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9.B.23.  The TMEM106 (TMEM106) Family 

TMEM106B variants are genetically associated with frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), and are considered a major risk factor for this disease. TMEM106B may also be involved in other pathologies such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Schwenk et al. 2014 combined loss-of-function experiments, live imaging and proteomics to unveil the physiological roles played by TMEM106B and its binding partner MAP6 in lysosomal function and transport. Neuronal TMEM106B plays a central role in regulating lysosomal size, motility and responsiveness to stress (Stagi et al. 2014). Single-nucleotide polymorphisms: rs5848 (GRN), rs1990622 (TMEM106B), and rs704180 (ABCC9) are associated with hippocampal sclerosis of aging (HS-Aging), a common high-morbidity neurodegenerative condition in elderly persons (Nelson et al. 2015). The up-regulation of TMEM106B may increase the risk of FTLD by directly causing neurotoxicity and a pathological phenotype linked to FTLD-TDP (Suzuki and Matsuoka 2016). Nicholson and Rademakers 2016 summarized what was known about TMEM106B and its role as a potential regulator of lysosomal function.

TMEM106C is overexpressed in hepatocellular carcinoma (HCC) cells, and inhibition of TMEM106C  suppressed the proliferation and metastasis of HCC (Duan et al. 2021). Upregulation of TMEM106C correlated with sex, tumor stage, tumor grade and prognosis. Overexpression of TMEM106C was linked to functional networks involving organelle fission and cell cycle signaling pathways through the regulation of CDK kinases, E2F1 transcription factors and miRNAs. Thus, TMEM106C contributes to malignant characteristics and poor prognosis in HCC (Duan et al. 2021).

TMEM106A is silenced by promoter region hypermethylation and suppresses gastric cancer growth by inducing apoptosis (Xu et al. 2014). It activates mouse peritoneal macrophages via the MAPK and NF-κB signaling pathways (Dai et al. 2015). It is a tumor suppressor in human renal cancer, and may play a role in prostate, breast and ovarian cancers (Wu et al. 2017; Babalyan et al. 2016; Du et al. 2018). It  inhibits cell proliferation and migration and induces apoptosis of lung cancer cells (Liu and Zhu 2018; Rizza et al. 2019). Moreover, inactivation of TMEM106A promotes lipopolysaccharide-induced inflammation via the MAPK and NF-kappaB signaling pathways in macrophages (Zhang et al. 2021).

 

 

 

References associated with 9.B.23 family:

Babalyan, K.A., R. Sultanov, E.V. Generozov, N.B. Zakharzhevskaya, E.I. Sharova, M.N. Peshkov, A.O. Vasilev, A.V. Govorov, D.Y. Pushkar, E.A. Prilepskaya, S.A. Danilenko, E.A. Babikova, A.K. Larin, and V.M. Govorun. (2016). [Genome-wide analysis of DNA methylation in prostate cancer using the technology of Infinium HumanMethylation450 BeadChip (HM450)]. Vopr Onkol 62: 122-132. 30444590
Busch, J.I., T.L. Unger, N. Jain, R. Tyler Skrinak, R.A. Charan, and A.S. Chen-Plotkin. (2016). Increased expression of the frontotemporal dementia risk factor TMEM106B causes C9orf72-dependent alterations in lysosomes. Hum Mol Genet 25: 2681-2697. 27126638
Dai, H., D. Xu, J. Su, J. Jang, and Y. Chen. (2015). Transmembrane protein 106a activates mouse peritoneal macrophages via the MAPK and NF-κB signaling pathways. Sci Rep 5: 12461. 26215746
Du, C., D. Mark, B. Wappenschmidt, B. Böckmann, B. Pabst, S. Chan, H. Cao, S. Morlot, C. Scholz, B. Auber, K. Rhiem, R. Schmutzler, T. Illig, B. Schlegelberger, and D. Steinemann. (2018). A tandem duplication of BRCA1 exons 1-19 through DHX8 exon 2 in four families with hereditary breast and ovarian cancer syndrome. Breast Cancer Res Treat 172: 561-569. 30191368
Duan, J., Y. Qian, X. Fu, M. Chen, K. Liu, H. Liu, J. Yang, C. Liu, and Y. Chang. (2021). TMEM106C contributes to the malignant characteristics and poor prognosis of hepatocellular carcinoma. Aging (Albany NY) 13:. [Epub: Ahead of Print] 33591950
Liu, J. and H. Zhu. (2018). TMEM106A inhibits cell proliferation, migration, and induces apoptosis of lung cancer cells. J. Cell. Biochem. [Epub: Ahead of Print] 30456879
Lok, H.C. and J.B. Kwok. (2021). The Role of White Matter Dysfunction and Leukoencephalopathy/Leukodystrophy Genes in the Aetiology of Frontotemporal Dementias: Implications for Novel Approaches to Therapeutics. Int J Mol Sci 22:. 33802612
Nelson, P.T., W.X. Wang, A.B. Partch, S.E. Monsell, O. Valladares, S.R. Ellingson, B.R. Wilfred, A.C. Naj, L.S. Wang, W.A. Kukull, and D.W. Fardo. (2015). Reassessment of risk genotypes (GRN, TMEM106B, and ABCC9 variants) associated with hippocampal sclerosis of aging pathology. J Neuropathol Exp Neurol 74: 75-84. 25470345
Nicholson, A.M. and R. Rademakers. (2016). What we know about TMEM106B in neurodegeneration. Acta Neuropathol 132: 639-651. 27543298
Rizza, R., K. Hackmann, I. Paris, A. Minucci, R. De Leo, E. Schrock, A. Urbani, E. Capoluongo, G. Gelli, and P. Concolino. (2019). Novel BRCA1 Large Genomic Rearrangements in Italian Breast/Ovarian Cancer Patients. Mol Diagn Ther 23: 121-126. 30506513
Schwenk, B.M., C.M. Lang, S. Hogl, S. Tahirovic, D. Orozco, K. Rentzsch, S.F. Lichtenthaler, C.C. Hoogenraad, A. Capell, C. Haass, and D. Edbauer. (2014). The FTLD risk factor TMEM106B and MAP6 control dendritic trafficking of lysosomes. EMBO. J. 33: 450-467. 24357581
Stagi, M., Z.A. Klein, T.J. Gould, J. Bewersdorf, and S.M. Strittmatter. (2014). Lysosome size, motility and stress response regulated by fronto-temporal dementia modifier TMEM106B. Mol. Cell Neurosci 61: 226-240. 25066864
Suzuki, H. and M. Matsuoka. (2016). The Lysosomal Trafficking Transmembrane Protein 106B Is Linked to Cell Death. J. Biol. Chem. 291: 21448-21460. 27563066
Wu, C., J. Xu, H. Wang, J. Zhang, J. Zhong, X. Zou, Y. Chen, G. Yang, Y. Zhong, D. Lai, X. Li, and A. Tang. (2017). TMEM106a is a Novel Tumor Suppressor in Human Renal Cancer. Kidney Blood Press Res 42: 853-864. 29131025
Xu, D., L. Qu, J. Hu, G. Li, P. Lv, D. Ma, M. Guo, and Y. Chen. (2014). Transmembrane protein 106A is silenced by promoter region hypermethylation and suppresses gastric cancer growth by inducing apoptosis. J Cell Mol Med 18: 1655-1666. 24975047
Zhang, X., T. Feng, X. Zhou, P.M. Sullivan, F. Hu, Y. Lou, J. Yu, J. Feng, H. Liu, and Y. Chen. (2021). Inactivation of TMEM106A promotes lipopolysaccharide-induced inflammation via the MAPK and NF-κB signaling pathways in macrophages. Clin Exp Immunol 203: 125-136. 33006758