NSMCE2

Summary

NSMCE2 (NSE2 SUMO ligase component of SMC5/6 complex, HGNC:26513) is a protein-coding gene on chromosome 8q24.13, encoding E3 SUMO-protein ligase NSE2 (Q96MF7). E3 SUMO-protein ligase component of the SMC5-SMC6 complex, a complex involved in DNA double-strand break repair by homologous recombination. It is a selective cancer dependency (DepMap: 40.0% of cell lines).

This gene encodes a member of a family of E3 small ubiquitin-related modifier (SUMO) ligases that mediates the attachment of a SUMO protein to proteins involved in nuclear transport, transcription, chromosome segregation and DNA repair. The encoded protein is part of the structural maintenance of chromosomes (SMC) 5/6 complex which plays a key role genome maintenance, facilitating chromosome segregation and suppressing mitotic recombination. A knockout of the orthologous mouse gene is lethal prior to embryonic day 10.5. Naturally occurring mutations in this gene, that abolish the SUMO ligase activity, are associated with primordial dwarfism and extreme insulin resistance.

Source: NCBI Gene 286053 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Seckel syndrome 10 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 20
• Clinical variants (ClinVar): 123 total — 8 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 57
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 40.0% of screened cell lines
• MANE Select transcript: NM_173685

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26513
Approved symbol	NSMCE2
Name	NSE2 SUMO ligase component of SMC5/6 complex
Location	8q24.13
Locus type	gene with protein product
Status	Approved
Aliases	FLJ32440, MMS21, NSE2, ZMIZ7
Ensembl gene	ENSG00000156831
Ensembl biotype	protein_coding
OMIM	617246
Entrez	286053

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 25 protein_coding, 2 nonsense_mediated_decay, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000287437, ENST00000517315, ENST00000517532, ENST00000518013, ENST00000518146, ENST00000519010, ENST00000519712, ENST00000520866, ENST00000521460, ENST00000522563, ENST00000523549, ENST00000523741, ENST00000523824, ENST00000897049, ENST00000897050, ENST00000897051, ENST00000897052, ENST00000897053, ENST00000897054, ENST00000897055, ENST00000897056, ENST00000897057, ENST00000916072, ENST00000916073, ENST00000916074, ENST00000916075, ENST00000916076, ENST00000965108, ENST00000965109, ENST00000965110

RefSeq mRNA: 4 — MANE Select: NM_173685 NM_001349485, NM_001349486, NM_001349487, NM_173685

CCDS: CCDS6356, CCDS87625

Canonical transcript exons

ENST00000287437 — 8 exons

Exon	Start	End
ENSE00001173804	125357712	125357818
ENSE00001236866	125357219	125357319
ENSE00001237234	125102051	125102146
ENSE00002096207	125366768	125367120
ENSE00002116636	125091860	125091958
ENSE00003491816	125151171	125151277
ENSE00003679859	125102317	125102487
ENSE00003788963	125182103	125182256

Expression profiles

Bgee: expression breadth ubiquitous, 259 present calls, max score 99.43.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.3046 / max 191.9413, expressed in 1811 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
90540	21.0244	1809
90539	1.0904	728
90541	0.6211	322
90542	0.3863	167
90543	0.1824	76

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
colonic epithelium	UBERON:0000397	99.43	gold quality
bone marrow cell	CL:0002092	97.65	gold quality
tibialis anterior	UBERON:0001385	94.86	gold quality
upper arm skin	UBERON:0004263	92.63	gold quality
calcaneal tendon	UBERON:0003701	92.46	gold quality
monocyte	CL:0000576	92.22	gold quality
leukocyte	CL:0000738	91.98	gold quality
deltoid	UBERON:0001476	91.74	gold quality
bone marrow	UBERON:0002371	91.54	gold quality
islet of Langerhans	UBERON:0000006	91.42	gold quality
left ventricle myocardium	UBERON:0006566	91.37	silver quality
adrenal tissue	UBERON:0018303	91.30	gold quality
myocardium	UBERON:0002349	91.15	silver quality
cardiac muscle of right atrium	UBERON:0003379	90.99	silver quality
skeletal muscle tissue	UBERON:0001134	90.95	gold quality
tendon	UBERON:0000043	90.93	gold quality
gastrocnemius	UBERON:0001388	90.83	gold quality
quadriceps femoris	UBERON:0001377	90.77	gold quality
muscle of leg	UBERON:0001383	90.77	gold quality
muscle tissue	UBERON:0002385	90.64	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.62	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.42	gold quality
vastus lateralis	UBERON:0001379	90.32	gold quality
biceps brachii	UBERON:0001507	90.28	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	90.21	gold quality
popliteal artery	UBERON:0002250	89.91	gold quality
tibial artery	UBERON:0007610	89.91	gold quality
bone element	UBERON:0001474	89.61	gold quality
hindlimb stylopod muscle	UBERON:0004252	89.58	gold quality
tendon of biceps brachii	UBERON:0008188	89.23	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

11 targeting NSMCE2, 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-4500	99.99	72.72	2367
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-498-5P	99.76	69.64	1807
HSA-MIR-1324	99.46	66.57	1302
HSA-MIR-4652-3P	99.33	70.02	2742
HSA-MIR-31-3P	95.17	69.82	575
HSA-MIR-4640-3P	94.58	63.02	263
HSA-MIR-6798-3P	94.55	68.78	325

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 40.0% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 10)

• the human SMC5/6 complex and the SUMO ligase activity of hMMS21 are required for the prevention of DNA damage-induced apoptosis by facilitating DNA repair in human cells (PMID:16055714)
• MMS21 dependent sumoylation is integral and important to the cohesion mechanism and mitotic progression and that this function appears to be independent of SMC6. (PMID:19502785)
• Studies indicate that Nse1 may function as a ubiquitin ligase, and is targeted to chromatin through its interaction with the Smc5/6 complex. (PMID:21550342)
• show that the Smc5/6 subunit Mms21 sumoylates multiple lysines of the cohesin subunit Scc1 (PMID:22751501)
• support a role for NSMCE2 in recovery from DNA damage and raise the possibility that loss of its function produces dwarfism through reduced tolerance of replicative stress (PMID:25105364)
• our study identified novel PVT1-NSMCE2 and CCDC26-NSMCE2 fusion genes that may play functional roles in leukemia. (PMID:25245984)
• Absence of NSMCE2 affects survival upon topoisomerase II inhibitor etoposide-induced DNA double-strand breaks double-strand breaks. (PMID:27792189)
• We demonstrate that Topo2a is SUMOylated in an ICRF193-dependent manner by NSE2 at a novel non-canonical site (K1520) and that K1520 sumoylation is required for chromosome segregation but not the G2 arrest. (PMID:30590722)
• Study the fate of collapsed replication forks generated by prolonged hydroxyurea treatment in NSMCE2-deficient cells. Double strand breaks accumulate during rescue by converging forks in normal cells but not in NSMCE2-deficient cells. Un-rescued forks persist into mitosis, leading to increased mitotic DNA damage. (PMID:30735491)
• NSMCE2, a novel super-enhancer-regulated gene, is linked to poor prognosis and therapy resistance in breast cancer. (PMID:36224576)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Nsmce2	ENSMUSG00000059586
rattus_norvegicus	Nsmce2	ENSRNOG00000003964

Protein

Protein identifiers

E3 SUMO-protein ligase NSE2 — Q96MF7 (reviewed: Q96MF7)

Alternative names: E3 SUMO-protein transferase NSE2, MMS21 homolog, Non-structural maintenance of chromosomes element 2 homolog

All UniProt accessions (8): Q96MF7, A0A087WTZ8, E5RFJ1, E5RG00, E5RHW9, E5RIM1, E5RK09, H0YB96

UniProt curated annotations — full annotation on UniProt →

Function. E3 SUMO-protein ligase component of the SMC5-SMC6 complex, a complex involved in DNA double-strand break repair by homologous recombination. Is not be required for the stability of the complex. The complex may promote sister chromatid homologous recombination by recruiting the SMC1-SMC3 cohesin complex to double-strand breaks. The complex is required for telomere maintenance via recombination in ALT (alternative lengthening of telomeres) cell lines and mediates sumoylation of shelterin complex (telosome) components which is proposed to lead to shelterin complex disassembly in ALT-associated PML bodies (APBs). Acts as an E3 ligase mediating SUMO attachment to various proteins such as SMC6L1 and TSNAX, the shelterin complex subunits TERF1, TERF2, TINF2 and TERF2IP, RAD51AP1, and maybe the cohesin components RAD21 and STAG2. Required for recruitment of telomeres to PML nuclear bodies. SUMO protein-ligase activity is required for the prevention of DNA damage-induced apoptosis by facilitating DNA repair, and for formation of APBs in ALT cell lines. Required for sister chromatid cohesion during prometaphase and mitotic progression.

Subunit / interactions. Component of the SMC5-SMC6 complex which consists at least of SMC5, SMC6, NSMCE2, NSMCE1, NSMCE4A or EID3 and NSMCE3.

Subcellular location. Nucleus. Chromosome. Telomere. PML body.

Post-translational modifications. Sumoylated, possibly via autosumoylation.

Disease relevance. Seckel syndrome 10 (SCKL10) [MIM:617253] A form of Seckel syndrome, a rare autosomal recessive disorder characterized by proportionate dwarfism of prenatal onset associated with low birth weight, growth retardation, severe microcephaly with a bird-headed like appearance, and intellectual disability. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Protein modification; protein sumoylation.

Similarity. Belongs to the NSE2 family.

RefSeq proteins (4): NP_001336414, NP_001336415, NP_001336416, NP_775956* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004181	Znf_MIZ	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR026846	Nse2(Mms21)	Family

Pfam: PF11789

UniProt features (28 total): mutagenesis site 5, cross-link 4, binding site 4, strand 3, helix 3, sequence variant 2, turn 2, modified residue 2, chain 1, zinc finger region 1, sequence conflict 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
9LWJ	ELECTRON MICROSCOPY	7.19
9LWL	ELECTRON MICROSCOPY	7.25
2YU4	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96MF7-F1	82.23	0.54

Functional residue map

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

Ligand- & substrate-binding residues (4): 185; 187; 210; 215

Post-translational modifications (6): 125, 130, 1, 116, 90, 107

Mutagenesis-validated functional residues (5):

Position	Phenotype
169	induces a strong decrease in sumo ligase activity.
185	induces a strong decrease in sumo ligase activity.
187	induces a strong decrease in sumo ligase activity.
210	induces a strong decrease in sumo ligase activity.
215	induces a strong decrease in sumo ligase activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-3108214	SUMOylation of DNA damage response and repair proteins

MSigDB gene sets: 350 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_DN, GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, GOBP_CHROMOSOME_ORGANIZATION, GOBP_POSITIVE_REGULATION_OF_MITOTIC_NUCLEAR_DIVISION, GOBP_REGULATION_OF_NUCLEAR_DIVISION, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_POSITIVE_REGULATION_OF_MITOTIC_CELL_CYCLE, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_TELOMERE_ORGANIZATION, GOBP_CHROMOSOME_SEPARATION, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_CELLULAR_SENESCENCE, GOBP_REGULATION_OF_TELOMERE_MAINTENANCE

GO Biological Process (12): telomere maintenance via recombination (GO:0000722), double-strand break repair via homologous recombination (GO:0000724), protein sumoylation (GO:0016925), regulation of telomere maintenance (GO:0032204), positive regulation of maintenance of mitotic sister chromatid cohesion (GO:0034184), positive regulation of mitotic metaphase/anaphase transition (GO:0045842), cell division (GO:0051301), cellular senescence (GO:0090398), chromatin looping (GO:0140588), DNA repair (GO:0006281), DNA recombination (GO:0006310), DNA damage response (GO:0006974)

GO Molecular Function (6): zinc ion binding (GO:0008270), SUMO transferase activity (GO:0019789), SUMO ligase activity (GO:0061665), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (7): chromosome, telomeric region (GO:0000781), nucleus (GO:0005634), nucleoplasm (GO:0005654), nuclear body (GO:0016604), PML body (GO:0016605), Smc5-Smc6 complex (GO:0030915), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
SUMO E3 ligases SUMOylate target proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
telomere maintenance	2
cellular process	2
cellular response to stress	2
DNA metabolic process	2
intracellular membraneless organelle	2
mitotic recombination	1
recombinational repair	1
double-strand break repair	1
peptidyl-lysine modification	1
protein modification by small protein conjugation	1
regulation of chromosome organization	1
regulation of DNA metabolic process	1
maintenance of mitotic sister chromatid cohesion	1
positive regulation of maintenance of sister chromatid cohesion	1
regulation of maintenance of mitotic sister chromatid cohesion	1
metaphase/anaphase transition of mitotic cell cycle	1
regulation of mitotic metaphase/anaphase transition	1
positive regulation of mitotic nuclear division	1
positive regulation of mitotic sister chromatid separation	1
positive regulation of mitotic cell cycle phase transition	1
positive regulation of metaphase/anaphase transition of cell cycle	1
chromatin organization	1
DNA damage response	1
transition metal ion binding	1
ubiquitin-like protein transferase activity	1
SUMO transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
cation binding	1
chromosomal region	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
nucleoplasm	1
nuclear body	1
condensed chromosome	1
SUMO ligase complex	1

Protein interactions and networks

STRING

1414 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NSMCE2	SMC5	Q8IY18	988
NSMCE2	SMC6	Q96SB8	983
NSMCE2	NSMCE3	Q96MG7	926
NSMCE2	UBE2I	P50550	853
NSMCE2	NSMCE4A	Q9NXX6	797
NSMCE2	PIAS2	O75928	795
NSMCE2	NSMCE1	Q8WV22	795
NSMCE2	UBA2	Q9UBT2	737
NSMCE2	RAD52	P43351	723
NSMCE2	TOP3A	Q13472	691
NSMCE2	SUMO1	P55856	672
NSMCE2	MUS81	Q96NY9	647
NSMCE2	RMI1	Q9H9A7	643
NSMCE2	SENP3	Q9H4L4	630
NSMCE2	PIAS4	Q8N2W9	627

IntAct

61 interactions, top by confidence:

A	B	Type	Score
SMC6	SMC5	psi-mi:“MI:0914”(association)	0.860
NSMCE1	SMC5	psi-mi:“MI:0914”(association)	0.760
NSMCE1	SMC5	psi-mi:“MI:0915”(physical association)	0.760
NSMCE2	TXLNA	psi-mi:“MI:0915”(physical association)	0.720
TXLNA	NSMCE2	psi-mi:“MI:0915”(physical association)	0.720
NSMCE2	SMC6	psi-mi:“MI:0915”(physical association)	0.710
NSMCE1	NSMCE2	psi-mi:“MI:0914”(association)	0.710
ZNF597	TASOR2	psi-mi:“MI:0914”(association)	0.640
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
DMWD	NSMCE2	psi-mi:“MI:0915”(physical association)	0.560
ELAVL4	NSMCE2	psi-mi:“MI:0915”(physical association)	0.560
NSMCE2	FGFR3	psi-mi:“MI:0915”(physical association)	0.560
NSMCE2	GSN	psi-mi:“MI:0915”(physical association)	0.560
KIF1B	NSMCE2	psi-mi:“MI:0915”(physical association)	0.560
NSMCE2	SPRED1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (75): NSMCE2 (Two-hybrid), USP28 (Biochemical Activity), NSMCE2 (Affinity Capture-MS), NSMCE2 (Affinity Capture-MS), NSMCE2 (Affinity Capture-MS), NDNL2 (Co-fractionation), NSMCE1 (Co-fractionation), SMC5 (Co-fractionation), SMC6 (Co-fractionation), NSMCE2 (Proximity Label-MS), NSMCE2 (Affinity Capture-MS), NSMCE2 (Affinity Capture-MS), NSMCE2 (Affinity Capture-MS), NSMCE2 (Affinity Capture-MS), NSMCE2 (Affinity Capture-MS)

ESM2 similar proteins: A0A1L8GLK3, A0A1W2PR95, A0A974CYQ5, E1C760, F1ND48, F4HRV8, O08836, P27641, P32780, P51948, P54729, P54731, P78318, Q2HJG8, Q2TBQ7, Q32KY9, Q3B8D4, Q498D5, Q4V8A0, Q4V8W7, Q5HZY0, Q5TZF3, Q5U2U7, Q5W9E7, Q61249, Q682V0, Q68F60, Q6NU18, Q6PCN7, Q6R1L1, Q6TLH3, Q7Z569, Q7ZXH2, Q810N6, Q8BSE0, Q8GYH7, Q8R5F7, Q8VCH8, Q8WTY4, Q91VT1

Diamond homologs: Q32KY9, Q4V8A0, Q7ZXH2, Q91VT1, Q96MF7, Q4PIR3, Q9SFX2

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
NSMCE2	“form complex”	SMC5/6	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 49 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
SUMOylation of DNA damage response and repair proteins	6	28.3×	1e-05

GO biological processes:

GO term	Partners	Fold	FDR
regulation of telomere maintenance	6	117.6×	1e-09
protein sumoylation	6	45.2×	4e-07
double-strand break repair via homologous recombination	7	25.4×	9e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	1
Uncertain significance	54
Likely benign	46
Benign	3

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
2427512	NC_000008.10:g.(?126369441)(126370080_?)del	Pathogenic
2696459	NM_173685.4(NSMCE2):c.20C>G (p.Ser7Ter)	Pathogenic
2793895	NM_173685.4(NSMCE2):c.466_470del (p.Glu156fs)	Pathogenic
372285	NM_173685.4(NSMCE2):c.346del (p.Ser116fs)	Pathogenic
372286	NM_173685.4(NSMCE2):c.697_700dup (p.Ala234fs)	Pathogenic
4748249	NM_173685.4(NSMCE2):c.25del (p.Ser9fs)	Pathogenic
657402	NM_173685.4(NSMCE2):c.394C>T (p.Gln132Ter)	Pathogenic
686069	GRCh37/hg19 8q24.13(chr8:126179381-126241524)x1	Pathogenic
3068125	NM_173685.4(NSMCE2):c.265-1G>A	Likely pathogenic

SpliceAI

3456 predictions. Top by Δscore:

Variant	Effect	Δscore
8:125102306:T:TA	acceptor_gain	1.0000
8:125102309:A:AG	acceptor_gain	1.0000
8:125102310:A:G	acceptor_gain	1.0000
8:125102312:CTTA:C	acceptor_loss	1.0000
8:125102313:TTAGG:T	acceptor_loss	1.0000
8:125102314:TAGGT:T	acceptor_loss	1.0000
8:125102483:TCAGA:T	donor_gain	1.0000
8:125102484:CAGA:C	donor_gain	1.0000
8:125102485:AGA:A	donor_gain	1.0000
8:125102486:GA:G	donor_gain	1.0000
8:125102486:GAG:G	donor_gain	1.0000
8:125102487:AGTA:A	donor_loss	1.0000
8:125102488:G:GG	donor_gain	1.0000
8:125102489:T:A	donor_loss	1.0000
8:125102490:AA:A	donor_loss	1.0000
8:125151169:A:AG	acceptor_gain	1.0000
8:125151170:G:GA	acceptor_gain	1.0000
8:125151170:GC:G	acceptor_gain	1.0000
8:125151170:GCT:G	acceptor_gain	1.0000
8:125151273:ATCAT:A	donor_gain	1.0000
8:125151274:TCAT:T	donor_gain	1.0000
8:125151274:TCATG:T	donor_loss	1.0000
8:125151275:CAT:C	donor_gain	1.0000
8:125151276:AT:A	donor_gain	1.0000
8:125151277:TG:T	donor_loss	1.0000
8:125151278:G:GA	donor_loss	1.0000
8:125151278:G:GG	donor_gain	1.0000
8:125151279:TAAG:T	donor_loss	1.0000
8:125151280:AA:A	donor_loss	1.0000
8:125182098:CTTA:C	acceptor_loss	1.0000

AlphaMissense

1663 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:125151254:G:C	A81P	0.993
8:125151237:T:C	L75P	0.989
8:125357719:T:C	M176T	0.989
8:125366815:T:C	L225P	0.989
8:125151258:T:A	V82D	0.988
8:125357728:C:A	P179Q	0.985
8:125357745:T:A	C185S	0.985
8:125357746:G:C	C185S	0.985
8:125357305:T:C	C169R	0.984
8:125366769:T:C	C210R	0.984
8:125357753:C:A	H187Q	0.983
8:125357753:C:G	H187Q	0.983
8:125357738:T:A	N182K	0.982
8:125357738:T:G	N182K	0.982
8:125357745:T:C	C185R	0.982
8:125151231:G:C	R73P	0.980
8:125366769:T:A	C210S	0.980
8:125366770:G:C	C210S	0.980
8:125357757:T:G	Y189D	0.979
8:125102473:T:C	L48P	0.977
8:125366784:T:A	C215S	0.976
8:125366785:G:C	C215S	0.976
8:125357746:G:A	C185Y	0.973
8:125366815:T:A	L225H	0.973
8:125357307:C:G	C169W	0.972
8:125357751:C:G	H187D	0.972
8:125366841:G:C	A234P	0.971
8:125151255:C:A	A81D	0.970
8:125366784:T:C	C215R	0.970
8:125357757:T:A	Y189N	0.968

dbSNP variants (sampled 300 via entrez): RS1000010653 (8:125219799 A>G), RS1000013060 (8:125107632 A>G), RS1000013929 (8:125292324 G>A), RS1000018143 (8:125286346 C>T), RS1000025246 (8:125330070 T>C), RS1000035135 (8:125245771 C>T), RS1000036312 (8:125127334 G>A,T), RS1000044688 (8:125279947 G>C,T), RS1000061941 (8:125099847 A>G), RS1000078568 (8:125330262 C>T), RS1000083342 (8:125109703 C>T), RS1000086748 (8:125256299 C>A), RS1000120138 (8:125151469 G>A), RS1000148648 (8:125281436 C>G,T), RS1000152252 (8:125183673 G>C)

Disease associations

OMIM: gene MIM:617246 | disease phenotypes: MIM:617253, MIM:603563, MIM:220210

GenCC curated gene-disease

Disease	Classification	Inheritance
Seckel syndrome 10	Strong	Autosomal recessive
microcephalic primordial dwarfism-insulin resistance syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Seckel syndrome 10	Moderate	AR

Mondo (5): Seckel syndrome 10 (MONDO:0014991), hereditary spastic paraplegia 8 (MONDO:0011339), Ritscher-Schinzel syndrome (MONDO:0019078), microcephaly (MONDO:0001149), (MONDO:0018575)

Orphanet (2): Autosomal dominant spastic paraplegia type 8 (Orphanet:100989), 3C syndrome (Orphanet:7)

HPO phenotypes

57 total (30 of 57 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000275	Narrow face
HP:0000308	Microretrognathia
HP:0000347	Micrognathia
HP:0000363	Abnormal earlobe morphology
HP:0000387	Absent earlobe
HP:0000444	Convex nasal ridge
HP:0000494	Downslanted palpebral fissures
HP:0000501	Glaucoma
HP:0000541	Retinal detachment
HP:0000682	Abnormal dental enamel morphology
HP:0000819	Diabetes mellitus
HP:0000822	Hypertension
HP:0000831	Insulin-resistant diabetes mellitus
HP:0000855	Insulin resistance
HP:0000956	Acanthosis nigricans
HP:0001249	Intellectual disability
HP:0001363	Craniosynostosis
HP:0001382	Joint hypermobility
HP:0001385	Hip dysplasia
HP:0001397	Hepatic steatosis
HP:0001511	Intrauterine growth retardation
HP:0001635	Congestive heart failure
HP:0001714	Ventricular hypertrophy
HP:0001735	Acute pancreatitis
HP:0001852	Sandal gap
HP:0001952	Glucose intolerance
HP:0002155	Hypertriglyceridemia
HP:0002209	Sparse scalp hair

GWAS associations

20 associations (top):

Study	Trait	p-value
GCST000635_6	Response to statin therapy	7.000000e-06
GCST002509_3	Amyotrophic lateral sclerosis	5.000000e-06
GCST002510_1	Amyotrophic lateral sclerosis or frontotemporal dementia	1.000000e-07
GCST005024_75	Pursuit maintenance gain	3.000000e-06
GCST007614_18	C-reactive protein levels	2.000000e-08
GCST007637_1	Diffusing capacity of carbon monoxide	7.000000e-06
GCST010244_355	Triglyceride levels	4.000000e-08
GCST010516_3	Fractures (paediatric)	1.000000e-07
GCST012073_17	Behcet’s disease	1.000000e-05
GCST90002381_379	Eosinophil count	2.000000e-10
GCST90002382_252	Eosinophil percentage of white cells	2.000000e-12
GCST90002393_360	Monocyte count	5.000000e-13
GCST90002398_235	Neutrophil count	5.000000e-14
GCST90002400_450	Plateletcrit	3.000000e-13
GCST90002402_54	Platelet count	2.000000e-15
GCST90002407_515	White blood cell count	3.000000e-14
GCST90020024_187	A body shape index	3.000000e-08
GCST90020025_827	Waist-to-hip ratio adjusted for BMI	8.000000e-09
GCST90020027_1384	Waist-hip index	8.000000e-09
GCST90020029_93	Waist circumference adjusted for body mass index	4.000000e-08

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0008433	pursuit maintenance gain measurement
EFO:0004458	C-reactive protein measurement
EFO:0009369	diffusing capacity of the lung for carbon monoxide
EFO:0004530	triglyceride measurement
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes
EFO:0005091	monocyte count
EFO:0004833	neutrophil count
EFO:0007985	platelet crit
EFO:0004309	platelet count
EFO:0007789	BMI-adjusted waist circumference
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (3)

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
C535313	3C syndrome (supp.)
C580458	Spastic Paraplegia Type 8 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4742315 (PROTEIN-PROTEIN INTERACTION)

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

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, decreases methylation	3
sodium arsenite	affects cotreatment, increases abundance, increases expression	2
Arsenic	increases abundance, increases expression, affects cotreatment	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases methylation	1
sodium arsenate	increases abundance, increases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, increases reaction	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	decreases expression, affects cotreatment	1
abrine	increases expression	1
bisphenol S	decreases methylation	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Cisplatin	increases expression	1
Doxorubicin	decreases expression	1
Estradiol	decreases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Thiram	increases expression	1
Urethane	increases expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	decreases expression	1
Cadmium Chloride	increases expression	1
Acrylamide	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4713778	Binding	Protac activity at CRBN/NSMCE2 in human BxPC-3 cells assessed as NSMCE2 degradation incubated for 16 hrs by proteomic analysis	Discovery of a Napabucasin PROTAC as an Effective Degrader of the E3 Ligase ZFP91. — J Med Chem

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.