MSI1

Summary

MSI1 (musashi RNA binding protein 1, HGNC:7330) is a protein-coding gene on chromosome 12q24.31, encoding RNA-binding protein Musashi homolog 1 (O43347). RNA binding protein that regulates the expression of target mRNAs at the translation level.

This gene encodes a protein containing two conserved tandem RNA recognition motifs. Similar proteins in other species function as RNA-binding proteins and play central roles in posttranscriptional gene regulation. Expression of this gene has been correlated with the grade of the malignancy and proliferative activity in gliomas and melanomas. A pseudogene for this gene is located on chromosome 11q13.

Source: NCBI Gene 4440 — RefSeq curated summary.

At a glance

• Gene–disease (curated): microcephaly (Limited, GenCC)
• GWAS associations: 5
• Clinical variants (ClinVar): 47 total
• MANE Select transcript: NM_002442

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7330
Approved symbol	MSI1
Name	musashi RNA binding protein 1
Location	12q24.31
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000135097
Ensembl biotype	protein_coding
OMIM	603328
Entrez	4440

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 11 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000257552, ENST00000546622, ENST00000546985, ENST00000854930, ENST00000854931, ENST00000923990, ENST00000923991, ENST00000923992, ENST00000923993, ENST00000923994, ENST00000923995, ENST00000923996

RefSeq mRNA: 15 — MANE Select: NM_002442 NM_001414485, NM_001414486, NM_001414487, NM_001414488, NM_001414489, NM_001414490, NM_001414491, NM_001414492, NM_001414493, NM_001414494, NM_001414495, NM_001414496, NM_001414497, NM_001414498, NM_002442

CCDS: CCDS9196

Canonical transcript exons

ENST00000257552 — 15 exons

Exon	Start	End
ENSE00000918194	120368833	120368873
ENSE00000918195	120368192	120368273
ENSE00000918196	120368008	120368092
ENSE00000918197	120364714	120364755
ENSE00000918198	120363043	120363135
ENSE00000918202	120353299	120353379
ENSE00000918203	120351344	120351400
ENSE00000918204	120347446	120347514
ENSE00000918205	120346135	120346322
ENSE00000918206	120345570	120345632
ENSE00001207974	120369033	120369164
ENSE00001300361	120341330	120343105
ENSE00003500227	120357816	120357898
ENSE00003546317	120359005	120359053
ENSE00003688577	120356902	120357019

Expression profiles

Bgee: expression breadth ubiquitous, 164 present calls, max score 98.65.

FANTOM5 (CAGE): breadth broad, TPM avg 4.7379 / max 130.1297, expressed in 589 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
133655	2.1277	419
133656	2.0266	505
133653	0.2857	137
133651	0.1242	68
133654	0.0946	46
133652	0.0752	35
133647	0.0040	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	98.65	gold quality
ganglionic eminence	UBERON:0004023	97.08	gold quality
Brodmann (1909) area 10	UBERON:0013541	91.51	silver quality
cortical plate	UBERON:0005343	91.09	gold quality
frontal pole	UBERON:0002795	88.75	silver quality
paraflocculus	UBERON:0005351	88.73	gold quality
middle frontal gyrus	UBERON:0002702	88.36	gold quality
left testis	UBERON:0004533	88.11	gold quality
right testis	UBERON:0004534	87.47	gold quality
adenohypophysis	UBERON:0002196	85.50	gold quality
testis	UBERON:0000473	84.59	gold quality
embryo	UBERON:0000922	84.41	gold quality
tongue squamous epithelium	UBERON:0006919	84.30	gold quality
pituitary gland	UBERON:0000007	81.79	gold quality
islet of Langerhans	UBERON:0000006	80.26	gold quality
cervix squamous epithelium	UBERON:0006922	78.98	gold quality
amygdala	UBERON:0001876	77.47	gold quality
endometrium epithelium	UBERON:0004811	77.31	gold quality
type B pancreatic cell	CL:0000169	77.14	gold quality
cingulate cortex	UBERON:0003027	77.14	gold quality
anterior cingulate cortex	UBERON:0009835	77.08	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	76.93	gold quality
caudate nucleus	UBERON:0001873	76.82	gold quality
buccal mucosa cell	CL:0002336	76.36	silver quality
right uterine tube	UBERON:0001302	76.15	gold quality
nucleus accumbens	UBERON:0001882	75.75	gold quality
right frontal lobe	UBERON:0002810	75.69	gold quality
putamen	UBERON:0001874	75.02	gold quality
pancreas	UBERON:0001264	74.93	gold quality
left adrenal gland cortex	UBERON:0035825	73.99	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.55
E-MTAB-6108	no	198.45

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CCND1, ERBB2, HES1, HNF4A, TBX15

miRNA regulators (miRDB)

140 targeting MSI1, 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-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AR-3P	99.85	71.26	3889

Literature-anchored findings (GeneRIF, showing 40)

• association between Musashi1 and the development of liver cancer (PMID:12054577)
• analysis of RNA binding affinity of domains in mouse musashi1 protein (PMID:12907678)
• The presence of Msi-1 in a significant percentage of neurons containing cytoplasmic inclusions in Alzheimer disease and Pick disease suggests that it may play a role in the pathogenesis of these lesions. (PMID:16106215)
• Msi-1’s ability to regulate progenitor maintenance is through the translational inhibition of the cyclin-dependent kinase inhibitor p21WAF-1. (PMID:16214366)
• Results indicate that Musashi1 is a useful marker for immature cells in periventricular areas inhabited by stem cells, progenitor cells, and differentiating cells. (PMID:16777095)
• We conclude that Helicobacter pylori infection strongly induces Msi-1 in the gastric corpus. Given its expression in dividing cells, Msi-1 may modulate the state of gastric progenitor cells. (PMID:17549630)
• may be involved in carcinogenesis of the cervix and progression of cervical carcinoma (PMID:18419830)
• Msi-1 involved in cancer cell proliferation, inhibition of apoptosis, and mitotic catastrophe, suggesting an important potential mechanism for its role in tumorigenesis. (PMID:18471519)
• study demonstrated endometrial expression of Musashi-1; Musashi-1 expressing stromal cell & cell group numbers were increased in endometriotic & endometrial carcinoma tissue compared to secretory endometrium (PMID:18473332)
• Msi1 may promote cancer cell proliferation and survival as its loss seems to have a detrimental effect in the maintenance of medulloblastoma cancer cells. (PMID:18826648)
• Msi-1 suppresses expression of Paneth cell-specific genes in IECs, presumably through a pathway independent from Notch or Wnt (PMID:19214660)
• Msi1 affects a network of genes and could function as a master regulator during development and tumor formation. (PMID:19258308)
• Musashi-1 and beta1-integrin may be involved in human colorectal tumor carcinogenesis and progression. (PMID:19714342)
• Msi1 is a negative prognostic indicator of breast cancer patient survival, and is indicative of tumor cells with stem cell-like characteristics. (PMID:20727204)
• We conclude that Ishikawa cells contain a subpopulation of cells with stem cell-like properties. Musashi-1 modulates endometrial carcinoma cell cycle progression and apoptosis via the stemness-related factors Notch-1, Hes-1 and p21(WAF1/CIP1) (PMID:21165952)
• APC as a key factor in MSI1 regulation through Wnt signaling and identify APC mRNA as a novel target of translational inhibition by MSI1. (PMID:21199875)
• Overexpression of Msi-1 was associated with lymph node metastasis in colon cancer. (PMID:21442350)
• Msi-1 positive cells have several characteristics of stem cells, such as high proliferative potentiality and multipotency (PMID:21751144)
• CD44 and Musashi-1 are frequently expressed in both premalignant gastric lesions and invasive gastric cancer, whereas CD133 expression is restricted mainly to neoplastic tissues. (PMID:21829201)
• study concludes that tumor suppressor miRNAs are direct and influential regulators of Msi1, affecting its expression pattern during tumorigenesis of malignant nervous system tumors (PMID:21881409)
• Our study suggested that Msi-1 and/or ALDH1 expression might be closely related to the carcinogenesis, progression, clinical biological behaviors, and prognosis of gallbladder adenocarcinoma. (PMID:22012766)
• Overexpression of MSI1 was sufficient to increase Hes1, stimulate proliferation, inhibit apoptosis and reduce insulin expression, whereas Msi1 knockdown had the converse effects on proliferation and insulin expression. (PMID:22113197)
• Musashi1 is regulated by HuR via mRNA translation and stability in glioblastoma cells. (PMID:22258704)
• Msi1 functions as a regulator of multiple processes in medulloblastoma formation and could become an important therapeutic target. (PMID:22985791)
• Msi1 has different expression patterns in glioma from Grade I to Grade IV, and the different expression patterns play diverse roles in angiogenesis of glioma. (PMID:23017339)
• was a statistical difference between the MSI1 gene expression in intestinal versus diffuse type gastric cancer (PMID:23164718)
• study provides novel insights into Hedgehog/Msi1 signaling and its role in the regulation of the self-renewal capability of human umbilical cord blood (UCB)-derived mesenchymal stem cells (PMID:23418578)
• Msi1 regulates the proliferation of stem-like spheroid lung tumor cells in associated with Notch and Wnt signaling. (PMID:23715514)
• Musashi-1 mediates the downregulation of the 26S proteasome by binding to the mRNA of NF-YA, the transcriptional factor regulating 26S proteasome subunit expression (PMID:24022895)
• High levels of Musashi-1 were associated with gliomas. (PMID:24057325)
• our data demonstrated that Musashi 1 is highly and un-differentially expressed in both examined tumoral and apparently normal bladder tissues. (PMID:24061461)
• Msi-1-positive cells may play a key role in the early events of gastric carcinogenesis and may be involved in invasion and metastasis of gastric cancer cells. (PMID:24151393)
• Msi1 was significantely overexpressed in 41.5 % of tumor samples. (PMID:24163304)
• Aberrant Musashi-1 expression in adenomyosis may be involved in the pathogenesis and pathophysiology of adenomyosis, but it does not correlate with changes in serum estradiol or progesterone levels. (PMID:24365097)
• oncogenic role in hepatocellular carcinoma may be through modulation of cell growth and cell cycle by activating Wnt pathway via direct downregulation of APC and DKK1 (PMID:24444033)
• The principal findings included significantly higher level of Msi-1 expression in younger gastric cancer patients compared to older ones, and probable association of tumor Msi-1 expression in young gastric cancer patients with more aggressive tumor type. (PMID:24452324)
• NOTCH3 signaling regulates MUSASHI-1 expression in metastatic colorectal cancer cells. (PMID:24525742)
• an association between a Musashi-1 genotype and lung cancer risk (PMID:24787949)
• High Msi1 promotes tumor growth and cell proliferation by targeting cell cycle checkpoint proteins p21, p27 and p53 in cervical carcinomas. (PMID:25362645)
• Msi proteins contribute to an epithelial gene expression program in neural and mammary cell types. (PMID:25380226)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	msi1b	ENSDARG00000010710
mus_musculus	Msi1	ENSMUSG00000054256
rattus_norvegicus	Msi1	ENSRNOG00000001156

Paralogs (36): DAZAP1 (ENSG00000071626), CIRBP (ENSG00000099622), RBM23 (ENSG00000100461), RBM3 (ENSG00000102317), NCL (ENSG00000115053), TIA1 (ENSG00000116001), HNRNPA2B1 (ENSG00000122566), RBM19 (ENSG00000122965), RBM39 (ENSG00000131051), HNRNPA1 (ENSG00000135486), HNRNPD (ENSG00000138668), HNRNPA1L2 (ENSG00000139675), RBMX (ENSG00000147274), A1CF (ENSG00000148584), TIAL1 (ENSG00000151923), RBM46 (ENSG00000151962), HNRNPDL (ENSG00000152795), MSI2 (ENSG00000153944), RBM47 (ENSG00000163694), RBMY1F (ENSG00000169800), HNRNPA3 (ENSG00000170144), RBMXL2 (ENSG00000170748), RBM4B (ENSG00000173914), RBM4 (ENSG00000173933), RBMXL3 (ENSG00000175718), HNRNPA0 (ENSG00000177733), TRNAU1AP (ENSG00000180098), HNRNPAB (ENSG00000197451), RBMXL1 (ENSG00000213516), HNRNPA1L3 (ENSG00000224578), RBMY1J (ENSG00000226941), RBMY1A1 (ENSG00000234414), RBMY1E (ENSG00000242389), RBMY1B (ENSG00000242875), RBMY1D (ENSG00000244395), DND1 (ENSG00000256453)

Protein

Protein identifiers

RNA-binding protein Musashi homolog 1 — O43347 (reviewed: O43347)

All UniProt accessions (2): O43347, H0YHB7

UniProt curated annotations — full annotation on UniProt →

Function. RNA binding protein that regulates the expression of target mRNAs at the translation level. Regulates expression of the NOTCH1 antagonist NUMB. Binds RNA containing the sequence 5’-GUUAGUUAGUUAGUU-3’ and other sequences containing the pattern 5’-[GA]U(1-3)AGU-3’. May play a role in the proliferation and maintenance of stem cells in the central nervous system.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Detected in fetal kidney, brain, liver and lung, and in adult brain and pancreas. Detected in hepatoma cell lines.

Domain organisation. The first RNA recognition motif binds more strongly to RNA compared to the second one.

Similarity. Belongs to the Musashi family.

RefSeq proteins (15): NP_001401414, NP_001401415, NP_001401416, NP_001401417, NP_001401418, NP_001401419, NP_001401420, NP_001401421, NP_001401422, NP_001401423, NP_001401424, NP_001401425, NP_001401426, NP_001401427, NP_002433* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000504	RRM_dom	Domain
IPR012677	Nucleotide-bd_a/b_plait_sf	Homologous_superfamily
IPR034126	MSI_RRM2	Domain
IPR035979	RBD_domain_sf	Homologous_superfamily

Pfam: PF00076

UniProt features (11 total): sequence conflict 5, domain 2, modified residue 2, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43347-F1	65.76	0.27

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): 1, 191

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-9010553	Regulation of expression of SLITs and ROBOs
R-HSA-1266738	Developmental Biology
R-HSA-376176	Signaling by ROBO receptors
R-HSA-422475	Axon guidance
R-HSA-9675108	Nervous system development

MSigDB gene sets: 169 (showing top): SHEPARD_BMYB_MORPHOLINO_UP, AP1_01, AAGCAAT_MIR137, GOBP_EPITHELIUM_DEVELOPMENT, MODULE_151, ENK_UV_RESPONSE_KERATINOCYTE_UP, MODULE_418, DARWICHE_SKIN_TUMOR_PROMOTER_DN, DARWICHE_PAPILLOMA_RISK_LOW_DN, DARWICHE_PAPILLOMA_RISK_HIGH_DN, DARWICHE_SQUAMOUS_CELL_CARCINOMA_DN, TAL1ALPHAE47_01, AP2_Q3, CACCAGC_MIR138, GGGTGGRR_PAX4_03

GO Biological Process (5): regulation of translation (GO:0006417), nervous system development (GO:0007399), central nervous system development (GO:0007417), response to hormone (GO:0009725), epithelial cell differentiation (GO:0030855)

GO Molecular Function (9): RNA binding (GO:0003723), mRNA binding (GO:0003729), poly(U) RNA binding (GO:0008266), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), molecular condensate scaffold activity (GO:0140693), nucleic acid binding (GO:0003676), single-stranded RNA binding (GO:0003727), protein binding (GO:0005515)

GO Cellular Component (2): nucleus (GO:0005634), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Signaling by ROBO receptors	1
Axon guidance	1
Nervous system development	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
system development	2
RNA binding	2
binding	2
translation	1
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
nervous system development	1
response to endogenous stimulus	1
response to chemical	1
cell differentiation	1
epithelium development	1
nucleic acid binding	1
poly-pyrimidine tract binding	1
protein binding	1
identical protein binding	1
protein dimerization activity	1
protein-macromolecule adaptor activity	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1608 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MSI1	NUMBL	Q9Y6R0	799
MSI1	NUMB	P49757	799
MSI1	SOX2	P48431	787
MSI1	NES	P48681	769
MSI1	LARP1	Q6PKG0	765
MSI1	CPEB1	Q9BZB8	756
MSI1	PROM1	O43490	672
MSI1	MOS	P00540	668
MSI1	RBBP7	Q16576	667
MSI1	LIN9	Q5TKA1	665
MSI1	LIN54	Q6MZP7	665
MSI1	LIN37	Q96GY3	665
MSI1	NOTCH1	P46531	660
MSI1	BMI1	P35226	628
MSI1	R4GMX3	R4GMX3	628

IntAct

66 interactions, top by confidence:

A	B	Type	Score
MRPS30	GTPBP10	psi-mi:“MI:0914”(association)	0.640
MSI1	HNRNPH2	psi-mi:“MI:0915”(physical association)	0.560
MSI1	HNRNPF	psi-mi:“MI:0915”(physical association)	0.560
BCOR	CBX4	psi-mi:“MI:0914”(association)	0.530
MRPL2	GTPBP10	psi-mi:“MI:0914”(association)	0.530
MRPL18	GTPBP10	psi-mi:“MI:0914”(association)	0.530
ESRP1	RGPD8	psi-mi:“MI:0914”(association)	0.530
MSI1	MSI1	psi-mi:“MI:0407”(direct interaction)	0.520
MAPT	MSI1	psi-mi:“MI:0407”(direct interaction)	0.440
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
DND1	RPSA2	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
LOXL3	MSI1	psi-mi:“MI:0914”(association)	0.350
ARHGAP31	TIMM23	psi-mi:“MI:0914”(association)	0.350
VAV1	DDX39A	psi-mi:“MI:0914”(association)	0.350
IRAK1	ILVBL	psi-mi:“MI:0914”(association)	0.350
LIMK2	HAX1	psi-mi:“MI:0914”(association)	0.350
LIN28A	MEX3A	psi-mi:“MI:0914”(association)	0.350
CEP63	CIT	psi-mi:“MI:0914”(association)	0.350
CEP135	MCRIP1	psi-mi:“MI:0914”(association)	0.350
CEP135	WWP2	psi-mi:“MI:0914”(association)	0.350
DYRK1A	TEX13D	psi-mi:“MI:0914”(association)	0.350
ITM2B	ILVBL	psi-mi:“MI:0914”(association)	0.350
MRPL30	GTPBP10	psi-mi:“MI:0914”(association)	0.350

BioGRID (139): MSI1 (Affinity Capture-MS), MSI1 (Proximity Label-MS), MSI1 (Affinity Capture-MS), MSI1 (Affinity Capture-MS), MSI1 (Affinity Capture-MS), MSI1 (Affinity Capture-MS), MSI1 (Affinity Capture-MS), MSI1 (Affinity Capture-MS), MSI1 (Affinity Capture-MS), MSI1 (Two-hybrid), HNRNPF (Two-hybrid), MSI1 (Protein-RNA), MSI1 (Protein-RNA), MSI1 (Protein-RNA), MSI1 (Protein-RNA)

ESM2 similar proteins: A0A8M1NHK4, A0AV96, B3M3R5, B4KX02, O22173, O43347, P86049, Q05196, Q15233, Q1LZD9, Q32NN2, Q3UEB3, Q4KLH4, Q5R469, Q5R5P4, Q5R9H4, Q5RFL9, Q5W9D5, Q5W9D6, Q5W9D7, Q5YD48, Q61474, Q66H68, Q6DEY7, Q6GR16, Q6IRN2, Q6P0D0, Q7JJZ8, Q8GZ26, Q8K3P4, Q8MSV2, Q8R326, Q8TBY0, Q8WXF1, Q91WT8, Q91XU1, Q920Q6, Q923K9, Q96DH6, Q96PU8

Diamond homologs: A0A0D1C8Z4, A0A2R8Y4L2, A5A6H4, A7VJC2, D0VWM8, G5EFS2, O14979, O43347, O88569, O89086, O93235, O94432, P04256, P07909, P09405, P09651, P09867, P13383, P17130, P19338, P19682, P19683, P21522, P22626, P28644, P41891, P48809, P48810, P49312, P51968, P51989, P51990, P51991, P51992, P60824, P60825, P60826, P98179, Q02926, Q03878

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
CCND1	“up-regulates quantity by expression”	MSI1	“transcriptional regulation”
ERBB2	“up-regulates quantity by expression”	MSI1	“transcriptional regulation”
MSI1	down-regulates	NUMB	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 72 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
Mitochondrial translation	7	20.9×	7e-06
Mitochondrial translation initiation	7	19.3×	7e-06
Mitochondrial translation elongation	7	19.3×	7e-06
Mitochondrial ribosome-associated quality control	7	18.7×	7e-06
Mitochondrial translation termination	7	16.7×	1e-05
Translation	7	9.4×	4e-04

GO biological processes:

GO term	Partners	Fold	FDR
regulation of alternative mRNA splicing, via spliceosome	5	18.5×	2e-03
mitochondrial translation	7	18.4×	5e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	34
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2665 predictions. Top by Δscore:

Variant	Effect	Δscore
12:120346130:CTCA:C	donor_loss	1.0000
12:120346131:TCA:T	donor_loss	1.0000
12:120346132:CA:C	donor_loss	1.0000
12:120346133:A:AC	donor_gain	1.0000
12:120346133:A:C	donor_loss	1.0000
12:120346133:AC:A	donor_gain	1.0000
12:120346133:ACC:A	donor_gain	1.0000
12:120346133:ACCC:A	donor_gain	1.0000
12:120346134:C:CC	donor_gain	1.0000
12:120346134:CC:C	donor_gain	1.0000
12:120346134:CCC:C	donor_gain	1.0000
12:120346134:CCCC:C	donor_gain	1.0000
12:120346134:CCCCA:C	donor_gain	1.0000
12:120347441:CTCAC:C	donor_loss	1.0000
12:120347442:TCA:T	donor_loss	1.0000
12:120347443:CA:C	donor_loss	1.0000
12:120347445:C:CT	donor_loss	1.0000
12:120347511:ATGG:A	acceptor_gain	1.0000
12:120347512:TGG:T	acceptor_gain	1.0000
12:120347513:GG:G	acceptor_gain	1.0000
12:120347515:C:CC	acceptor_gain	1.0000
12:120347821:AAC:A	donor_gain	1.0000
12:120348200:ATC:A	donor_gain	1.0000
12:120348200:ATCC:A	donor_gain	1.0000
12:120356838:AGCC:A	donor_gain	1.0000
12:120357811:CTCA:C	donor_loss	1.0000
12:120357812:TCA:T	donor_loss	1.0000
12:120357813:CA:C	donor_loss	1.0000
12:120357814:A:AT	donor_loss	1.0000
12:120357815:C:CG	donor_loss	1.0000

AlphaMissense

2369 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:120356992:C:T	E188K	1.000
12:120356993:C:A	K187N	1.000
12:120356993:C:G	K187N	1.000
12:120356995:T:C	K187E	1.000
12:120356997:G:T	P186Q	1.000
12:120357003:G:A	A184V	1.000
12:120357003:G:T	A184D	1.000
12:120357004:C:T	A184T	1.000
12:120357005:T:A	K183N	1.000
12:120357005:T:G	K183N	1.000
12:120357007:T:C	K183E	1.000
12:120357008:C:A	K182N	1.000
12:120357008:C:G	K182N	1.000
12:120357009:T:A	K182M	1.000
12:120357009:T:G	K182T	1.000
12:120357010:T:C	K182E	1.000
12:120357010:T:G	K182Q	1.000
12:120357011:A:C	C181W	1.000
12:120357012:C:A	C181F	1.000
12:120357012:C:T	C181Y	1.000
12:120357013:A:G	C181R	1.000
12:120357014:T:A	E180D	1.000
12:120357014:T:G	E180D	1.000
12:120357015:T:A	E180V	1.000
12:120357015:T:C	E180G	1.000
12:120357016:C:T	E180K	1.000
12:120357018:A:T	V179E	1.000
12:120357019:C:A	V179L	1.000
12:120357019:C:G	V179L	1.000
12:120357019:C:T	V179M	1.000

dbSNP variants (sampled 300 via entrez): RS1000102146 (12:120347053 G>A), RS1000173275 (12:120353002 G>A), RS1000216424 (12:120366741 G>A), RS1000362790 (12:120368485 G>A,C), RS1000373930 (12:120360146 T>C), RS1000434256 (12:120349906 A>G), RS1000459343 (12:120342040 G>A), RS1000499842 (12:120357297 G>A), RS1000537327 (12:120349442 C>T), RS1000619452 (12:120363606 C>T), RS1000779312 (12:120343841 A>C), RS1000880557 (12:120354637 G>A,C), RS1000963512 (12:120371008 G>A), RS1001063002 (12:120348105 C>G,T), RS1001075203 (12:120341684 C>T)

Disease associations

OMIM: gene MIM:603328 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
microcephaly	Limited	Autosomal recessive

Mondo (1): microcephaly (MONDO:0001149)

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST007843_22	Rheumatoid arthritis	2.000000e-08
GCST008103_87	Bipolar disorder	1.000000e-06
GCST008159_63	Waist-to-hip ratio adjusted for BMI	5.000000e-06
GCST008180_12	Spontaneous preterm birth with premature rupture of membranes	8.000000e-06
GCST90020028_952	Hip circumference adjusted for BMI	2.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0006917	spontaneous preterm birth
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, increases methylation, decreases expression, decreases methylation, decreases reaction	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects expression, affects cotreatment, increases expression	2
Lead	affects expression, affects splicing, decreases expression	2
FR900359	decreases phosphorylation	1
mivebresib	decreases expression	1
mono-(2-ethylhexyl)phthalate	increases abundance, increases methylation	1
sodium arsenite	increases expression	1
eckol	decreases expression	1
tamibarotene	affects expression	1
abrine	decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
excavatolide B	decreases expression	1
Resveratrol	decreases expression	1
Decitabine	decreases expression, affects reaction	1
Arsenic Trioxide	increases reaction, increases expression, affects reaction, increases phosphorylation, decreases reaction (+2 more)	1
Fulvestrant	affects cotreatment, increases methylation	1
Benzo(a)pyrene	increases methylation	1
Cadmium	increases expression	1
Calcitriol	increases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Diethylhexyl Phthalate	increases abundance, increases methylation	1
Doxorubicin	affects binding, increases reaction	1
Estradiol	increases expression	1
Poly I-C	increases reaction, increases expression	1
Ribonucleotides	affects binding	1
Rotenone	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	affects expression	1
Valproic Acid	increases methylation	1

Cellosaurus cell lines

7 cell lines: 4 cancer cell line, 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A4F5	SEES3-1V human MSI1, clone1	Embryonic stem cell	Male
CVCL_A4F6	SEES3-1V human MSI1, clone2	Embryonic stem cell	Male
CVCL_A4F7	SEES3-1V human MSI1, clone3	Embryonic stem cell	Male
CVCL_D1XN	Abcam A-549 MSI1 KO	Cancer cell line	Male
CVCL_D2BZ	Abcam HCT 116 MSI1 KO	Cancer cell line	Male
CVCL_SZ04	HAP1 MSI1 (-) 1	Cancer cell line	Male
CVCL_XQ64	HAP1 MSI1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.