MTMR8

Summary

MTMR8 (myotubularin related protein 8, HGNC:16825) is a protein-coding gene on chromosome Xq11.2, encoding Phosphatidylinositol-3,5-bisphosphate 3-phosphatase MTMR8 (Q96EF0). Lipid phosphatase that specifically dephosphorylates the D-3 position of phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate, generating phosphatidylinositol and phosphatidylinositol 5-phosphate.

This gene encodes a member of the myotubularin-related family and is part of the MTMR6 subgroup. Family members are dual-specificity phosphatases and the encoded protein contains a phosphoinositide-binding domain (PID) and a SET-interacting domain (SID). Defects in other family members have been found in myotubular myopathic diseases.

Source: NCBI Gene 55613 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 182 total
• MANE Select transcript: NM_017677

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16825
Approved symbol	MTMR8
Name	myotubularin related protein 8
Location	Xq11.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20126
Ensembl gene	ENSG00000102043
Ensembl biotype	protein_coding
OMIM	301061
Entrez	55613

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding_CDS_not_defined, 1 protein_coding

ENST00000374852, ENST00000461403, ENST00000462447, ENST00000478487

RefSeq mRNA: 1 — MANE Select: NM_017677 NM_017677

CCDS: CCDS14379

Canonical transcript exons

ENST00000374852 — 14 exons

Exon	Start	End
ENSE00000671876	64328772	64328900
ENSE00000671877	64331557	64331757
ENSE00000897841	64270947	64271073
ENSE00001148454	64395340	64395452
ENSE00001672426	64268081	64269043
ENSE00001739305	64349942	64350070
ENSE00001753171	64354777	64354934
ENSE00001765566	64359405	64359527
ENSE00001803410	64356176	64356338
ENSE00003530635	64343611	64343720
ENSE00003554760	64337268	64337393
ENSE00003569327	64336079	64336128
ENSE00003624461	64345045	64345177
ENSE00003667109	64348660	64348794

Expression profiles

Bgee: expression breadth ubiquitous, 167 present calls, max score 96.88.

FANTOM5 (CAGE): breadth broad, TPM avg 1.9678 / max 36.6681, expressed in 746 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
199478	1.9678	746

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	96.88	gold quality
type B pancreatic cell	CL:0000169	87.71	gold quality
olfactory bulb	UBERON:0002264	87.20	gold quality
hair follicle	UBERON:0002073	86.09	gold quality
diaphragm	UBERON:0001103	85.63	gold quality
superficial temporal artery	UBERON:0001614	82.75	gold quality
tongue squamous epithelium	UBERON:0006919	78.39	gold quality
quadriceps femoris	UBERON:0001377	76.14	gold quality
vastus lateralis	UBERON:0001379	75.93	gold quality
mammary duct	UBERON:0001765	75.25	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	75.25	gold quality
gingival epithelium	UBERON:0001949	74.88	gold quality
colonic epithelium	UBERON:0000397	73.93	gold quality
triceps brachii	UBERON:0001509	73.66	gold quality
gluteal muscle	UBERON:0002000	73.63	gold quality
biceps brachii	UBERON:0001507	73.52	gold quality
epithelium of mammary gland	UBERON:0003244	73.37	gold quality
secondary oocyte	CL:0000655	73.02	silver quality
thymus	UBERON:0002370	72.85	gold quality
cerebellar vermis	UBERON:0004720	72.39	gold quality
nasal cavity epithelium	UBERON:0005384	72.12	gold quality
lower esophagus mucosa	UBERON:0035834	71.09	gold quality
skeletal muscle tissue	UBERON:0001134	71.06	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	71.05	gold quality
calcaneal tendon	UBERON:0003701	70.78	gold quality
gingiva	UBERON:0001828	70.76	gold quality
muscle tissue	UBERON:0002385	70.70	gold quality
left ventricle myocardium	UBERON:0006566	70.60	gold quality
germinal epithelium of ovary	UBERON:0001304	70.40	gold quality
squamous epithelium	UBERON:0006914	69.99	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	4.51

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

26 targeting MTMR8, 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-23C	99.95	73.92	3192
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-4517	99.76	69.19	1867
HSA-MIR-545-5P	99.66	70.18	2308
HSA-MIR-17-3P	99.55	66.77	1311
HSA-MIR-4687-5P	99.14	66.26	488
HSA-MIR-4504	99.10	69.14	1328
HSA-MIR-5587-5P	99.07	68.58	838
HSA-MIR-5583-3P	99.06	65.68	1018
HSA-MIR-605-5P	98.79	68.24	1161
HSA-MIR-330-5P	98.73	67.63	1788
HSA-MIR-758-3P	98.42	68.60	1122
HSA-MIR-326	98.25	66.44	1565
HSA-MIR-4436B-3P	98.25	65.26	1494
HSA-MIR-6735-5P	98.24	65.36	1488
HSA-MIR-7843-5P	98.12	65.26	1421
HSA-MIR-4632-5P	97.82	65.38	1470
HSA-MIR-6879-5P	97.77	65.52	1521
HSA-MIR-509-3-5P	97.21	67.74	1517
HSA-MIR-509-5P	97.21	67.90	1512
HSA-MIR-4418	97.04	67.16	1372
HSA-MIR-1178-5P	95.83	64.12	504
HSA-MIR-7848-3P	95.69	65.00	363
HSA-MIR-3679-5P	94.75	66.46	862
HSA-MIR-1185-5P	94.47	65.95	725

Literature-anchored findings (GeneRIF, showing 2)

• East African population that gave rise to non-Africans underwent a selective sweep affecting the subcentromeric region where MTMR8 is located (PMID:24282552)
• Here, the crystal structure of the phosphatase domain of MTMR8 is reported. (PMID:26143924)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mtmr8	ENSDARG00000008592
drosophila_melanogaster	Mtmr6	FBGN0028497
drosophila_melanogaster	CG3632	FBGN0030735
caenorhabditis_elegans		WBGENE00003476
caenorhabditis_elegans		WBGENE00003478

Paralogs (13): MTMR7 (ENSG00000003987), MTMR11 (ENSG00000014914), MTMR1 (ENSG00000063601), MTMR2 (ENSG00000087053), SBF1 (ENSG00000100241), MTMR3 (ENSG00000100330), MTMR9 (ENSG00000104643), MTMR4 (ENSG00000108389), SBF2 (ENSG00000133812), MTMR6 (ENSG00000139505), MTMR12 (ENSG00000150712), MTMR10 (ENSG00000166912), MTM1 (ENSG00000171100)

Protein

Protein identifiers

Phosphatidylinositol-3,5-bisphosphate 3-phosphatase MTMR8 — Q96EF0 (reviewed: Q96EF0)

Alternative names: Myotubularin-related protein 8, Phosphatidylinositol-3-phosphate phosphatase

All UniProt accessions (1): Q96EF0

UniProt curated annotations — full annotation on UniProt →

Function. Lipid phosphatase that specifically dephosphorylates the D-3 position of phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate, generating phosphatidylinositol and phosphatidylinositol 5-phosphate. In complex with MTMR9, negatively regulates autophagy.

Subunit / interactions. Homodimer. Heterodimer with MTMR9.

Subcellular location. Nucleus envelope.

Activity regulation. Interaction with MTMR9 increases phosphatase activity.

Similarity. Belongs to the protein-tyrosine phosphatase family. Non-receptor class myotubularin subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96EF0-1	1	yes
Q96EF0-2	2

RefSeq proteins (1): NP_060147* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003595	Tyr_Pase_cat	Domain
IPR010569	Myotubularin-like_Pase_dom	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR016130	Tyr_Pase_AS	Active_site
IPR029021	Prot-tyrosine_phosphatase-like	Homologous_superfamily
IPR030564	Myotubularin	Family
IPR030591	MTMR8_PTP	Domain
IPR048994	PH-GRAM_MTMR6-9	Domain

Pfam: PF06602, PF21098

Enzyme classification (BRENDA):

• EC 3.1.3.95 — phosphatidylinositol-3,5-bisphosphate 3-phosphatase (BRENDA: 2 organisms, 16 substrates, 1 inhibitors, 0 Km, 0 kcat entries)

Catalyzed reactions (Rhea), 3 shown:

• a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3-phosphate) + H2O = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol) + phosphate (RHEA:12316)
• a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,5-bisphosphate) + H2O = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-5-phosphate) + phosphate (RHEA:39019)
• 1,2-dioctanoyl-sn-glycero-3-phospho-(1D-myo-inositol-3,5-bisphosphate) + H2O = 1,2-dioctanoyl-sn-glycero-3-phospho-(1D-myo-inositol-5-phosphate) + phosphate (RHEA:45632)

UniProt features (75 total): binding site 26, helix 20, strand 12, turn 7, sequence variant 2, mutagenesis site 2, chain 1, domain 1, coiled-coil region 1, active site 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4Y7I	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96EF0-F1	82.98	0.65

Functional residue map

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

Catalytic / active sites (1): 338 (phosphocysteine intermediate)

Ligand- & substrate-binding residues (26): 339; 339; 339; 340; 340; 340; 341; 341; 342; 342; 342; 343 …

Mutagenesis-validated functional residues (2):

Position	Phenotype
253	increased phosphatidylinositol-3,5-bisphosphate 3-phosphatase activity.
255	decreased phosphatidylinositol-3,5-bisphosphate 3-phosphatase activity.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-1660499	Synthesis of PIPs at the plasma membrane
R-HSA-1430728	Metabolism
R-HSA-1483255	PI Metabolism
R-HSA-1483257	Phospholipid metabolism
R-HSA-556833	Metabolism of lipids

MSigDB gene sets: 63 (showing top): GOBP_LIPID_MODIFICATION, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, GOBP_PHOSPHOLIPID_DEPHOSPHORYLATION, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_MACROAUTOPHAGY, GOBP_GLYCEROLIPID_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_AUTOPHAGY, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_GLYCEROPHOSPHOLIPID_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLINOSITOL_DEPHOSPHORYLATION, GOBP_LIPID_METABOLIC_PROCESS, GOBP_DEPHOSPHORYLATION, SHEN_SMARCA2_TARGETS_DN

GO Biological Process (6): negative regulation of autophagy (GO:0010507), regulation of macroautophagy (GO:0016241), phosphatidylinositol dephosphorylation (GO:0046856), lipid metabolic process (GO:0006629), dephosphorylation (GO:0016311), phosphatidylinositol metabolic process (GO:0046488)

GO Molecular Function (5): phosphatidylinositol-3-phosphate phosphatase activity (GO:0004438), phosphatidylinositol-3,5-bisphosphate 3-phosphatase activity (GO:0052629), phosphatidylinositol-3,5-bisphosphate phosphatase activity (GO:0106018), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (5): nuclear envelope (GO:0005635), cytoplasm (GO:0005737), cytosol (GO:0005829), protein-containing complex (GO:0032991), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
PI Metabolism	1
Phospholipid metabolism	1
Metabolism of lipids	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of autophagy	2
cellular anatomical structure	2
autophagy	1
negative regulation of catabolic process	1
macroautophagy	1
phosphatidylinositol metabolic process	1
phospholipid dephosphorylation	1
primary metabolic process	1
phosphate-containing compound metabolic process	1
phosphorus metabolic process	1
phosphatidylinositol monophosphate phosphatase activity	1
phosphatidylinositol-3,5-bisphosphate phosphatase activity	1
phosphatidylinositol bisphosphate phosphatase activity	1
binding	1
catalytic activity	1
nucleus	1
endomembrane system	1
organelle envelope	1
intracellular anatomical structure	1
cytoplasm	1
cellular_component	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

931 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MTMR8	BLK	P51451	645
MTMR8	KRT9	P35527	640
MTMR8	KRT1	P04264	545
MTMR8	MTMR14	Q8NCE2	470
MTMR8	PIK3C3	Q8NEB9	449
MTMR8	UQCC6	Q69YU5	449
MTMR8	GCSAML	Q5JQS6	438
MTMR8	ZNF71	Q9NQZ8	428
MTMR8	CCDC71L	Q8N9Z2	423
MTMR8	CFAP77	Q6ZQR2	419
MTMR8	CLVS1	Q8IUQ0	394
MTMR8	ZC4H2	Q9NQZ6	379
MTMR8	LONRF3	Q496Y0	369
MTMR8	ZC3H12B	Q5HYM0	368
MTMR8	CSTPP1	Q9H6J7	355

IntAct

25 interactions, top by confidence:

A	B	Type	Score
MTMR8	MTMR9	psi-mi:“MI:0915”(physical association)	0.890
MTMR9	MTMR8	psi-mi:“MI:0915”(physical association)	0.890
EFNB3	DENND11	psi-mi:“MI:0914”(association)	0.640
IMPDH1	BCAT2	psi-mi:“MI:0914”(association)	0.530
MTMR9	CENPF	psi-mi:“MI:0914”(association)	0.530
ARL11	SESTD1	psi-mi:“MI:0914”(association)	0.530
MTMR8	AATK	psi-mi:“MI:0915”(physical association)	0.370
MTMR8	ERBB3	psi-mi:“MI:0915”(physical association)	0.370
MTMR8	MTMR9	psi-mi:“MI:0915”(physical association)	0.370
IMPDH1	LCMT2	psi-mi:“MI:0914”(association)	0.350
MTMR9	APOD	psi-mi:“MI:0914”(association)	0.350
MTMR7	HNRNPC	psi-mi:“MI:0914”(association)	0.350
ARL11	SELENBP1	psi-mi:“MI:0914”(association)	0.350
MTMR8	MADD	psi-mi:“MI:0914”(association)	0.350
MTMR9	DSP	psi-mi:“MI:0914”(association)	0.350
DNAJA2	DENND11	psi-mi:“MI:0914”(association)	0.350
MTMR7	RALGAPA2	psi-mi:“MI:0914”(association)	0.350
GUCD1	HNRNPA1L2	psi-mi:“MI:0914”(association)	0.350
MTMR9	ACTN3	psi-mi:“MI:0914”(association)	0.350
DNAJA2	ENC1	psi-mi:“MI:0914”(association)	0.350

BioGRID (43): MTMR9 (Two-hybrid), MTMR8 (Affinity Capture-MS), MADD (Affinity Capture-MS), MTMR9 (Affinity Capture-MS), TUBB6 (Affinity Capture-MS), MTMR8 (Affinity Capture-MS), MTMR8 (Affinity Capture-MS), MTMR9 (Affinity Capture-MS), TXNDC5 (Affinity Capture-MS), STIP1 (Affinity Capture-MS), SOAT1 (Affinity Capture-MS), TAB1 (Affinity Capture-MS), CCT8L1P (Affinity Capture-MS), CARM1 (Affinity Capture-MS), CDK4 (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2JXT6, A0JMF6, A0JMK5, A2ALK8, A2BGG1, A6QLT4, A7MB43, G5ED68, O13819, O14830, P26045, P33402, P51432, Q09M05, Q13496, Q13613, Q15111, Q3USB7, Q4KWH5, Q4R6N0, Q4U2V3, Q52KU6, Q5EB32, Q5F452, Q5R6F6, Q5R9S3, Q5U581, Q62688, Q6AXQ4, Q6NU08, Q6TEL0, Q6XPS3, Q7TPM9, Q7ZXF1, Q8K394, Q8NCE2, Q8VE11, Q8VEL2, Q96EF0, Q96MI9

Diamond homologs: A0A0G2JXT6, A0JMK5, A2BGG1, A4FU01, A6QLT2, A6QLT4, A7MB43, E9PXF8, F4J3T8, F4JWB3, G5ED68, O13819, P47147, Q13496, Q13613, Q13614, Q13615, Q22712, Q2KJ24, Q3V1L6, Q52KU6, Q54GQ1, Q55E58, Q5EB32, Q5F452, Q5PQT2, Q5R6F6, Q5R9S3, Q5REB9, Q5U581, Q5ZIV1, Q6AXQ4, Q6NTN5, Q6NU08, Q6TEL0, Q7TPM9, Q7ZXF1, Q80TA6, Q8K296, Q8VE11

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	101
Likely benign	13
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

4698 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:64336079:C:A	R384M	1.000
X:64336110:A:G	W374R	1.000
X:64336110:A:T	W374R	1.000
X:64337338:C:G	R344P	1.000
X:64337341:T:A	D343V	1.000
X:64337341:T:G	D343A	1.000
X:64337342:C:G	D343H	1.000
X:64337345:A:G	W342R	1.000
X:64337345:A:T	W342R	1.000
X:64337347:C:T	G341E	1.000
X:64337355:A:C	C338W	1.000
X:64345081:G:C	H277D	1.000
X:64345100:G:C	F270L	1.000
X:64345100:G:T	F270L	1.000
X:64345102:A:G	F270L	1.000
X:64345143:C:T	G256E	1.000
X:64345144:C:G	G256R	1.000
X:64345144:C:T	G256R	1.000
X:64345164:G:T	A249D	1.000
X:64348667:C:A	R242I	1.000
X:64348667:C:G	R242T	1.000
X:64348674:C:G	D240H	1.000
X:64348771:C:A	Q207H	1.000
X:64348771:C:G	Q207H	1.000
X:64348775:C:A	S206I	1.000
X:64349990:T:A	R183S	1.000
X:64349990:T:G	R183S	1.000
X:64349991:C:A	R183I	1.000
X:64349991:C:G	R183T	1.000
X:64328875:A:G	W460R	0.999

dbSNP variants (sampled 300 via entrez): RS1000022310 (X:64284522 T>G), RS1000029405 (X:64336216 G>A), RS1000037907 (X:64321575 G>A,C), RS1000038063 (X:64343442 G>A), RS1000057411 (X:64346599 A>T), RS1000085233 (X:64395787 C>A,T), RS1000093328 (X:64315134 C>T), RS1000114080 (X:64310973 G>C), RS1000127360 (X:64339342 T>A), RS1000128368 (X:64269186 T>G), RS1000136875 (X:64352128 A>G), RS1000171656 (X:64378234 A>C), RS1000182140 (X:64369324 T>C,G), RS1000190304 (X:64301928 G>C), RS1000218830 (X:64283715 G>T)

Disease associations

OMIM: gene MIM:301061 | disease phenotypes: MIM:148840

GenCC curated gene-disease

Mondo (1): Kleine-Levin syndrome (MONDO:0007863)

Orphanet (1): Kleine-Levin syndrome (Orphanet:33543)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D017593	Kleine-Levin Syndrome	C10.886.425.800.200.500; F03.870.400.800.200.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

10 total (human), top 10 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, increases methylation	2
triphenyl phosphate	affects expression	1
sodium arsenite	increases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression	1
jinfukang	increases expression	1
Tretinoin	increases expression	1
Vanadates	decreases expression	1
S-Nitrosoglutathione	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT02337023	Not specified	COMPLETED	Brain Scintigraphy in Normal Versus Kleine-Levin Syndrome Subjects
NCT03754348	Not specified	COMPLETED	Microglial Activation in Narcolepsy Type 1 and Kleine-Levin Syndrome: Positron Emission Tomography (PET) Study in [18F] DPA-714