examined, with highest expression in heart and skeletal muscle, and moderate expression in brain, spleen, kidney, placenta, and peripheral blood leukocytes.
Shiels et al. (2007) noted that the CHMP4B gene contains 5 exons.
By genomic sequence analysis, Katoh et al. (2003) mapped the CHMP4B gene to chromosome 20q11.21.
By yeast 2-hybrid analysis, coimmunoprecipitation analysis, and in vitro protein pull-down assays, Katoh et al. (2003) showed that CHMP4B interacted with ALIX. Overexpression of CHMP4B in HeLa cells caused redistribution of ALIX from the cytoplasm to the perinuclear area, where the 2 proteins colocalized. Transient overexpression of the ALIX N-terminal region in HEK293 cells stably expressing CHMP4B induced formation of vesicle-like structures in which CHMP4B and truncated ALIX colocalized. Overexpression of CHMP4B in HeLa cells induced accumulation of ubiquitinated proteins and inhibited degradation of endocytosed EGF (131530). A dominant-negative form of the AAA-type ATPase SKD1 (VPS4B; 609983), which plays critical roles in the endocytic pathway, coimmunoprecipitated with CHMP4B. Furthermore, both CHMP4B and ALIX colocalized with dominant-negative SKD1 in perinuclear dot-like distributions in transfected HeLa cells, suggesting that the 3 proteins are involved in formation of multivesicular bodies.
Using in vitro pull-down assays, Katoh et al. (2004) showed that ALIX interacted more strongly with CHMP4B than with CHMP4A (610051) or CHMP4C (610899).
By coimmunoprecipitation of epitope-tagged proteins expressed in HEK293 cells, Yorikawa et al. (2005) showed that CHMP6 (610901) interacted with CHMP4B and EAP20 (VPS25; 610907). In vitro pull-down assays using recombinant proteins demonstrated direct physical interaction that was mediated by the N-terminal basic half of CHMP6.
Tsang et al. (2006) performed a systematic yeast 2-hybrid analysis of human ESCRT-III components, including CHMP4B. CHMP4B interacted with the ESCRT-III protein VPS4A (609982) and with the signal transduction molecule CC2D1A (610055). In addition, CHMP4B interacted with the SUMO (see SUMO1; 601912)-conjugating enzyme UBE2I (601661) and appeared to be part of a network connecting CHMP1A, CHMP4B, and CHMP5 (610900) with UBE2I, SUMO1, PIAS2 (603567), and HIPK2 (606868), all of which are involved in nuclear sumoylation processes.
Olmos et al. (2015) demonstrated that ESCRT-III machinery localizes to sites of annular fusion in the forming nuclear envelope in human cells, and is necessary for proper postmitotic nucleocytoplasmic compartmentalization. The ESCRT-III component CHMP2A (610893) is directed to the forming nuclear envelope through binding to CHMP4B, and provides an activity essential for nuclear envelope reformation. Localization also requires the p97 complex (see 601023) member UFD1 (601754). Olmos et al. (2015) concluded that their results described a novel role for the ESCRT machinery in cell division and demonstrated a conservation of the machineries involved in topologically equivalent mitotic membrane remodeling events.
Shiels et al. (2007) performed linkage analysis in a large 6-generation Caucasian family with autosomal dominant progressive childhood posterior subcapsular cataract (CTPP3; 605387) and found significant linkage on chromosome 20q with a maximum 2-point lod score of 5.50 at D20S847. Analysis of recombinant events in affected individuals followed by genotyping with biallelic SNP markers narrowed the region of interest to a 0.9-Mb interval containing approximately 80 genes, none of which were obvious functional candidates for cataracts. Sequence analysis of positional candidate genes revealed a heterozygous mutation (D129V; 610897.0001) in the CHMP4B gene that cosegregated with disease and was not found in 384 control chromosomes. Shiels et al. (2007) also identified a heterozygous mutation (E161K; 610897.0002) in the CHMP4B gene in affected individuals of a Japanese family with a similar juvenile progressive cataract phenotype, previously reported by Yamada et al. (2000) and Yamada et al. (2000).
In affected members of a 6-generation Caucasian family segregating autosomal dominant childhood posterior subcapsular cataract, progressing to affect the nucleus and anterior subcapsular regions (CTRCT31; 605387), Shiels et al. (2007) identified heterozygosity for a 386A-T transversion in exon 3 of the CHMP4B gene, resulting in an asp129-to-val (D129V) substitution. The mutation was not found in unaffected family members except for a 17-year-old male who was believed to be either nonpenetrant or presymptomatic, and was not found in 384 control chromosomes. Transfection studies of cultured cells revealed that a truncated form of recombinant D129V-CHMP4B had a different subcellular distribution than wildtype and an increased capacity to inhibit release of virus-like particles from the cell surface, consistent with deleterious gain-of-function effects. Shiels et al. (2007) concluded that CHMP4B plays a vital role in the maintenance of lens transparency.
In affected members of a Japanese family with a juvenile progressive subcapsular form of autosomal dominant posterior polar cataract (CTRCT31; 605387), previously described by Yamada et al. (2000), Shiels et al. (2007) identified heterozygosity for a 481G-A transition in exon 3 of the CHMP4B gene, resulting in a glu161-to-lys (E161K) substitution. The mutation was not found in unaffected members of the family or in 384 control chromosomes.
Katoh, K., Shibata, H., Hatta, K., Maki, M. CHMP4b is a major binding partner of the ALG-2-interacting protein Alix among the three CHMP4 isoforms. Arch. Biochem. Biophys. 421: 159-165, 2004. [PubMed: 14678797] [Full Text: https://doi.org/10.1016/j.abb.2003.09.038]
Katoh, K., Shibata, H., Suzuki, H., Nara, A., Ishidoh, K., Kominami, E., Yoshimori, T., Maki, M. The ALG-2-interacting protein Alix associates with CHMP4b, a human homologue of yeast Snf7 that is involved in multivesicular body sorting. J. Biol. Chem. 278: 39104-39113, 2003. [PubMed: 12860994] [Full Text: https://doi.org/10.1074/jbc.M301604200]
Olmos, Y., Hodgson, L., Mantell, J., Verkade, P., Carlton, J. G. ESCRT-III controls nuclear envelope reformation. Nature 522: 236-239, 2015. [PubMed: 26040713] [Full Text: https://doi.org/10.1038/nature14503]
Shiels, A., Bennett, T. M., Knopf, H. L. S., Yamada, K., Yoshiura, K., Niikawa, N., Shim, S., Hanson, P. I. CHMP4B, a novel gene for autosomal dominant cataracts linked to chromosome 20q. Am. J. Hum. Genet. 81: 596-606, 2007. [PubMed: 17701905] [Full Text: https://doi.org/10.1086/519980]
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]
Yamada, K., Tomita, H., Kanazawa, S., Mera, A., Amemiya, T., Niikawa, N. Genetically distinct autosomal dominant posterior polar cataract in a four-generation Japanese family. Am. J. Ophthal. 129: 159-165, 2000. [PubMed: 10682967] [Full Text: https://doi.org/10.1016/s0002-9394(99)00313-x]
Yamada, K., Tomita, H., Yoshiura, K., Kondo, S., Wakui, K., Fukushima, Y., Ikegawa, S., Nakamura, Y., Amemiya, T., Niikawa, N. An autosomal dominant posterior polar cataract locus maps to human chromosome 20p12-q12. Europ. J. Hum. Genet. 8: 535-539, 2000. [PubMed: 10909854] [Full Text: https://doi.org/10.1038/sj.ejhg.5200485]
Yorikawa, C., Shibata, H., Waguri, S., Hatta, K., Horii, M., Katoh, K., Kobayashi, T., Uchiyama, Y., Maki, M. Human CHMP6, a myristoylated ESCRT-III protein, interacts directly with an ESCRT-II component EAP20 and regulates endosomal cargo sorting. Biochem. J. 387: 17-26, 2005. [PubMed: 15511219] [Full Text: https://doi.org/10.1042/BJ20041227]