TMEM106B: A Lysosomal Transmembrane Protein in Neurodegeneration and Frontotemporal Dementia
Explore the genetics, expression, mutations, and clinical significance of TMEM106B, a key modifier of neurodegeneration and a risk factor for frontotemporal dementia.
Gene Information Card
| Symbol | TMEM106B |
|---|---|
| Full Name | Transmembrane protein 106B |
| Gene Type | Protein coding |
| Chromosomal Location | 7p21.3 |
| NCBI Gene ID | 54664 ncbi.nlm.nih.gov/gene/54664 |
| Ensembl ID | ENSG00000106460 |
| UniProt ID | Q9NUM4 |
| OMIM ID | 613413 |
| HGNC ID | 22407 |
| Aliases | FLJ11273, MGC33920, T106B |
Description
TMEM106B encodes a type II transmembrane protein localized to the lysosomal membrane. It is involved in lysosomal function, dendritic trafficking, and neuronal survival. TMEM106B is a well-established genetic modifier of frontotemporal dementia (FTD) and has been implicated in the pathogenesis of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. The protein is widely expressed, particularly in the brain, and its dysregulation is associated with altered lysosomal homeostasis and neurodegeneration.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Frontotemporal Dementia (FTD) | TMEM106B risk variants (e.g., rs1990622) are associated with altered TMEM106B expression and lysosomal function, influencing disease risk and progression, particularly in FTD with TDP-43 pathology. | Genome-wide association studies (GWAS) and functional studies (e.g., van Blitterswijk et al., 2014; Nicholson et al., 2013) support the role of TMEM106B as a risk factor and disease modifier. |
| Amyotrophic Lateral Sclerosis (ALS) | TMEM106B variants may modify ALS risk and survival, possibly through effects on lysosomal function and TDP-43 pathology. | Genetic association studies (e.g., van Blitterswijk et al., 2014) and meta-analyses have shown TMEM106B SNPs associated with ALS. |
| Alzheimer's Disease (AD) | TMEM106B is implicated in AD through its role in lysosomal function and amyloid clearance; risk variants may influence AD pathology. | Studies have shown TMEM106B expression changes in AD brains and genetic associations in some cohorts (e.g., Rutherford et al., 2012). |
| Hippocampal Sclerosis of Aging (HS-Aging) | TMEM106B risk variants are associated with increased risk of HS-Aging, a common pathology in elderly with dementia. | Genetic studies (e.g., Aoki et al., 2015) identified TMEM106B as a risk locus for HS-Aging. |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain (cerebral cortex) | High (e.g., ~20-30 nTPM) | High expression in neurons and glia |
| Lung | Moderate (e.g., ~10-15 nTPM) | Expressed in alveolar cells |
| Kidney | Moderate (e.g., ~8-12 nTPM) | Expressed in tubular cells |
| Liver | Low (e.g., ~3-5 nTPM) | Low expression |
| Heart | Low (e.g., ~2-4 nTPM) | Low expression |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| SH-SY5Y (neuroblastoma) | High (e.g., ~25 nTPM) | Neuronal-like cell line |
| U-87 MG (glioblastoma) | Moderate (e.g., ~15 nTPM) | Glial cell line |
| HepG2 (hepatocellular carcinoma) | Low (e.g., ~5 nTPM) | Liver cell line |
| A549 (lung carcinoma) | Moderate (e.g., ~10 nTPM) | Lung epithelial cell line |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| rs1990622 (C/T) | SNP (intronic) | Risk allele frequency ~0.3-0.4 in Europeans | Risk allele associated with increased TMEM106B expression and increased FTD risk |
| rs3173615 (p.Thr185Ser) | Missense | Minor allele frequency ~0.2 | May affect protein stability or function; associated with altered FTD risk |
| rs6966915 (C/T) | SNP (intronic) | Risk allele frequency ~0.3 | Associated with FTD risk and TMEM106B expression levels |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations in TMEM106B are rare and not well characterized; complete loss may impair lysosomal function, but no clear pathogenic loss-of-function variants have been reported in human disease.
Gain of Function (GOF)
Risk alleles (e.g., rs1990622) are associated with increased TMEM106B expression, suggesting a gain-of-function effect that may disrupt lysosomal trafficking and contribute to neurodegeneration.
Dominant Negative (DN)
No evidence for dominant-negative effects of TMEM106B mutations; the protein functions as a homodimer, but pathogenic dominant-negative variants have not been identified.
View complete mutation data：
Gene Ontology (GO)
| • lysosomal membrane | • integral component of membrane |
| • protein homodimerization activity | • regulation of lysosomal pH |
| • dendrite morphogenesis | • neuron projection development |
| • response to endoplasmic reticulum stress |
Pathways
• Lysosome function and biogenesis
• Endosomal-lysosomal trafficking
• Neurodegeneration pathways (e.g.
• TDP-43 proteinopathy)
Protein Summary
TMEM106B is a 274-amino acid type II transmembrane protein with a C-terminal lysosomal targeting motif. It localizes primarily to the lysosomal membrane and is involved in maintaining lysosomal pH, trafficking, and proteostasis. The protein forms homodimers and interacts with other lysosomal proteins. TMEM106B is highly expressed in the brain and is critical for neuronal health. Its expression is regulated by genetic variants that influence disease susceptibility. Dysregulation of TMEM106B leads to lysosomal dysfunction, impaired clearance of protein aggregates, and neurodegeneration.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| TMEM106B Knockout HEK293 Cell Line | EDJ-KQ10810 | Human | 54664 | Details Get a Quote |
| TMEM106B Knockout HeLa Cell Line | EDJ-KQ18248 | Human | 54664 | Details Get a Quote |
| TMEM106B Knockout A-549 Cell Line | EDJ-KQ39799 | Human | 54664 | Details Get a Quote |
| TMEM106B Knockout HCT 116 Cell Line | EDJ-KQ39801 | Human | 54664 | Details Get a Quote |
