TMEM106B

TMEM106B
Identifiers
Aliases	TMEM106B, transmembrane protein 106B, HLD16
External IDs	OMIM: 613413 MGI: 1919150 HomoloGene: 56806 GeneCards: TMEM106B
Gene location (Human)
Chr.	Chromosome 7 (human)
End	12,243,367 bp
Gene location (Mouse)
Chr.	Chromosome 6 (mouse)
End	13,089,268 bp
RNA expression pattern
	Top expressed in
	corpus epididymis; ; caput epididymis; ; kidney; ; medulla oblongata; ; retinal pigment epithelium; ; myometrium;
	More reference expression data
	More reference expression data
Gene ontology
Molecular function	GO:0001948 protein binding; molecular function;
Cellular component	integral component of membrane; lysosomal membrane; late endosome membrane; membrane; lysosome; endosome;
Biological process	lysosome localization; dendrite morphogenesis; lysosome organization; lysosomal transport; positive regulation of dendrite development;
	Sources:Amigo / QuickGO
Orthologs
	54664
	71900
	ENSG00000106460
	ENSMUSG00000029571
	Q9NUM4
	Q80X71
	NM_001134232; NM_018374
	NM_027992
	NP_001127704; NP_060844; NP_001127704.1; NP_060844.2
	NP_082268
	Wikidata
View/Edit Human	View/Edit Mouse

Transmembrane protein 106B is a protein that in humans is encoded by the TMEM106B gene.^[5]

Functions[]

TMEM106B is involved in:^[6]^[7]

Dendrite morphogenesis and maintenance by regulating lysosomal trafficking via its interaction with MAP6.
Dendrite branching.

Clinical implications[]

Frontotemporal dementia is the third most common neurodegenerative disease after AD and Parkinson disease. A study performed in 515 FTLD-TDP cases, including 89 individuals carrying pathogenic mutations in the granulin (GRN) gene, a known cause of familial FTLD-TDP, identified rs1990622, located 6.9 kilobases downstream of the TMEM106B gene (chromosome 7p21) as a genome-wide signal.^[8] Interestingly, this signal was stronger among the GRN mutation carriers than in the other FTLD-TDP samples.

Based on these findings, Cruchaga et al.,,^[9] analyzed if TMEM106B variants modify GRN levels. The found that The risk allele of rs1990622 was associated with a mean decrease of the age at onset of 13 years (P = 9.9 × 10⁻⁷) and with lower plasma GRN levels in both healthy older adults (P = 4 × 10⁻⁴) and GRN mutation carriers (P = 0.0027). Analysis of the HapMap database identified a nonsynonymous single-nucleotide polymorphism rs3173615 (p.T185S) in perfect linkage disequilibrium with rs1990622, that my represent the functional variant driving the association. In summary, these results indicate that the association of rs1990622 with age at onset explains, in part, the wide range in the onset of disease among GRN mutation carriers. The rs1990622 or another variant in linkage disequilibrium could act in a manner similar to APOE in Alzheimer disease, increasing risk for disease in the general population and modifying AAO in mutation carriers. Genetic variation in TMEM106B may influence risk for FTLD-TDP by modulating secreted levels of GRN.

A recent genome-wide association study (GWAS) has found that genetic variations in TMEM106 are associated with late-onset sporadic Alzheimer’s disease (LOAD). These genetic variations change the degradation pathways of misfolded protein contributing misfolded β-amyloid accumulation and plaque formation.^[10]

Mechanism[]

Li et al.,^[11] developed and validated a digital deconvolution algorithm to determine the cell proportions in a bulk RNA-seq experiment . Then, they leveraged this method to identify genes associated with the neuronal proportions in the human cortex.^[12] In this study, Cruchaga (https://neurogenomics.wustl.edu/) and his team s demonstrated that the TMEM106B variants, that are associated with lower Frontotemporal dementia risk are also associated with higher neuronal content. They also demonstrated that this association was independent of disease status and that TMEM106B is a general protective factor for neruodegeneration, which opens the doors to novel therapeutical approaches targeting TMEM106B.

Interactions[]

TMEM106B has been shown to interact with C6orf201.^[13]

References[]

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000106460 - Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000029571 - Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Entrez Gene: TMEM106B transmembrane protein 106B".
^ Schwenk BM, Lang CM, Hogl S, Tahirovic S, Orozco D, Rentzsch K, et al. (March 2014). "The FTLD risk factor TMEM106B and MAP6 control dendritic trafficking of lysosomes". The EMBO Journal. 33 (5): 450–467. doi:10.1002/embj.201385857. PMC 3989627. PMID 24357581.
^ Brady OA, Zheng Y, Murphy K, Huang M, Hu F (February 2013). "The frontotemporal lobar degeneration risk factor, TMEM106B, regulates lysosomal morphology and function". Human Molecular Genetics. 22 (4): 685–695. doi:10.1093/hmg/dds475. PMC 3554197. PMID 23136129.
^ Van Deerlin VM, Sleiman PM, Martinez-Lage M, Chen-Plotkin A, Wang LS, Graff-Radford NR, et al. (March 2010). "Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions". Nature Genetics. 42 (3): 234–239. doi:10.1038/ng.536. PMC 2828525. PMID 20154673.
^ Cruchaga C, Graff C, Chiang HH, Wang J, Hinrichs AL, Spiegel N, et al. (May 2011). "Association of TMEM106B gene polymorphism with age at onset in granulin mutation carriers and plasma granulin protein levels". Archives of Neurology. 68 (5): 581–586. doi:10.1001/archneurol.2010.350. PMC 3090529. PMID 21220649.
^ Wightman DP, Jansen IE, Savage JE, Shadrin AA, Bahrami S, Holland D, et al. (September 2021). "A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer's disease". Nature Genetics. 53 (9): 1276–1282. doi:10.1038/s41588-021-00921-z. PMID 34493870.
^ Li Z, Del-Aguila JL, Dube U, Budde J, Martinez R, Black K, et al. (June 2018). "Genetic variants associated with Alzheimer's disease confer different cerebral cortex cell-type population structure". Genome Medicine. 10 (1): 43. doi:10.1186/s13073-018-0551-4. PMC 5992755. PMID 29880032.
^ Li Z, Farias FH, Dube U, Del-Aguila JL, Mihindukulasuriya KA, Fernandez MV, et al. (January 2020). "The TMEM106B FTLD-protective variant, rs1990621, is also associated with increased neuronal proportion". Acta Neuropathologica. 139 (1): 45–61. doi:10.1007/s00401-019-02066-0. PMC 6942643. PMID 31456032.
^ Rolland T, Taşan M, Charloteaux B, Pevzner SJ, Zhong Q, Sahni N, et al. (November 2014). "A proteome-scale map of the human interactome network". Cell. 159 (5): 1212–1226. doi:10.1016/j.cell.2014.10.050. PMC 4266588. PMID 25416956.