MICAL1

Summary

MICAL1 (microtubule associated monooxygenase, calponin and LIM domain containing 1, HGNC:20619) is a protein-coding gene on chromosome 6q21, encoding [F-actin]-monooxygenase MICAL1 (Q8TDZ2). Monooxygenase that promotes depolymerization of F-actin by mediating oxidation of specific methionine residues on actin to form methionine-sulfoxide, resulting in actin filament disassembly and preventing repolymerization.

This gene encodes an enzyme that oxidizes methionine residues on actin, thereby promoting depolymerization of actin filaments. This protein interacts with and regulates signalling by NEDD9/CAS-L (neural precursor cell expressed, developmentally down-regulated 9). Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 64780 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal dominant epilepsy with auditory features (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 1,337 total — 2 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 35
• MANE Select transcript: NM_022765

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20619
Approved symbol	MICAL1
Name	microtubule associated monooxygenase, calponin and LIM domain containing 1
Location	6q21
Locus type	gene with protein product
Status	Approved
Aliases	MICAL, FLJ11937, DKFZp434B1517, FLJ21739
Ensembl gene	ENSG00000135596
Ensembl biotype	protein_coding
OMIM	607129
Entrez	64780

Gene structure

Transcript identifiers

Ensembl transcripts: 55 — 52 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000358577, ENST00000358807, ENST00000431946, ENST00000433205, ENST00000456101, ENST00000465904, ENST00000483856, ENST00000630715, ENST00000856836, ENST00000856837, ENST00000856838, ENST00000856839, ENST00000856840, ENST00000856841, ENST00000856842, ENST00000856843, ENST00000856844, ENST00000856845, ENST00000856846, ENST00000856847, ENST00000856848, ENST00000856849, ENST00000856850, ENST00000856851, ENST00000856852, ENST00000856853, ENST00000856854, ENST00000923395, ENST00000923396, ENST00000923397, ENST00000923398, ENST00000923399, ENST00000923400, ENST00000923401, ENST00000923402, ENST00000923403, ENST00000923404, ENST00000923405, ENST00000923406, ENST00000923407, ENST00000923408, ENST00000923409, ENST00000970739, ENST00000970740, ENST00000970741, ENST00000970742, ENST00000970743, ENST00000970744, ENST00000970745, ENST00000970746, ENST00000970747, ENST00000970748, ENST00000970749, ENST00000970750, ENST00000970751

RefSeq mRNA: 3 — MANE Select: NM_022765 NM_001159291, NM_001286613, NM_022765

CCDS: CCDS5076, CCDS55047, CCDS69170

Canonical transcript exons

ENST00000358807 — 25 exons

Exon	Start	End
ENSE00001346540	109455719	109455772
ENSE00002190488	109451600	109451700
ENSE00002199952	109446136	109446412
ENSE00003465455	109450300	109450557
ENSE00003474980	109448203	109448393
ENSE00003493220	109444725	109444798
ENSE00003526668	109447875	109447963
ENSE00003529770	109452511	109452615
ENSE00003532877	109453263	109453367
ENSE00003560809	109453939	109454239
ENSE00003568463	109452246	109452401
ENSE00003570875	109447073	109447229
ENSE00003582477	109444062	109444339
ENSE00003587368	109453638	109453845
ENSE00003598873	109448732	109448879
ENSE00003606724	109449970	109450085
ENSE00003615366	109445197	109445290
ENSE00003629445	109444896	109444995
ENSE00003634212	109447681	109447722
ENSE00003645655	109449400	109449481
ENSE00003651907	109449657	109449783
ENSE00003674621	109446696	109446772
ENSE00003680001	109445771	109445862
ENSE00003689053	109445416	109445529
ENSE00003789922	109447357	109447440

Expression profiles

Bgee: expression breadth ubiquitous, 234 present calls, max score 97.45.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.0992 / max 379.3068, expressed in 1785 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
75005	12.0280	1735
75010	8.9779	1752
75006	5.5906	1126
75007	3.9165	1403
75004	0.7043	298
74999	0.6503	262
75000	0.1863	95
75008	0.0232	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right coronary artery	UBERON:0001625	97.45	gold quality
granulocyte	CL:0000094	97.36	gold quality
left coronary artery	UBERON:0001626	96.30	gold quality
small intestine Peyer’s patch	UBERON:0003454	96.09	gold quality
endocervix	UBERON:0000458	96.04	gold quality
spleen	UBERON:0002106	95.98	gold quality
left uterine tube	UBERON:0001303	95.96	gold quality
popliteal artery	UBERON:0002250	95.95	gold quality
tibial artery	UBERON:0007610	95.94	gold quality
coronary artery	UBERON:0001621	95.85	gold quality
ganglionic eminence	UBERON:0004023	95.61	gold quality
aorta	UBERON:0000947	95.46	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.41	gold quality
stromal cell of endometrium	CL:0002255	95.30	gold quality
right lung	UBERON:0002167	95.25	gold quality
descending thoracic aorta	UBERON:0002345	95.23	gold quality
ascending aorta	UBERON:0001496	95.01	gold quality
upper lobe of left lung	UBERON:0008952	95.00	gold quality
thoracic aorta	UBERON:0001515	94.99	gold quality
tibial nerve	UBERON:0001323	94.94	gold quality
ectocervix	UBERON:0012249	94.87	gold quality
cortical plate	UBERON:0005343	94.65	gold quality
small intestine	UBERON:0002108	94.59	gold quality
cerebellar hemisphere	UBERON:0002245	94.59	gold quality
cerebellar cortex	UBERON:0002129	94.47	gold quality
vermiform appendix	UBERON:0001154	94.39	gold quality
mucosa of transverse colon	UBERON:0004991	94.32	gold quality
upper lobe of lung	UBERON:0008948	94.26	gold quality
lymph node	UBERON:0000029	94.24	gold quality
blood	UBERON:0000178	94.14	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-99795	yes	313.57
E-GEOD-81383	yes	131.35
E-ANND-3	yes	8.07
E-CURD-10	no	119.97

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SOX14

miRNA regulators (miRDB)

9 targeting MICAL1, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-3160-5P	99.28	69.07	1938
HSA-MIR-891A-3P	98.05	67.99	970
HSA-MIR-1292-5P	96.74	62.14	238

Literature-anchored findings (GeneRIF, showing 21)

• a CasL interacting molecule that associates with vimentin (PMID:11827972)
• MICAL-1 isoforms with their multidomain structure are novel rab1 interacting proteins that function as scaffold proteins connecting different components in the cell. (PMID:12788069)
• The unfolding of MICAL-1 calpolnin homology (CH) domain was studied. (PMID:17662518)
• Faint and scattered immunoreactivity for Mical-1 is observed in neurons of the neocortex of the temporal lobe epilepsy group, while strong immunoreactivity for Mical-1 is shown in control subjects. (PMID:21638339)
• Findings show a biological role for MICAL-1 in apoptosis and define a novel negative regulatory mechanism of MST-NDR signaling. (PMID:21730291)
• although MICAL1 is auto-inhibited by its C-terminal coiled-coil region, MICAL2 remains constitutively active and affects stress fibers, suggesting differential but complementary roles for MICAL1 and MICAL2 in actin microfilament regulation (PMID:22331357)
• The MICAL1 directly induce oxidation of actin molecules, leading to actin depolymerization. ROS production by MICAL1 also causes oxidation of collapsin response mediator protein-2 which subsequently undergoes phosphorylation. (PMID:23834433)
• Data suggest that Sema6A and Mical1 may represent new potential therapeutic targets in BRAFV600E melanoma. (PMID:25576923)
• The results provide evidence that MICAL1 plays an essential role in the activation of ROS/Akt signaling and cell invasive phenotype and identify a novel link between RAB35 and MICAL1 in regulating breast cancer cell invasion. (PMID:27430308)
• describe methods to characterize MICAL-mediated F-actin disassembly using in vitro assays with purified proteins (PMID:27787846)
• Methionine oxidation is regulated in vivo by monooxygenases of the MICAL family. (Review) (PMID:28229915)
• Two autosomal-dominant lateral temporal epilepsy-causing variants were identified in the MICAL1 gene. (PMID:29394500)
• our results suggest that MICAL1 exhibits its effect on proliferation via maintaining cyclin D expression through ROS-sensitive PI3K/Akt/ERK signalling in breast cancer cells (PMID:29524295)
• Human MICAL1: Activation by the small GTPase Rab8 and small-angle X-ray scattering studies on the oligomerization state of MICAL1 and its complex with Rab8. (PMID:30242933)
• GRAF2, WDR44, and MICAL1 mediate Rab8/10/11-dependent export of E-cadherin, MMP14, and CFTR DeltaF508. (PMID:32344433)
• MICAL1 constrains cardiac stress responses and protects against disease by oxidizing CaMKII. (PMID:32749237)
• MICAL1 regulates actin cytoskeleton organization, directional cell migration and the growth of human breast cancer cells as orthotopic xenograft tumours. (PMID:34314753)
• MICAL1 inhibits colorectal cancer cell migration and proliferation by regulating the EGR1/beta-catenin signaling pathway. (PMID:34902339)
• Mical modulates Tau toxicity via cysteine oxidation in vivo. (PMID:35379354)
• High MICAL1 expression correlates with cancer progression and immune infiltration in renal clear cell carcinoma. (PMID:36575439)
• PlexinA1 promotes gastric cancer migration through preventing MICAL1 protein ubiquitin/proteasome-mediated degradation in a Rac1-dependent manner. (PMID:38508474)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	mical1	ENSDARG00000011809
mus_musculus	Mical1	ENSMUSG00000019823
rattus_norvegicus	Mical1	ENSRNOG00000000307

Paralogs (36): SYNE2 (ENSG00000054654), SPTB (ENSG00000070182), ACTN1 (ENSG00000072110), ACTN2 (ENSG00000077522), DSP (ENSG00000096696), DRP2 (ENSG00000102385), SPTBN1 (ENSG00000115306), MACF1 (ENSG00000127603), FLNC (ENSG00000128591), ACTN4 (ENSG00000130402), SYNE1 (ENSG00000131018), MICAL2 (ENSG00000133816), DTNA (ENSG00000134769), FLNB (ENSG00000136068), SPTBN5 (ENSG00000137877), DTNB (ENSG00000138101), GAS2L3 (ENSG00000139354), DST (ENSG00000151914), UTRN (ENSG00000152818), SPTBN4 (ENSG00000160460), SPTA1 (ENSG00000163554), CLMN (ENSG00000165959), PKHD1 (ENSG00000170927), SPTBN2 (ENSG00000173898), SYNE3 (ENSG00000176438), PLEC (ENSG00000178209), SMTNL2 (ENSG00000188176), FLNA (ENSG00000196924), SPTAN1 (ENSG00000197694), DMD (ENSG00000198947), PKHD1L1 (ENSG00000205038), DYTN (ENSG00000232125), MICAL3 (ENSG00000243156), ACTN3 (ENSG00000248746), EPPK1 (ENSG00000261150), GAS2L2 (ENSG00000270765)

Protein

Protein identifiers

[F-actin]-monooxygenase MICAL1 — Q8TDZ2 (reviewed: Q8TDZ2)

Alternative names: Molecule interacting with CasL protein 1, NEDD9-interacting protein with calponin homology and LIM domains

All UniProt accessions (3): Q8TDZ2, H0Y6Z4, Q5TED7

UniProt curated annotations — full annotation on UniProt →

Function. Monooxygenase that promotes depolymerization of F-actin by mediating oxidation of specific methionine residues on actin to form methionine-sulfoxide, resulting in actin filament disassembly and preventing repolymerization. In the absence of actin, it also functions as a NADPH oxidase producing H(2)O(2). Acts as a cytoskeletal regulator that connects NEDD9 to intermediate filaments. Also acts as a negative regulator of apoptosis via its interaction with STK38 and STK38L; acts by antagonizing STK38 and STK38L activation by MST1/STK4. Involved in regulation of lamina-specific connectivity in the nervous system such as the development of lamina-restricted hippocampal connections. Through redox regulation of the actin cytoskeleton controls the intracellular distribution of secretory vesicles containing L1/neurofascin/NgCAM family proteins in neurons, thereby regulating their cell surface levels. May act as Rab effector protein and play a role in vesicle trafficking. Promotes endosomal tubule extension by associating with RAB8 (RAB8A or RAB8B), RAB10 and GRAF (GRAF1/ARHGAP26 or GRAF2/ARHGAP10) on the endosomal membrane which may connect GRAFs to Rabs, thereby participating in neosynthesized Rab8-Rab10-Rab11-dependent protein export.

Subunit / interactions. Interacts with STK38 and STK38L. Interacts with RAB1B, RAB8A, RAB10, RAB13, RAB15 and RAB35 (in their GTP-bound forms); binding to RAB1B is of low affinity compared to other Rab proteins; at least in case of RAB8A and RAB10 can bind 2 molecules of the Rab proteins simultaneously; ternary complex formation of RAB8A, RAB13 and MICAL1 is possible. Associates with the SH3 domain of NEDD9. Interacts with VIM and PLXNA3. Interacts with GRAF1/ARHGAP26, GRAF2/ARHGAP10, RAB8A, RAB8B and RAB10; may bind simultaneously to GRAFs and Rabs and connects GRAFs to Rabs. Does not interact with RAB1 and RAB11A.

Subcellular location. Cytoplasm. Cytoskeleton. Endosome membrane. Midbody.

Tissue specificity. Expressed in the thymus, lung, spleen, kidney, testis and hematopoietic cells.

Domain organisation. The bivalent Mical/EHBP Rab binding (bMERB) domain, mediates binding to predominantly Rab8, Rab10, Rab13 and Rab15 (in their GTP-bound forms). The C-terminal coiled coil part contains the plexin-interacting region.

Similarity. Belongs to the Mical family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q8TDZ2-1	1, MICAL-1a	yes
Q8TDZ2-2	2, MICAL-1b
Q8TDZ2-3	3
Q8TDZ2-4	4

RefSeq proteins (3): NP_001152763, NP_001273542, NP_073602* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001715	CH_dom	Domain
IPR001781	Znf_LIM	Domain
IPR002938	FAD-bd	Domain
IPR022735	bMERB_dom	Domain
IPR036188	FAD/NAD-bd_sf	Homologous_superfamily
IPR036872	CH_dom_sf	Homologous_superfamily
IPR050540	F-actin_Monoox_Mical	Family
IPR057494	Rossman_Mical	Domain

Pfam: PF00307, PF00412, PF01494, PF12130, PF25413

Enzyme classification (BRENDA):

• EC 1.14.13.225 — F-actin monooxygenase (BRENDA: 3 organisms, 6 substrates, 2 inhibitors, 16 Km, 13 kcat entries)

Substrate kinetics (BRENDA)

3 substrates with measured Km, best-characterized 3. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
NADPH	0.019–0.499	7
[F-ACTIN]-L-METHIONINE	0.03–1.438	6
NADH	0.58	1

Catalyzed reactions (Rhea), 2 shown:

• NADPH + O2 + H(+) = H2O2 + NADP(+) (RHEA:11260)
• L-methionyl-[F-actin] + NADPH + O2 + H(+) = L-methionyl-(R)-S-oxide-[F-actin] + NADP(+) + H2O (RHEA:51308)

UniProt features (133 total): helix 34, strand 28, binding site 14, turn 11, sequence variant 11, modified residue 6, compositionally biased region 5, region of interest 5, sequence conflict 5, splice variant 4, domain 3, coiled-coil region 3, mutagenesis site 2, chain 1, site 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
8HLO	X-RAY DIFFRACTION	1.17
6KU0	X-RAY DIFFRACTION	1.6
9G0C	X-RAY DIFFRACTION	1.8
9G0D	X-RAY DIFFRACTION	2.05
5LPN	X-RAY DIFFRACTION	2.8
9EWY	ELECTRON MICROSCOPY	3.1
5LE0	X-RAY DIFFRACTION	3.3
8Y6K	ELECTRON MICROSCOPY	3.94
1WYL	SOLUTION NMR
2CO8	SOLUTION NMR
2DK9	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TDZ2-F1	75.56	0.40

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): 832 (important for interaction with arhgap26 and arhgap10)

Ligand- & substrate-binding residues (14): 95; 114–116; 121–123; 181; 293; 393; 697; 700; 718; 721; 724; 727 …

Post-translational modifications (6): 475, 617, 872, 875, 876, 1057

Mutagenesis-validated functional residues (2):

Position	Phenotype
91–96	increased association with rab8- rab10- and graphs-positive endosomal tubules. decreased wdr44-positive endosomal tubule
832	abolishes interaction with arhgap26 and arhgap10.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-983231	Factors involved in megakaryocyte development and platelet production
R-HSA-109582	Hemostasis

MSigDB gene sets: 268 (showing top): WALLACE_PROSTATE_CANCER_RACE_UP, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, GOBP_REGULATION_OF_EXOCYTOSIS, LINDGREN_BLADDER_CANCER_CLUSTER_3_DN, GOBP_VESICLE_MEDIATED_TRANSPORT, GOMF_GTPASE_BINDING, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, GOBP_EXOCYTOSIS, ONKEN_UVEAL_MELANOMA_UP, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_DN, WOO_LIVER_CANCER_RECURRENCE_UP, RUTELLA_RESPONSE_TO_CSF2RB_AND_IL4_UP, ROSS_LEUKEMIA_WITH_MLL_FUSIONS

GO Biological Process (7): cytoskeleton organization (GO:0007010), signal transduction (GO:0007165), sulfur oxidation (GO:0019417), actin filament depolymerization (GO:0030042), negative regulation of apoptotic process (GO:0043066), actin filament bundle assembly (GO:0051017), regulation of regulated secretory pathway (GO:1903305)

GO Molecular Function (13): actin binding (GO:0003779), monooxygenase activity (GO:0004497), NAD(P)H oxidase H2O2-forming activity (GO:0016174), oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, NAD(P)H as one donor, and incorporation of one atom of oxygen (GO:0016709), SH3 domain binding (GO:0017124), protein kinase binding (GO:0019901), small GTPase binding (GO:0031267), metal ion binding (GO:0046872), actin filament binding (GO:0051015), FAD binding (GO:0071949), F-actin monooxygenase activity (GO:0120501), protein binding (GO:0005515), oxidoreductase activity (GO:0016491)

GO Cellular Component (17): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), intermediate filament (GO:0005882), actin filament (GO:0005884), plasma membrane (GO:0005886), cilium (GO:0005929), endosome membrane (GO:0010008), actin cytoskeleton (GO:0015629), midbody (GO:0030496), ciliary basal body (GO:0036064), intercellular bridge (GO:0045171), hippocampal mossy fiber expansion (GO:1990026), endosome (GO:0005768), cytoskeleton (GO:0005856), membrane (GO:0016020), plasma membrane bounded cell projection (GO:0120025)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Hemostasis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
polymeric cytoskeletal fiber	2
organelle organization	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
sulfur compound metabolic process	1
actin polymerization or depolymerization	1
protein depolymerization	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
cellular component assembly	1
actin filament bundle organization	1
regulation of exocytosis	1
regulated exocytosis	1
cytoskeletal protein binding	1
oxidoreductase activity	1
oxidoreductase activity, acting on NAD(P)H, oxygen as acceptor	1
monooxygenase activity	1
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen	1
protein domain specific binding	1
kinase binding	1
GTPase binding	1
cation binding	1
actin binding	1
protein-containing complex binding	1
flavin adenine dinucleotide binding	1
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, NAD(P)H as one donor, and incorporation of one atom of oxygen	1
binding	1
catalytic activity	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
intermediate filament cytoskeleton	1
actin cytoskeleton	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

878 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MICAL1	NEDD9	Q14511	998
MICAL1	PLXNA1	Q9UIW2	870
MICAL1	PLXNA4	Q9HCM2	824
MICAL1	RAB35	Q15286	797
MICAL1	PLXNA3	P51805	796
MICAL1	PLXNA2	O75051	755
MICAL1	STK38	Q15208	723
MICAL1	RAB8A	P24407	669
MICAL1	RAB10	P61026	657
MICAL1	RUSC2	Q8N2Y8	642
MICAL1	OCRL	Q01968	627
MICAL1	RAB13	P51153	543
MICAL1	STK38L	Q9Y2H1	531
MICAL1	MSRB1	Q9NZV6	520
MICAL1	RAB1B	Q9H0U4	515

IntAct

74 interactions, top by confidence:

A	B	Type	Score
CSNK2B	RPS6KA5	psi-mi:“MI:0914”(association)	0.660
NCK2	SH3PXD2B	psi-mi:“MI:0914”(association)	0.640
RAB8A	WDR91	psi-mi:“MI:0914”(association)	0.600
CASS4	MICAL1	psi-mi:“MI:0915”(physical association)	0.570
USH1G	POTEF	psi-mi:“MI:0914”(association)	0.530
GJB7	PALM3	psi-mi:“MI:0914”(association)	0.530
SLC25A41	NUDT19	psi-mi:“MI:0914”(association)	0.530
ZNF517	GGPS1	psi-mi:“MI:0914”(association)	0.530
FBXL17	KLHL2	psi-mi:“MI:0914”(association)	0.530
TMEM88	MLYCD	psi-mi:“MI:0914”(association)	0.530
ARHGAP26	ARHGAP10	psi-mi:“MI:0914”(association)	0.510
TAS2R7	ATP2B4	psi-mi:“MI:0914”(association)	0.500
MICAL1	NPM1	psi-mi:“MI:0915”(physical association)	0.400
KLHL7	MICAL1	psi-mi:“MI:0915”(physical association)	0.400
MICAL1	H2BC21	psi-mi:“MI:0915”(physical association)	0.400
GIMAP6	MICAL1	psi-mi:“MI:0915”(physical association)	0.400
CASS4	MICAL1	psi-mi:“MI:0915”(physical association)	0.400
PSORS1C2	MICAL1	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
GADD45A	MICAL1	psi-mi:“MI:0915”(physical association)	0.370
MICAL1	GSK3B	psi-mi:“MI:0915”(physical association)	0.370
TAB1	MICAL1	psi-mi:“MI:0915”(physical association)	0.370
MICAL1	PIK3R3	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (93): MICAL1 (Affinity Capture-MS), MICAL1 (Affinity Capture-MS), MICAL1 (Affinity Capture-MS), MICAL1 (Affinity Capture-MS), MICAL1 (Affinity Capture-MS), MICAL1 (Affinity Capture-MS), MICAL1 (Affinity Capture-MS), MICAL1 (Affinity Capture-MS), MICAL1 (Affinity Capture-MS), MICAL1 (Affinity Capture-MS), MICAL1 (Affinity Capture-MS), MICAL1 (Affinity Capture-MS), MICAL1 (Affinity Capture-MS), VIM (Affinity Capture-Western), MICAL1 (Affinity Capture-Western)

ESM2 similar proteins: A0A061IR73, A0A7N9VSG0, A7YSY2, D3KCC4, D3ZU57, D4A2B7, O08644, O15197, O19179, O43542, O75064, O95382, P0C0K6, P0C0K7, P51840, P52785, P52824, P54777, Q02846, Q05932, Q13470, Q13608, Q1HG60, Q3ZBE0, Q4KM32, Q5JZY3, Q643R3, Q6MG64, Q6NVG1, Q6ZPS2, Q76MJ5, Q7TNJ2, Q80SX8, Q8BYG9, Q8IZY2, Q8NFF5, Q8R5G7, Q8TDZ2, Q8WWN8, Q91V24

Diamond homologs: A5D7D1, A8MU46, D3ZBP4, D3ZHV2, D3ZQL6, D4A1F2, E1BBG2, E7F9T0, F1MF74, F1MH07, F1QH17, F1QWK4, F1RA39, F6QZ15, G3MWR8, L7UZ85, O13728, O15020, O43707, O76329, O80839, O88990, O94851, O97592, P05094, P05095, P11277, P11530, P11531, P11532, P11533, P12814, P13466, P15508, P18091, P20111, P30427, P35609, P46939, P53814

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ABL1	“up-regulates activity”	MICAL1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

1337 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	3
Uncertain significance	743
Likely benign	479
Benign	47

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
1525979	NM_022765.4(MICAL1):c.-43-1G>A	Pathogenic
3246029	NC_000006.11:g.(?109765394)(109798153_?)del	Pathogenic
1723181	NM_022765.4(MICAL1):c.763G>T (p.Val255Leu)	Likely pathogenic
2179770	NM_022765.4(MICAL1):c.2743C>T (p.Arg915Cys)	Likely pathogenic
2722147	NM_022765.4(MICAL1):c.3189_3190del (p.Ala1065fs)	Likely pathogenic

SpliceAI

4049 predictions. Top by Δscore:

Variant	Effect	Δscore
6:109444335:GTTTT:G	acceptor_gain	1.0000
6:109444336:TTTT:T	acceptor_gain	1.0000
6:109444337:TTT:T	acceptor_gain	1.0000
6:109444338:TT:T	acceptor_gain	1.0000
6:109444340:C:CA	acceptor_loss	1.0000
6:109444340:C:CC	acceptor_gain	1.0000
6:109444720:CCTA:C	donor_loss	1.0000
6:109444723:A:AC	donor_gain	1.0000
6:109444723:ACCTT:A	donor_gain	1.0000
6:109444724:C:CC	donor_gain	1.0000
6:109444724:CCTT:C	donor_gain	1.0000
6:109444724:CCTTC:C	donor_gain	1.0000
6:109444727:T:A	donor_gain	1.0000
6:109444797:CC:C	acceptor_gain	1.0000
6:109444798:CC:C	acceptor_gain	1.0000
6:109444800:T:G	acceptor_loss	1.0000
6:109444809:C:CT	acceptor_gain	1.0000
6:109444888:CCCCT:C	donor_loss	1.0000
6:109444889:CCCTT:C	donor_loss	1.0000
6:109444890:CCTTA:C	donor_loss	1.0000
6:109444891:CTTA:C	donor_loss	1.0000
6:109444892:TTAC:T	donor_loss	1.0000
6:109444893:T:TG	donor_loss	1.0000
6:109444894:A:AC	donor_gain	1.0000
6:109444894:ACGT:A	donor_loss	1.0000
6:109444895:C:CC	donor_gain	1.0000
6:109444914:T:TA	donor_gain	1.0000
6:109444993:AAC:A	acceptor_gain	1.0000
6:109444996:C:CC	acceptor_gain	1.0000
6:109444997:T:G	acceptor_loss	1.0000

AlphaMissense

6909 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:109453722:A:G	W128R	0.998
6:109453722:A:T	W128R	0.998
6:109451652:A:G	F294S	0.997
6:109453700:A:G	L135P	0.997
6:109450079:A:G	W400R	0.996
6:109450079:A:T	W400R	0.996
6:109450393:G:C	F366L	0.995
6:109450393:G:T	F366L	0.995
6:109450395:A:G	F366L	0.995
6:109451684:G:C	N283K	0.995
6:109451684:G:T	N283K	0.995
6:109453681:C:A	K141N	0.995
6:109453681:C:G	K141N	0.995
6:109454007:A:G	W64R	0.995
6:109454007:A:T	W64R	0.995
6:109449698:G:T	R465S	0.994
6:109450481:G:T	A337D	0.994
6:109451640:G:T	A298D	0.994
6:109451677:A:C	Y286D	0.994
6:109452268:G:C	F270L	0.994
6:109452268:G:T	F270L	0.994
6:109452270:A:G	F270L	0.994
6:109452347:A:G	F244S	0.994
6:109453355:A:G	L160P	0.994
6:109449695:A:C	Y466D	0.992
6:109450033:T:A	D415V	0.992
6:109450047:G:C	F410L	0.992
6:109450047:G:T	F410L	0.992
6:109450049:A:G	F410L	0.992
6:109450317:C:A	G392W	0.992

dbSNP variants (sampled 300 via entrez): RS1000087555 (6:109447541 G>A,C), RS1000131103 (6:109464469 C>A,T), RS1000141342 (6:109444595 C>G), RS1000178060 (6:109458660 A>G), RS1000243128 (6:109460380 G>T), RS1000258667 (6:109467938 A>C), RS1000628974 (6:109451435 TGA>T), RS1000972741 (6:109462097 A>G), RS1001084108 (6:109462410 G>A), RS1001192634 (6:109456969 C>G), RS1001344754 (6:109456822 C>G,T), RS1001577548 (6:109451440 C>T), RS1001818045 (6:109463882 T>C), RS1001958101 (6:109456823 A>G), RS1002431056 (6:109450989 CTATG>C)

Disease associations

OMIM: gene MIM:607129 | disease phenotypes: MIM:614069, MIM:600512

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal dominant epilepsy with auditory features	Moderate	Autosomal dominant
epilepsy	Limited	Autosomal dominant

Mondo (4): immunodeficiency-centromeric instability-facial anomalies syndrome 2 (MONDO:0013553), epilepsy, familial temporal lobe, 1 (MONDO:0700090), epilepsy (MONDO:0005027), autosomal dominant epilepsy with auditory features (MONDO:0010898)

Orphanet (2): ICF syndrome (Orphanet:2268), Epilepsy with auditory features (Orphanet:101046)

HPO phenotypes

35 total (30 of 35 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000708	Atypical behavior
HP:0000716	Depression
HP:0001249	Intellectual disability
HP:0002069	Bilateral tonic-clonic seizure
HP:0002076	Migraine
HP:0002197	Generalized-onset seizure
HP:0002266	Focal clonic seizure
HP:0002349	Focal aware seizure
HP:0002367	Visual hallucination
HP:0002381	Aphasia
HP:0002384	Focal impaired awareness seizure
HP:0003596	Middle age onset
HP:0003621	Juvenile onset
HP:0007334	Bilateral tonic-clonic seizure with focal onset
HP:0007359	Focal-onset seizure
HP:0008765	Auditory hallucination
HP:0011154	Focal autonomic seizure
HP:0011158	Focal sensory seizure with auditory features
HP:0011159	Focal autonomic seizure with epigastric sensation/nausea/vomiting/other gastrointestinal phenomena
HP:0011161	Focal sensory seizure with olfactory features
HP:0011165	Focal sensory seizure with visual features
HP:0011182	Interictal epileptiform activity
HP:0011185	EEG with focal epileptiform discharges
HP:0011462	Young adult onset
HP:0012005	Deja vu aura
HP:0012332	Abnormal autonomic nervous system physiology
HP:0031951	Nocturnal seizures
HP:0032759	Focal sensory seizure with vestibular features
HP:0032773	Focal autonomic seizure with palpitations/tachycardia/bradycardia/asystole

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006427_17	Depression in smokers	3.000000e-06
GCST008163_224	Height	4.000000e-07

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D004827	Epilepsy	C10.228.140.490
C537297	Autosomal Dominant Lateral Temporal Lobe Epilepsy (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases methylation	7
bisphenol A	decreases expression, decreases methylation, affects cotreatment	3
trichostatin A	affects cotreatment, decreases expression	3
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Air Pollutants	increases abundance, affects expression, decreases expression, affects methylation	3
Benzo(a)pyrene	increases methylation, increases expression	3
Cyclosporine	decreases methylation, increases expression	3
Smoke	decreases expression, increases abundance	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
decabromobiphenyl ether	decreases expression	1
beta-lapachone	decreases expression, increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
perfluorodecanoic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
clothianidin	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
jinfukang	increases expression	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	increases expression	1
Troglitazone	increases expression	1
Arsenic	increases abundance, affects cotreatment, decreases expression	1
Caffeine	decreases phosphorylation	1
Calcitriol	increases expression, affects cotreatment	1

Cellosaurus cell lines

2 cell lines: 1 transformed cell line, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D9KA	Ubigene HEK293 MICAL1 KO	Transformed cell line	Female
CVCL_E2C8	HAP1 MICAL1 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00004637	PHASE4	COMPLETED	Double-Blind, Placebo-Controlled Trial of Vitamin E as Add-on Therapy for Children With Epilepsy
NCT00043914	PHASE4	COMPLETED	Measurement Of Serum Levels Of Two Antiepileptic Drugs During Conversion In Patients With Epilepsy
NCT00132223	PHASE4	UNKNOWN	Effects on the Diagnostic Accuracy of Magnetic Imaging Angiographies of the Supra-Aortic Vessels by Three Different Magnetic Resonance Contrast Agents in Patients
NCT00133081	PHASE4	UNKNOWN	Study to Improve the Treatment of Epilepsy (SITE)
NCT00137709	PHASE4	UNKNOWN	Hormone Profiles in Adults With Newly Diagnosed Epilepsy
NCT00154076	PHASE4	COMPLETED	A Multicenter Comparative Trial of Zonisamide and Topiramate as Initial Monotherapy in Untreated Epilepsies
NCT00165828	PHASE4	TERMINATED	Efficacy and Safety of an add-on Treatment With Zonisamide in Adults With Focal Epileptic Seizures With or Without Secondary Generalization
NCT00181116	PHASE4	COMPLETED	Levetiracetam for Benign Rolandic Epilepsy
NCT00207935	PHASE4	COMPLETED	Use of Sustained Release Antiepileptic Medication (Depakote® ER) for Pediatric Epilepsy in a Mental Retardation/Developmental Disorder Population
NCT00215592	PHASE4	COMPLETED	Open Label, Zonegran (Zonisamide) In Partial Onset Seizures
NCT00266604	PHASE4	COMPLETED	A Study to Evaluate the Dosing, Effectiveness and Safety of Topiramate for the Treatment of Epilepsy
NCT00288639	PHASE4	COMPLETED	Lyrica (Pregabalin) Administered as an Add-on Therapy for Partial Seizures (LEADER).
NCT00312676	PHASE4	UNKNOWN	Compare Tolerability of an Overnight Switch to Gradual Switch Between Two Different Forms of Depakote
NCT00323947	PHASE4	COMPLETED	Methylphenidate for Treating Attention Deficit Hyperactivity Disorder in Children With Both ADHD and Epilepsy
NCT00385411	PHASE4	COMPLETED	Study of Valproate in Young Patients Suffering From Epilepsy
NCT00522418	PHASE4	TERMINATED	Study Comparing Best Medical Practice With or Without VNS Therapy in Pharmacoresistant Partial Epilepsy Patients
NCT00537940	PHASE4	COMPLETED	Comparative Study Of Pregabalin And Gabapentin As Adjunctive Therapy In Subjects With Partial Seizures
NCT00552526	PHASE4	UNKNOWN	Ketogenic Diet vs.Antiepileptic Drug Treatment in Drug Resistant Epilepsy
NCT00564915	PHASE4	COMPLETED	RCT of the Efficacy of the Ketogenic Diet in the Treatment of Epilepsy
NCT00571155	PHASE4	COMPLETED	Trial of Levetiracetam in Patients With Primary Brain Tumors and Symptomatic Seizures Who Undergo Surgery
NCT00572195	PHASE4	COMPLETED	RNS® System LTT Study
NCT00610532	PHASE4	TERMINATED	Evaluating the Transporter Protein Inhibitor Probenecid In Patients With Epilepsy
NCT00630357	PHASE4	COMPLETED	Trial to Evaluate the Safety and Efficacy of Keppra After Conversion to Mono-therapy in Subjects With Partial Epilepsy
NCT00630630	PHASE4	COMPLETED	Study on Safety and Efficacy of Levetiracetam in the Adjunctive Treatment of Female Subjects With C1 Catamenial Epilepsy
NCT00630968	PHASE4	COMPLETED	S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00631150	PHASE4	COMPLETED	A Phase IV-Pharmacovigilance Study of Keppra Greece - S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00659958	PHASE4	COMPLETED	ZAGAL Study: Evaluating Effectiveness and Tolerability of Zonisamide as Adjunctive Therapy in Patients With Partial Onset Seizures Treated With Two Antiepileptic Drugs
NCT00713622	PHASE4	COMPLETED	Comparing The Effect On Cognition Of Adjunctive Therapy With Zonisamide Versus Sodium Valproate
NCT00807989	PHASE4	COMPLETED	The Efficacy and Safety of Low Dose Combination of LTG and VPA Compared to CBZ Monotherapy
NCT00832884	PHASE4	COMPLETED	The Safety of Intravenous Lacosamide
NCT00869622	PHASE4	COMPLETED	Antiepileptic Drugs and Osteoporotic Prevention Trial
NCT00896987	PHASE4	COMPLETED	Lamotrigine Cognitive Function Study in Adult Untreated Epilepsies
NCT00952081	PHASE4	COMPLETED	A Pilot Study to Evaluate Efficacy and Safety of Clevidipine in Neurosurgical Patients
NCT01118455	PHASE4	TERMINATED	Trial to Assess Vagus Nerve Stimulation Therapy vs. Anti-Epileptic Drug (AED) Treatment in Children With Refractory Seizures
NCT01127165	PHASE4	COMPLETED	Low and High Dose Zonisamide in Children as Monotherapy
NCT01127256	PHASE4	COMPLETED	Comparative Study of Zonisamide and Carbamazepine as an Initial Monotherapy: Efficacy and Safety Evaluation
NCT01140867	PHASE4	COMPLETED	Open-label, Multi-center Trial of Zonisamide as Adjunctive Therapy in Patients With Uncontrolled Partial Epilepsy
NCT01175954	PHASE4	COMPLETED	Cognitive and Behavioral Effects of Lacosamide
NCT01229735	PHASE4	COMPLETED	Levetiracetam Versus Topiramate as Adjunctive Therapy to Evaluate Efficacy and Safety in Subjects With Refractory Partial Onset Seizures
NCT01244724	PHASE4	TERMINATED	Lexapro for Major Depression in Patients With Epilepsy