Disease relevance of CHMP2B

• RESULTS: Perl's staining showed increased iron in colorectal cancers, and there was a corresponding overexpression of components of the intracellular iron import machinery (DCYTB, DMT1, and TfR1) [1].
• The facilitated transport of Fe by DMT1 at the blood-CSF barrier may partly contribute to Mn-induced neurodegenerative Parkinsonism [2].
• We propose that DMT1(C1246T) (R416C) represents a complete loss-of-function, and that a quantitative reduction in DMT1 expression is the cause of the microcytic anemia and iron overload in the patient [3].

Psychiatry related information on CHMP2B

• Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia [4].

High impact information on CHMP2B

• The idea that this reflects a shared pathogenesis has received strong support from the identification of new genetic loci on chromosome 9p and of mutations in specific genes (CHMP2B and DCN1) in families with co-segregation of ALS and FTD [5].
• DMT1 mutation: response of anemia to darbepoetin administration and implications for iron homeostasis [6].
• These observations indicate that Fe(II) transport by DMT1 can be modulated by cellular redox status and suggest that ebselen may act therapeutically to limit iron-catalyzed damage due to transport inhibition [7].
• Ebselen inhibited Fe(II) uptake (IC(50) of approximately 0.22 muM), but did not influence Fe(III) transport or DMT1-mediated manganese uptake [7].
• An unrelated antioxidant, pyrrolidine dithiobarbamate (PDTC), also inhibited DMT1 activity (IC(50) of approximately 1.54 muM) [7].

Biological context of CHMP2B

• In order to determine whether CHMP2B mutations are a common cause of disease in patients with frontotemporal lobar degeneration (FTLD) we sequenced all exons and flanking regions of CHMP2B in 141 familial FTLD probands from the USA and UK [8].
• Sequence analysis of all identified open reading frames on the frontal temporal dementia haplotype on chromosome 3 fails to identify unique coding variants except in CHMP2B [9].
• The putative pathogenicity of CHMP2B mutations for dementia is discussed [10].
• Upregulation of DMT1 expression in choroidal epithelia of the blood-CSF barrier following manganese exposure in vitro [2].
• ALS phenotypes with mutations in CHMP2B (charged multivesicular body protein 2B) [11].

Anatomical context of CHMP2B

• This is accompanied by an increased expression of divalent metal transporter-1 (DMT1) in the lesioned hippocampus, suggesting that the transporter may be partially responsible for the iron accumulation [12].
• This study was designed to test the hypothesis that Mn treatment, by acting on protein-mRNA binding between IRP and DMT1 mRNA, altered the expression of DMT1 in an immortalized choroidal epithelial Z310 cell line which was derived from rat choroid plexus epithelia, leading to a compartmental shift of Fe from the blood to the CSF [2].
• Immunohistochemical experiments revealed that DMT1 was localized to both the lumen microvilli and end feet of the sustentacular cells of the olfactory epithelium [13].

Associations of CHMP2B with chemical compounds

• For example, DCT1 (divalent cation transporter-1; also known as NRAMP2 or DMT1) is considered to be a major cellular uptake mechanism for Fe(2+) and other essential divalent metals, but this protein also mediates uptake of Cd(2+), Pb(2+), and possibly of other toxic divalent metals [14].
• DMT1 has a broad substrate range that includes other divalent metals such as lead (Pb) and cadmium (Cd), and the present study was carried out to elucidate the uptake of these metals in the kainate-injected brain [12].
• To examine the potential role of this transporter in uptake of inhaled manganese, we studied the Belgrade rat, since these animals display significant defects in both iron and manganese metabolism due to a glycine-to-arginine substitution (G185R) in their DMT1 gene product [13].

Analytical, diagnostic and therapeutic context of CHMP2B

• DMT1 is also mutated in Belgrade rats, an animal model with a thalassemic-like disorder of microcytic anemia with hyperferrinemia [15].
• Moreover, real-time RT-PCR revealed no changes in DMT1 heterogeneous nuclear RNA (hnRNA) levels following Mn exposure [2].
• Immunocytochemistry confirmed the presence of DMT1 in Z310 cell [2].
• Accordingly, Western blot analysis revealed a significant increase of DMT1 protein concentrations at 48 h after Mn exposure (100 microM) [2].
• Electrophoretic mobility shift assay (EMSA) showed that Mn exposure increased binding of IRP to DMT1 mRNA in cultured choroidal Z310 cells [2].

References