TMEM106B

Summary

TMEM106B (transmembrane protein 106B, HGNC:22407) is a protein-coding gene on chromosome 7p21.3, encoding Transmembrane protein 106B (Q9NUM4). In neurons, involved in the transport of late endosomes/lysosomes.

Enables ATPase binding activity. Involved in dendrite morphogenesis and lysosome localization. Located in endosome and lysosomal membrane. Implicated in hypomyelinating leukodystrophy 16.

Source: NCBI Gene 54664 — RefSeq curated summary.

At a glance

• Gene–disease (curated): leukodystrophy, hypomyelinating, 16 (Definitive, ClinGen)
• GWAS associations: 32
• Clinical variants (ClinVar): 142 total — 1 pathogenic
• Phenotypes (HPO): 96
• MANE Select transcript: NM_001134232

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:22407
Approved symbol	TMEM106B
Name	transmembrane protein 106B
Location	7p21.3
Locus type	gene with protein product
Status	Approved
Aliases	MGC33727, FLJ11273
Ensembl gene	ENSG00000106460
Ensembl biotype	protein_coding
OMIM	613413
Entrez	54664

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 15 protein_coding, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000396667, ENST00000396668, ENST00000420833, ENST00000442107, ENST00000444443, ENST00000453686, ENST00000462754, ENST00000492762, ENST00000704347, ENST00000704348, ENST00000704349, ENST00000704382, ENST00000704416, ENST00000704417, ENST00000704455, ENST00000704457, ENST00000903750, ENST00000903751, ENST00000965695, ENST00000965696, ENST00000965697

RefSeq mRNA: 2 — MANE Select: NM_001134232 NM_001134232, NM_018374

CCDS: CCDS5358

Canonical transcript exons

ENST00000396668 — 8 exons

Exon	Start	End
ENSE00001525875	12231837	12243367
ENSE00003482968	12218458	12218521
ENSE00003558198	12230389	12230438
ENSE00003605469	12224226	12224385
ENSE00003644805	12229679	12229819
ENSE00003672101	12231062	12231115
ENSE00003703816	12214809	12215027
ENSE00003991563	12211294	12211425

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 98.84.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 38.6617 / max 334.0271, expressed in 1806 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
77271	20.3179	1786
77270	18.3439	1782

Top tissues by expression

288 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
caput epididymis	UBERON:0004358	98.84	gold quality
corpus epididymis	UBERON:0004359	98.84	gold quality
cauda epididymis	UBERON:0004360	98.84	gold quality
adrenal tissue	UBERON:0018303	97.74	gold quality
pigmented layer of retina	UBERON:0001782	97.71	gold quality
superior vestibular nucleus	UBERON:0007227	97.45	gold quality
medial globus pallidus	UBERON:0002477	97.36	gold quality
globus pallidus	UBERON:0001875	97.29	gold quality
subthalamic nucleus	UBERON:0001906	97.26	gold quality
cerebellar vermis	UBERON:0004720	97.11	gold quality
seminal vesicle	UBERON:0000998	97.00	gold quality
palpebral conjunctiva	UBERON:0001812	96.91	gold quality
postcentral gyrus	UBERON:0002581	96.89	gold quality
parietal lobe	UBERON:0001872	96.87	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	96.87	gold quality
upper leg skin	UBERON:0004262	96.78	gold quality
inferior vagus X ganglion	UBERON:0005363	96.72	gold quality
lateral globus pallidus	UBERON:0002476	96.67	gold quality
renal medulla	UBERON:0000362	96.66	gold quality
entorhinal cortex	UBERON:0002728	96.49	gold quality
substantia nigra pars reticulata	UBERON:0001966	96.48	gold quality
substantia nigra pars compacta	UBERON:0001965	96.44	gold quality
lateral nuclear group of thalamus	UBERON:0002736	96.36	gold quality
trigeminal ganglion	UBERON:0001675	96.32	gold quality
tibia	UBERON:0000979	96.22	gold quality
dorsal root ganglion	UBERON:0000044	96.13	gold quality
pons	UBERON:0000988	96.08	gold quality
mucosa of paranasal sinus	UBERON:0005030	96.02	gold quality
ventral tegmental area	UBERON:0002691	95.93	gold quality
parotid gland	UBERON:0001831	95.92	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-10	yes	19.08
E-CURD-10	no	681.21
E-CURD-112	no	3.26
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

261 targeting TMEM106B, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-548N	99.98	71.94	4170

Literature-anchored findings (GeneRIF, showing 40)

• Variants in TMEM106B are strong risk factors for frontotemporal lobar degeneration with TDP-43 inculsions. (PMID:20154673)
• The genome-wide association study revealed a strong association between FTLD-TDP and several single nucleotide polymorphisms (SNPs) that mapped in the region of the TMEM106B gene (PMID:20383883)
• FTLD-TDP risk gene TMEM106B is involved in the development of cognitive impairment in amyotrophic lateral sclerosis. (PMID:21104415)
• Our results suggest that genetic variation in TMEM106B (rs1990622) may influence risk for frontotemporal lobar degeneration with TAR DNA-binding protein inclusions (FTLD-TDP) by modulating secreted levels of GRN. (PMID:21220649)
• This study strongly supported TMEM106B as a risk gene for frontotemporal lobar degeneration. (PMID:21354975)
• Endogenous as well as overexpressed TMEM106B localizes to late endosomes and lysosomes. Interestingly, the inhibition of vacuolar H(+)-ATPases significantly increased the levels of TMEM106B. (PMID:22511793)
• Our data implicate TMEM106B in the pathological presentation of Alzheimer Disease. (PMID:22855871)
• This study demonistrated that aberrant overexpression of TMEM106B affects the distribution and intracellular levels of progranulin, suggesting that the two proteins may act in the same pathogenic pathway in FTLD-TDP. (PMID:22895706)
• TMEM106B is localized in the late endosome/lysosome compartments and TMEM106B levels are regulated by lysosomal activities. (PMID:23136129)
• These findings suggest that low TMEM106B levels might protect against frontotemporal lobar degeneration TAR DNA binding protein 43 in these patients (PMID:23742080)
• This study demonstrate that TMEM106B and APOE interact to increase late-onset Alzheimer’s disease in Han Chinese. (PMID:24166182)
• Data provide an initial neuropathological characterization of the newly discovered frontotemporal lobar degeneration-associated protein TMEM106B (PMID:24252750)
• TMEM106B polymorphism modulates brain connectivity in granulin mutation carriers. (PMID:24343233)
• These data show that TMEM106B/MAP6 interaction is crucial for controlling dendritic trafficking of lysosomes, presumably by acting as a molecular brake for retrograde transport. (PMID:24357581)
• Study identifies TMEM106B as the first genetic factor modifying disease presentation in C9ORF72 expansion carriers (PMID:24385136)
• Study demonstrates that TMEM106B is the first reported genetic modifier in C9orf72 expansion-related frontotemporal lobar degeneration (PMID:24442578)
• results show that, in nondemented persons, TMEM106B influences the volume of temporal brain regions that are important for language processing. (PMID:24731779)
• Regulated intramembrane proteolysis of the frontotemporal lobar degeneration risk factor, TMEM106B, by signal peptide peptidase-like 2a (SPPL2a). (PMID:24872421)
• The HpScl groups (Hippocampual Sclerosis and Hippocampual Sclerosis-AD) were more likely to exhibit genetic variants in TMEM106B that are associated with frontotemporal lobar degeneration. (PMID:24899141)
• Neuronal TMEM106B plays a central role in regulating lysosomal size, motility and responsiveness to stress, highlighting the possible role of lysosomal biology in FTLD-TDP. (PMID:25066864)
• It is a risk factor for frontotemporal lobar degeneration. (PMID:25085782)
• Study suggests that TMEM106B is associated with frontotemporal dementia, although the extent of this effect is difficult to be estimated by using clinical frontotemporal dementia series (PMID:25096617)
• TMEM106b variability does not influence Alzheimer disease risk or plasma progranulin levels. (PMID:25114081)
• This study confirmed that specific TMEM106B single-nucleotide polymorphisms is associated with HS-Aging pathology in the Alzheimer disease. (PMID:25470345)
• Common variants in TMEM106B serve as a distinct risk factor for TDP-43 pathology in older persons without frontotemporal lobe dementia. (PMID:25653292)
• Endogenous TMEM106B was partly sequestered in CHMP2B-positive structures. The roles of SNPs T185, S185, or S134N in endosomal sorting complexes required for transport were studied. T185 is a risk factor in neurodegeneration with endolysosomal defects. (PMID:26651479)
• This review revealed TMEM106B variants as significant contributors to one’s risk of developing various TDP-43 proteinopathies, both in patients harboring disease-causing mutations and in subjects with TDP-43 pathology of unknown cause. (PMID:27543298)
• These findings suggest that the up-regulation of TMEM106B may increase the risk of frontotemporal lobar degeneration by directly causing neurotoxicity and a pathological phenotype linked to FTLD-TDP. (PMID:27563066)
• Study developed a TMEM106B transgenic mouse model that recapitulates the interaction between progranulin and TMEM106B in human patients and supports a regulation of TMEM106B by progranulin in the aged brain and a role of TMEM106B in frontotemporal lobar degeneration-progranulin disease progression. (PMID:28126008)
• Genetic variation within TMEM106B is associated with aging phenotypes. (PMID:28330615)
• we expanded our understanding of the TMEM106B haplotype that is protective against TDP-43 proteinopathy. (PMID:28441426)
• Homozygosity for the TMEM106B risk allele is associated with reduced grey matter volume in key cortical regions implicated in frontotemporal dementia. (PMID:28446602)
• TMEM106B enhances the benefit of cognitive reserve on brain structure in fronto-temporal dementia. (PMID:28460069)
• This study demonstrated that in Chinese patient minor alleles of rs1990622 and rs3173615 in TMEM106B may be associated with PD patients with initial symptom of rigidity/bradykinesia. (PMID:28477711)
• Single-nucleotide polymorphisms in the TMEM106B gene have been identified as a risk factor in frontotemporal dementia (FTD). (PMID:28888721)
• A common causal variant underlying both association with disease and association with TMEM106B expression in lymphoblastoid cell lines. (PMID:29056226)
• Four unrelated patients with brain hypomyelination were identified with the same recurrent dominant mutation in TMEM106B. (PMID:29186371)
• These findings illustrate the profound effect of TMEM106B haplotypes on brain health and highlight the importance to better understand TMEM106B’s function and dysfunction in the context of neurodegenerative diseases. (PMID:29970152)
• TMEM106B drives lung cancer metastasis by inducing TFEB-dependent lysosome synthesis and secretion of cathepsins. (PMID:30013069)
• TMEM106B is a risk factor for frontotemporal lobar degeneration and aging; its intrinsic disorder may allow the TMEM106B cytoplasmic domain to dynamically and transiently interact with a variety of distinct partners (PMID:30332472)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmem106bb	ENSDARG00000035949
mus_musculus	Tmem106b	ENSMUSG00000029571
rattus_norvegicus	Tmem106b	ENSRNOG00000006206

Protein

Protein identifiers

Transmembrane protein 106B — Q9NUM4 (reviewed: Q9NUM4)

All UniProt accessions (9): Q9NUM4, A0A994J4C4, A0A994J4F8, A0A994J4M3, A0A994J517, A0A994J7D5, C9J998, C9JZ87, F2Z3N7

UniProt curated annotations — full annotation on UniProt →

Function. In neurons, involved in the transport of late endosomes/lysosomes. May be involved in dendrite morphogenesis and maintenance by regulating lysosomal trafficking. May act as a molecular brake for retrograde transport of late endosomes/lysosomes, possibly via its interaction with MAP6. In motoneurons, may mediate the axonal transport of lysosomes and axonal sorting at the initial segment. It remains unclear whether TMEM106B affects the transport of moving lysosomes in the anterograde or retrograde direction in neurites and whether it is important in the sorting of lysosomes in axons or in dendrites. In neurons, may also play a role in the regulation of lysosomal size and responsiveness to stress. Required for proper lysosomal acidification. (Microbial infection) Plays a role in human coronavirus SARS-CoV-2 infection, but not in common cold coronaviruses HCoV-229E and HCoV-OC43 infections. Involved in ACE2-independent SARS-CoV-2 cell entry. Required for post-endocytic stage of virus entry, facilitates spike-mediated membrane fusion. Virus attachment and endocytosis can also be mediated by other cell surface receptors.

Subunit / interactions. Can form homomers. Interacts (via N-terminus) with MAP6 (via C-terminus). Interacts (via C-terminus) with the vacuolar-type ATPase subunit ATP6AP1. Interacts (via N-terminus) with AP2M1 and CLTC. Interacts with TMEM106C. (Microbial infection) Interacts with SARS coronavirus-2/SARS-CoV-2 spike protein (via RBD domain).

Subcellular location. Late endosome membrane. Lysosome membrane. Cell membrane.

Tissue specificity. Expressed in the brain, including in the frontal cortex (at protein level). Expressed in lung epithelial cells.

Disease relevance. Frontotemporal dementia 2 (FTD2) [MIM:607485] A form of dementia characterized by pathologic finding of frontotemporal lobar degeneration, presenile dementia with behavioral changes, deterioration of cognitive capacities and loss of memory. Gestural apraxia, parkinsonism, visual loss, and visual hallucinations are present in 25 to 40% of patients. The gene represented in this entry may act as a disease modifier. Risk alleles confer genetic susceptibility by increasing gene expression. Increased expression may be the result of down-regulation of microRNA miR-132 and miR-212, that repress TMEM106B expression. Thr-185 is a risk allele associated with lower GRN protein levels and early age at onset in GRN FTD2 mutation carriers: it presents slower protein degradation that leads to higher steady-state TMEM106B levels, leading to alterations in the intracellular versus extracellular partitioning of GRN. Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 (FTDALS1) [MIM:105550] An autosomal dominant neurodegenerative disorder characterized by adult onset of frontotemporal dementia and/or amyotrophic lateral sclerosis in an affected individual. There is high intrafamilial variation. Frontotemporal dementia is characterized by frontal and temporal lobe atrophy associated with neuronal loss, gliosis, and dementia. Patients exhibit progressive changes in social, behavioral, and/or language function. Amyotrophic lateral sclerosis is characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. The gene represented in this entry acts as a disease modifier. Leukodystrophy, hypomyelinating, 16 (HLD16) [MIM:617964] An autosomal dominant disorder characterized by hypomyelination, leukodystrophy, and thin corpus callosum observed on brain imaging. Clinical features include hypotonia, nystagmus, and mildly delayed motor development with onset in infancy, ataxic or broad-based gait, hyperreflexia, intention tremor, dysmetria, and a mild pyramidal syndrome. Some patients have cognitive impairment, whereas others may have normal cognition or mild intellectual disability with speech difficulties. The disease may be caused by variants affecting the gene represented in this entry. A TMEM106B truncated C-terminal fragment (residues 120 through 254) was found to aggregate into stable amyloid fibrils in the brain of patients suffering from diverse genetic and sporadic tauopathies, amyloid-beta amyloidoses, synucleinopathies and TDP-43 proteinopathies. It is currently unclear whether TMEM106B fibrils are associated with a pathogenic process or represents a non-specific secondary phenomenon, a general downstream marker of lysosomal stress for instance. TMEM106B amyloid filaments form in an age-dependent manner in human brains, however fibrillization of TMEM106B seems substantially greater in patients with known neurodegeneration compared to age-matched unaffected individuals.

Similarity. Belongs to the TMEM106 family.

RefSeq proteins (2): NP_001127704, NP_060844 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009790	TMEM106	Family
IPR048509	TMEM106_C	Domain
IPR048511	TMEM106_N	Domain

Pfam: PF07092, PF21002

UniProt features (36 total): strand 10, glycosylation site 5, mutagenesis site 3, sequence conflict 3, sequence variant 2, topological domain 2, helix 2, initiator methionine 1, chain 1, disulfide bond 1, turn 1, transmembrane region 1, region of interest 1, compositionally biased region 1, modified residue 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

29 structures.

PDB	Method	Resolution (Å)
8B7D	X-RAY DIFFRACTION	2.59
8OTD	ELECTRON MICROSCOPY	2.6
7QVC	ELECTRON MICROSCOPY	2.64
9FNB	ELECTRON MICROSCOPY	2.64
7U16	ELECTRON MICROSCOPY	2.7
7U18	ELECTRON MICROSCOPY	2.7
7QWM	ELECTRON MICROSCOPY	2.76
7SAQ	ELECTRON MICROSCOPY	2.9
7U13	ELECTRON MICROSCOPY	2.9
7U10	ELECTRON MICROSCOPY	3
7U15	ELECTRON MICROSCOPY	3
7U17	ELECTRON MICROSCOPY	3
7X84	ELECTRON MICROSCOPY	3
8J7N	ELECTRON MICROSCOPY	3
7SAR	ELECTRON MICROSCOPY	3.2
7U11	ELECTRON MICROSCOPY	3.2
7TMC	ELECTRON MICROSCOPY	3.25
7QWG	ELECTRON MICROSCOPY	3.38
7X83	ELECTRON MICROSCOPY	3.4
8F9K	ELECTRON MICROSCOPY	3.4
8J7P	ELECTRON MICROSCOPY	3.4
7QWL	ELECTRON MICROSCOPY	3.47
8X5H	ELECTRON MICROSCOPY	3.47
7U12	ELECTRON MICROSCOPY	3.5
8OTE	ELECTRON MICROSCOPY	3.6
7QVF	ELECTRON MICROSCOPY	3.64
7SAS	ELECTRON MICROSCOPY	3.7
7U14	ELECTRON MICROSCOPY	4.5
9GI8	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NUM4-F1	76.05	0.57

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (2): 33, 2

Disulfide bonds (1): 214–253

Glycosylation sites (5): 151, 164, 183, 256, 145

Mutagenesis-validated functional residues (3):

Position	Phenotype
210–213	highly decreased number of infected cells by sars-cov-2. no effect on infection with hcov-229e.
210	decreased number of infected cells by sars-cov-2. no effect on infection with hcov-229e.
213	decreased number of infected cells by sars-cov-2. no effect on infection with hcov-229e.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 371 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_DN, GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, GOBP_DENDRITE_DEVELOPMENT, HORIUCHI_WTAP_TARGETS_DN, GOBP_LYSOSOMAL_TRANSPORT, GOBP_VACUOLE_ORGANIZATION, GCM_GSPT1, GOCC_VACUOLAR_MEMBRANE, SHEPARD_CRASH_AND_BURN_MUTANT_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_VACUOLAR_TRANSPORT, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_VACUOLE_ORGANIZATION, CHANDRAN_METASTASIS_DN

GO Biological Process (9): lysosome organization (GO:0007040), lysosomal transport (GO:0007041), lysosomal lumen acidification (GO:0007042), lysosome localization (GO:0032418), dendrite morphogenesis (GO:0048813), neuron cellular homeostasis (GO:0070050), positive regulation of dendrite development (GO:1900006), lysosomal protein catabolic process (GO:1905146), regulation of lysosome organization (GO:1905671)

GO Molecular Function (2): ATPase binding (GO:0051117), protein binding (GO:0005515)

GO Cellular Component (6): lysosome (GO:0005764), lysosomal membrane (GO:0005765), endosome (GO:0005768), plasma membrane (GO:0005886), late endosome membrane (GO:0031902), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
dendrite development	2
lysosome	2
lytic vacuole organization	1
vacuolar transport	1
vacuolar acidification	1
vacuolar localization	1
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
cellular homeostasis	1
positive regulation of neuron projection development	1
regulation of dendrite development	1
positive regulation of developmental process	1
protein catabolic process in the vacuole	1
lysosome organization	1
regulation of vacuole organization	1
enzyme binding	1
binding	1
lytic vacuole	1
lytic vacuole membrane	1
endomembrane system	1
cytoplasmic vesicle	1
membrane	1
cell periphery	1
late endosome	1
endosome membrane	1
cellular anatomical structure	1

Protein interactions and networks

STRING

990 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMEM106B	TARDBP	Q13148	935
TMEM106B	GRN	P23781	907
TMEM106B	MAP6	Q96JE9	784
TMEM106B	C9orf72	Q96LT7	754
TMEM106B	MAPT	P10636	750
TMEM106B	CHMP2B	Q9UQN3	709
TMEM106B	APOE	P02649	594
TMEM106B	ROS1	P08922	568
TMEM106B	SORT1	Q99523	565
TMEM106B	VCP	P55072	546
TMEM106B	ABCC9	O60706	517
TMEM106B	PSAP	P07292	516
TMEM106B	LRIG3	Q6UXM1	509
TMEM106B	KDELR2	P33947	507
TMEM106B	TPD52L1	Q16890	506

IntAct

82 interactions, top by confidence:

A	B	Type	Score
TMEM106B	TMEM106C	psi-mi:“MI:0915”(physical association)	0.670
TRDN	TMEM223	psi-mi:“MI:0914”(association)	0.640
B3GAT3	GOLIM4	psi-mi:“MI:0914”(association)	0.640
SLC17A5	LGALS8	psi-mi:“MI:0914”(association)	0.640
SLC39A5	FAM171A2	psi-mi:“MI:0914”(association)	0.640
CANX	PGRMC1	psi-mi:“MI:0914”(association)	0.570
HTT	TMEM106B	psi-mi:“MI:0915”(physical association)	0.560
SLC39A4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
GPRC5B	STXBP3	psi-mi:“MI:0914”(association)	0.530
TMEM106A	B4GALT3	psi-mi:“MI:0914”(association)	0.530
SLC15A4	PGRMC1	psi-mi:“MI:0914”(association)	0.530
TGOLN2	PGRMC1	psi-mi:“MI:0914”(association)	0.420
C6orf201	TMEM106B	psi-mi:“MI:0915”(physical association)	0.400
	TMEM106B	psi-mi:“MI:0915”(physical association)	0.400
TMEM106B		psi-mi:“MI:0915”(physical association)	0.370
LAMP1	HAX1	psi-mi:“MI:0914”(association)	0.350
BTNL8	TMEM131L	psi-mi:“MI:0914”(association)	0.350
incE	STX7	psi-mi:“MI:0914”(association)	0.350
NTRK3	ILVBL	psi-mi:“MI:0914”(association)	0.350
STYK1	MYO1C	psi-mi:“MI:0914”(association)	0.350
TYRO3	HAX1	psi-mi:“MI:0914”(association)	0.350
Npc1	ESYT2	psi-mi:“MI:0914”(association)	0.350
TMEM106B	STX7	psi-mi:“MI:0914”(association)	0.350
TMEM106A	QSOX1	psi-mi:“MI:0914”(association)	0.350
LMAN2L	PTGS2	psi-mi:“MI:0914”(association)	0.350

BioGRID (377): TMEM106B (Affinity Capture-MS), CHMP2B (Affinity Capture-Western), CHMP2B (Co-localization), TMEM106B (Affinity Capture-MS), TMEM106B (Affinity Capture-MS), TMEM106B (Proximity Label-MS), TMEM106B (Affinity Capture-MS), TMEM106B (Affinity Capture-MS), TMEM106B (Affinity Capture-MS), TMEM106B (Synthetic Lethality), TMEM106B (Co-fractionation), TMEM106C (Two-hybrid), TMEM106B (Proximity Label-MS), TMEM106B (Proximity Label-MS), TMEM106B (Proximity Label-MS)

ESM2 similar proteins: A0JM23, A6NFN9, D5K8A9, F1LW30, P38551, P40200, Q08AW4, Q14956, Q1LWC2, Q29RU0, Q3SXY7, Q3T144, Q3ZC25, Q504C1, Q566M8, Q5BK83, Q5DTZ6, Q5EA90, Q5RF74, Q5RJK0, Q6AYA5, Q6GMZ9, Q6NRX0, Q6P4S2, Q6P7C7, Q6UXZ4, Q6Y290, Q7T2L7, Q7TNJ4, Q80VP8, Q80X71, Q80ZD9, Q86XS8, Q8K1S2, Q8N8Z6, Q8QHJ9, Q8TEB7, Q8VC04, Q8VEM1, Q90372

Diamond homologs: Q1LWC2, Q3T144, Q3ZC25, Q5BK83, Q5EA90, Q5RJK0, Q6AYA5, Q80VP8, Q80X71, Q8VC04, Q96A25, Q9BVX2, Q9NUM4

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 98 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Metal ion SLC transporters	7	61.0×	4e-09
SLC-mediated transmembrane transport	9	7.7×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
zinc ion transmembrane transport	7	57.1×	2e-08
intracellular zinc ion homeostasis	7	39.2×	2e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

142 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	73
Likely benign	33
Benign	12

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3772686	NM_001134232.2(TMEM106B):c.754G>C (p.Asp252His)	Pathogenic

SpliceAI

1162 predictions. Top by Δscore:

Variant	Effect	Δscore
7:12212782:A:T	donor_gain	1.0000
7:12214807:A:AG	acceptor_gain	1.0000
7:12214808:G:GG	acceptor_gain	1.0000
7:12214842:A:AG	acceptor_gain	1.0000
7:12214974:G:GT	donor_gain	1.0000
7:12215013:G:GT	donor_gain	1.0000
7:12215024:AGGGG:A	donor_loss	1.0000
7:12215025:GGG:G	donor_gain	1.0000
7:12215026:GG:G	donor_gain	1.0000
7:12215026:GGGTA:G	donor_gain	1.0000
7:12215027:GG:G	donor_gain	1.0000
7:12215028:G:GC	donor_loss	1.0000
7:12215028:G:GG	donor_gain	1.0000
7:12224225:GAAA:G	acceptor_gain	1.0000
7:12224386:G:GG	donor_gain	1.0000
7:12229673:TTGTA:T	acceptor_loss	1.0000
7:12229674:TGTAG:T	acceptor_loss	1.0000
7:12229675:GTAG:G	acceptor_loss	1.0000
7:12229676:TAGAA:T	acceptor_loss	1.0000
7:12229677:A:AG	acceptor_gain	1.0000
7:12229677:A:T	acceptor_loss	1.0000
7:12229678:G:GG	acceptor_gain	1.0000
7:12229678:GA:G	acceptor_gain	1.0000
7:12229678:GAA:G	acceptor_gain	1.0000
7:12229678:GAAC:G	acceptor_gain	1.0000
7:12229678:GAACA:G	acceptor_gain	1.0000
7:12229820:G:GG	donor_gain	1.0000
7:12230422:GAAA:G	donor_gain	1.0000
7:12230436:GTA:G	donor_gain	1.0000
7:12230439:G:GG	donor_gain	1.0000

AlphaMissense

1800 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:12214967:T:C	F53L	1.000
7:12214968:T:C	F53S	1.000
7:12214969:T:A	F53L	1.000
7:12214969:T:G	F53L	1.000
7:12214991:T:A	C61S	1.000
7:12214991:T:C	C61R	1.000
7:12214992:G:A	C61Y	1.000
7:12214992:G:C	C61S	1.000
7:12214993:C:G	C61W	1.000
7:12215000:T:A	C64S	1.000
7:12215000:T:C	C64R	1.000
7:12215001:G:A	C64Y	1.000
7:12215001:G:C	C64S	1.000
7:12215001:G:T	C64F	1.000
7:12215002:T:G	C64W	1.000
7:12215006:G:A	G66R	1.000
7:12215006:G:C	G66R	1.000
7:12215007:G:A	G66E	1.000
7:12215013:G:A	G68E	1.000
7:12218473:T:A	L78Q	1.000
7:12218473:T:C	L78P	1.000
7:12218482:T:C	L81S	1.000
7:12218485:T:A	I82N	1.000
7:12218485:T:C	I82T	1.000
7:12218485:T:G	I82S	1.000
7:12218496:G:C	D86H	1.000
7:12218497:A:C	D86A	1.000
7:12218497:A:G	D86G	1.000
7:12218497:A:T	D86V	1.000
7:12218504:A:C	R88S	1.000

dbSNP variants (sampled 300 via entrez): RS1000027806 (7:12216710 A>C), RS1000055928 (7:12237472 C>G,T), RS1000068433 (7:12226798 A>G,T), RS1000072925 (7:12242867 T>A,C), RS1000085553 (7:12222785 T>C), RS1000199808 (7:12222506 G>A), RS1000238352 (7:12209394 G>T), RS1000288585 (7:12232671 A>G,T), RS1000344972 (7:12237680 TA>T,TAA), RS1000347070 (7:12213063 G>C), RS1000509923 (7:12238805 T>A,C), RS1000665796 (7:12228048 C>G), RS1000754556 (7:12218530 T>G), RS1000790810 (7:12226728 T>C), RS1000932194 (7:12218110 C>T)

Disease associations

OMIM: gene MIM:613413 | disease phenotypes: MIM:617964

GenCC curated gene-disease

Disease	Classification	Inheritance
leukodystrophy, hypomyelinating, 16	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
leukodystrophy, hypomyelinating, 16	Definitive	AD

Mondo (2): leukodystrophy, hypomyelinating, 16 (MONDO:0054791), vascular dementia (MONDO:0004648)

Orphanet (0):

HPO phenotypes

96 total (30 of 96 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000474	Thickened nuchal skin fold
HP:0000543	Optic disc pallor
HP:0000639	Nystagmus
HP:0000640	Gaze-evoked nystagmus
HP:0000666	Horizontal nystagmus
HP:0000708	Atypical behavior
HP:0000709	Psychosis
HP:0000710	Hyperorality
HP:0000711	Restlessness
HP:0000716	Depression
HP:0000718	Aggressive behavior
HP:0000719	Inappropriate behavior
HP:0000723	Restrictive behavior
HP:0000726	Dementia
HP:0000733	Motor stereotypy
HP:0000734	Disinhibition
HP:0000737	Irritability
HP:0000739	Anxiety
HP:0000741	Apathy
HP:0000750	Delayed speech and language development
HP:0000751	Personality changes
HP:0000757	Lack of insight
HP:0001152	Saccadic smooth pursuit interruptions
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001266	Choreoathetosis

GWAS associations

32 associations (top):

Study	Trait	p-value
GCST001635_7	Tourette syndrome	6.000000e-06
GCST001651_48	Response to amphetamines	7.000000e-06
GCST001694_3	Response to taxane treatment (paclitaxel)	6.000000e-06
GCST001994_3	Adverse response to chemotherapy (neutropenia/leucopenia) (all topoisomerase inhibitors)	4.000000e-06
GCST002814_1	Alzheimer’s disease (APOE e4 interaction)	4.000000e-06
GCST004291_4	Residual cognition	9.000000e-06
GCST005195_52	Coronary artery disease	3.000000e-08
GCST005196_144	Coronary artery disease	3.000000e-08
GCST005232_30	Neuroticism	6.000000e-09
GCST005342_2	Plasma kynurenine levels in major depressive disorder	4.000000e-06
GCST005588_33	Idiopathic dilated cardiomyopathy	7.000000e-07
GCST005839_11	Depression	3.000000e-08
GCST006148_4	Frontotemporal dementia with GRN mutation	2.000000e-14
GCST006154_1	Frontotemporal dementia	4.000000e-16
GCST006585_956	Blood protein levels	6.000000e-27
GCST006611_150	HDL cholesterol	2.000000e-09
GCST006613_88	Triglycerides	7.000000e-09
GCST006940_106	Neurociticism	9.000000e-11
GCST006944_6	Experiencing mood swings	4.000000e-11
GCST007709_27	General factor of neuroticism	1.000000e-08
GCST008795_1	Differential aging in older adults (frontal cortex)	3.000000e-23
GCST008800_1	Differential aging (frontal cortex)	2.000000e-19
GCST009575_5	Lifetime anxiety disorder	5.000000e-08
GCST010241_311	Apolipoprotein A1 levels	2.000000e-08
GCST010242_362	HDL cholesterol levels	1.000000e-10
GCST010577_22	Crohn’s disease	8.000000e-06
GCST010866_121	Coronary artery disease	3.000000e-08
GCST011365_134	Myocardial infarction	1.000000e-06
GCST012180_5	Cigarettes smoked per day in Schizophrenia	3.000000e-08
GCST012355_40	Depression	3.000000e-22

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0007659	APOE carrier status
EFO:0003925	cognition
EFO:0022597	aging
EFO:0007660	neuroticism measurement
EFO:0008529	kynurenine measurement
EFO:0009094	idiopathic dilated cardiomyopathy
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004530	triglyceride measurement
EFO:0008475	mood instability measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0006525	cigarettes per day measurement
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D015140	Dementia, Vascular	C10.228.140.300.400; C10.228.140.300.510.800.500; C10.228.140.380.230; C10.228.140.695.500; C14.907.137.126.372.500; C14.907.253.560.350.500; F03.615.400.350

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

51 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, affects cotreatment, decreases expression	7
Tretinoin	increases expression, decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
titanium dioxide	affects expression	1
trichostatin A	decreases expression	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
butyraldehyde	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
beta-methylcholine	affects expression	1
tebuconazole	increases expression	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
nutlin 3	affects cotreatment, increases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	decreases expression	1
NSC 689534	affects binding, increases expression	1
Vorinostat	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Caffeine	decreases phosphorylation	1
Calcitriol	increases expression, affects cotreatment	1
Clorgyline	increases expression	1
Copper	affects binding, increases expression	1
Coumestrol	decreases expression	1

Cellosaurus cell lines

6 cell lines: 5 cancer cell line, 1 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2QM	Abcam A-549 TMEM106B KO	Cancer cell line	Male
CVCL_E0R5	Ubigene HeLa TMEM106B KO	Cancer cell line	Female
CVCL_E4Q0	KOLF2.1J TMEM106B 17.7kbdel DEL/DEL	Induced pluripotent stem cell	Male
CVCL_TS75	HAP1 TMEM106B (-) 1	Cancer cell line	Male
CVCL_XU37	HAP1 TMEM106B (-) 2	Cancer cell line	Male
CVCL_XU38	HAP1 TMEM106B (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

88 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00165763	PHASE4	COMPLETED	Efficacy and Safety of Donepezil Hydrochloride (Aricept) in Vascular Dementia
NCT00847860	PHASE4	COMPLETED	Cilostazol Verse Asprin for Vascular Dementia in Poststroke Patients With White Matter Lesions
NCT00947531	PHASE4	COMPLETED	A Clinical Trial to Evaluate the Safety and Efficacy of 20 ml Cerebrolysin in Patients With Vascular Dementia
NCT00950430	PHASE4	ENROLLING_BY_INVITATION	Imaging of Brain Amyloid Plaques in the Aging Population
NCT00099216	PHASE3	COMPLETED	Efficacy and Safety of Rivastigmine Capsules in Patients With Probable Vascular Dementia
NCT00130338	PHASE3	COMPLETED	Rivastigmine Capsules in Patients With Probable Vascular Dementia
NCT00209456	PHASE3	COMPLETED	Dopamine Transporter Scintigraphy Imaging (DAT-Imaging) in Patients With Lewy Body Dementia
NCT00249158	PHASE3	COMPLETED	A Study of the Effectiveness and Safety of Risperidone in the Treatment of Behavioral Disturbances in Patients With Dementia
NCT00261573	PHASE3	COMPLETED	A Study of the Safety and Effectiveness of Galantamine Versus Placebo in the Treatment of Patients With Vascular Dementia or Mixed Dementia
NCT00621647	PHASE3	COMPLETED	Seroquel- Agitation Associated With Dementia
NCT02453932	PHASE3	COMPLETED	Efficacy and Safety of Tianzhi Granule in Mild to Moderate Vascular Dementia
NCT03682185	PHASE3	COMPLETED	The Healthy Patterns Sleep Study
NCT03789760	PHASE3	COMPLETED	The Clinical Trial of Chinese Herbal Medicine (SaiLuoTong) Capsule
NCT03804229	PHASE3	ACTIVE_NOT_RECRUITING	Efficacy and Safety of Butylphthalide Soft Capsule for the Treatment of Vascular Dementia
NCT03986424	PHASE3	COMPLETED	Local Study of Akatinol Memantine in VaD in Russia
NCT04552041	PHASE3	COMPLETED	Prospekta in the Treatment of Cognitive, Behavioral and Psychiatric Disorders in Patients With Vascular Dementia.
NCT01466543	PHASE2	UNKNOWN	Effect of Zydena (Udenafil) on Cerebral Blood Flow and Peripheral Blood Viscosity
NCT01475578	PHASE2	COMPLETED	Study of STA-1 Capsule in Patients With Vascular Dementia (Marrow-Sea Deficiency)
NCT01608217	PHASE2	COMPLETED	Delta-THC in Dementia
NCT01761227	PHASE2	COMPLETED	Efficacy and Safety of Fufangdanshen Tablets in Mild to Moderate Vascular Dementia
NCT01953705	PHASE2	UNKNOWN	n-3 PUFA for Vascular Cognitive Aging
NCT01965756	PHASE2	COMPLETED	Effect of Insulin Sensitizer Metformin on AD Biomarkers
NCT01978730	PHASE2	UNKNOWN	The Clinical Trial of Chinese Herbal Medicine SaiLuoTong Capsule
NCT02467413	PHASE2	WITHDRAWN	BAC in Patient With Alzheimer’s Disease or Vascular Dementia
NCT03230071	PHASE2	COMPLETED	Efficacy and Safety of TMBCZG in Mild to Moderate Vascular Dementia
NCT04109963	PHASE2	UNKNOWN	Trial of Remote Ischemic Pre-conditioning in Vascular Cognitive Impairment
NCT05371639	PHASE2	UNKNOWN	Efficacy and Safety of Tian Ma Bian Chun Zhi Gan Tablets in Mild to Moderate Vascular Dementia
NCT00457769	PHASE1	UNKNOWN	Aricept to Improve Functional Tasks in Vascular Dementia
NCT03702543	PHASE1	UNKNOWN	Managing Vascular Dementia Risk Factors With SymTrend
NCT04567745	PHASE1	COMPLETED	Automated Retinal Image Analysis System (EyeQuant) for Computation of Vascular Biomarkers
NCT02098824	PHASE2/PHASE3	UNKNOWN	Symptomatic Treatment of Vascular Cognitive Impairment
NCT04248270	PHASE1/PHASE2	UNKNOWN	A Noval Tau Tracer in Young Onset Dementia
NCT00172900	Not specified	UNKNOWN	MRS and DTI of White Matter in Alzheimer’s Disease
NCT00506818	Not specified	COMPLETED	Cognitive and Emotional Impairment After Stroke
NCT00889603	Not specified	COMPLETED	Non-Interventional Study With Aricept® Evess
NCT01208675	Not specified	COMPLETED	The Swedish BioFINDER Study
NCT01345110	Not specified	COMPLETED	A Longitudinal Multidimensional Population Study on Brain Aging
NCT01370954	Not specified	COMPLETED	NAC-003 P.L.U.S. Program (Progress Through Learning Understanding & Support)
NCT01465360	Not specified	COMPLETED	Performance of AclarusDx™, a Blood-Based Transcriptomic Test for AD, in US Patients Newly Referred to a Memory Center
NCT01815112	Not specified	TERMINATED	Early Diagnosis of Alzheimer-like Dementia: Benefit of MRI and PET Imaging