HGNC Approved Gene Symbol: TMCC2
Cytogenetic location: 1q32.1 Genomic coordinates (GRCh38): 1:205,227,946-205,273,343 (from NCBI)
TMCC2 is an evolutionarily conserved neuronal protein that contains 2 transmembrane domains and 2 coiled-coil domains (Hopkins et al., 2011).
Hopkins et al. (2011) reported that human TMCC2 is an evolutionarily conserved 709-amino acid protein. TMCC2 orthologs from human, mouse, and rat share more than 90% amino acid identity. TMCC2 contains 2 transmembrane domains near the C terminus and 2 coiled-coil domains. In situ hybridization and Western blot analyses showed that Tmcc2 was expressed in rodent brain and primary neurons. Immunofluorescence analysis revealed that human TMCC2 localized predominantly to endoplasmic reticulum in transfected human SHSY5Y cells.
Hopkins (2013) reported that human and mouse contain 4 orthologs of Drosophila dementin, including TMCC2. In Drosophila central nervous system, dementin is widely expressed in glia and in subsets of neurons of the optic lobe, both dynamically during development and in adults.
Gross (2021) mapped the TMCC2 gene to chromosome 1q32.1 based on an alignment of the TMCC2 sequence (GenBank BC131629) with the genomic sequence (GRCh38).
Using a yeast 2-hybrid screen and coimmunoprecipitation analysis, Hopkins et al. (2011) showed that human TMCC2 bound to apolipoprotein E (APOE; 107741) in an isoform-specific manner. Immunoprecipitation analysis revealed that TMCC2 also formed complexes with amyloid-beta protein precursor (APP; 104760) in rat brain extracts and transfected human cells. Coexpression of APOE and TMCC2 in SHSY5Y cells increased production of amyloid-beta from the Swedish variant of APP (104760.0008) and from the 99-amino acid C-terminal fragment of APP, and this effect was greater with APOE4 than APOE3. The authors proposed that interaction of TMCC2 with APOE may contribute to disrupted APP metabolism and altered amyloid-beta production.
Hopkins (2013) showed that Drosophila dementin, an ortholog of TMCC2, interacted genetically with human APP and with its Drosophila ortholog, Appl. Ectopic expression of dementin rescued developmental and behavioral defects caused by neuronal expression of human APP in Drosophila. Expression of a hypomorphic lethal mutation in dementin (dmtn1) or knockdown of dementin caused accumulation of fragments derived from Appl. Drosophila homozygous for the dmtn1 mutation (dmtn1 flies) died during metamorphosis, and adult escapers died within a few days, whereas heterozygous mutant flies had a normal life span. Examination of brains of newly eclosed dmtn1 flies showed that dementin was required for normal brain development and that glial dementin was required for development of medulla neuropil. Expression of wildtype dementin in either neurons or glia of dmtn1 flies rescued developmental lethality. In addition, dmtn1 flies displayed neurodegeneration with pathologic features resembling early-onset Alzheimer disease (104300).
Gross, M. B. Personal Communication. Baltimore, Md. 7/12/2021.
Hopkins, P. C. R., Sainz-Fuertes, R., Lovestone, S. The impact of a novel apolipoprotein E and amyloid-beta protein precursor-interacting protein on the production of amyloid-beta. J. Alzheimers Dis. 26: 239-253, 2011. [PubMed: 21593558] [Full Text: https://doi.org/10.3233/JAD-2011-102115]
Hopkins, P. C. R. Neurodegeneration in a Drosophila model for the function of TMCC2, an amyloid protein precursor-interacting and apolipoprotein E-binding protein. PLoS One 8: e55810, 2013. [PubMed: 23409049] [Full Text: https://doi.org/10.1371/journal.pone.0055810]