IDS

Summary

IDS (iduronate 2-sulfatase, HGNC:5389) is a protein-coding gene on chromosome Xq28, encoding Iduronate 2-sulfatase (P22304). Lysosomal enzyme involved in the degradation pathway of dermatan sulfate and heparan sulfate. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a member of the sulfatase family of proteins. The encoded preproprotein is proteolytically processed to generate two polypeptide chains. This enzyme is involved in the lysosomal degradation of heparan sulfate and dermatan sulfate. Mutations in this gene are associated with the X-linked lysosomal storage disease mucopolysaccharidosis type II, also known as Hunter syndrome. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed.

Source: NCBI Gene 3423 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mucopolysaccharidosis type 2 (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 1,468 total — 458 pathogenic, 219 likely-pathogenic
• Phenotypes (HPO): 53
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000202

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5389
Approved symbol	IDS
Name	iduronate 2-sulfatase
Location	Xq28
Locus type	gene with protein product
Status	Approved
Aliases	ID2S
Ensembl gene	ENSG00000010404
Ensembl biotype	protein_coding
OMIM	300823
Entrez	3423

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 16 protein_coding, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000340855, ENST00000370441, ENST00000428056, ENST00000464251, ENST00000466019, ENST00000466323, ENST00000490775, ENST00000521702, ENST00000875667, ENST00000875668, ENST00000875669, ENST00000875670, ENST00000875671, ENST00000875672, ENST00000875673, ENST00000875674, ENST00000930297, ENST00000930298, ENST00000947400, ENST00000947401

RefSeq mRNA: 3 — MANE Select: NM_000202 NM_000202, NM_001166550, NM_006123

CCDS: CCDS14685, CCDS14686

Canonical transcript exons

ENST00000340855 — 9 exons

Exon	Start	End
ENSE00000677390	149504157	149504293
ENSE00000677392	149503312	149503489
ENSE00001368349	149476988	149483218
ENSE00003486921	149498107	149498307
ENSE00003584734	149500949	149501037
ENSE00003617711	149490314	149490440
ENSE00003629250	149496346	149496516
ENSE00003670465	149486925	149487098
ENSE00003845145	149505035	149505306

Expression profiles

Bgee: expression breadth ubiquitous, 238 present calls, max score 98.86.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 96.7012 / max 1736.7729, expressed in 1815 samples.

FANTOM5 promoters (28 alternative TSS)

Promoter ID	TPM avg	Samples expressed
200814	72.6765	1808
200813	14.2398	1700
200782	2.6493	789
200783	1.3352	334
200780	1.0189	417
200790	0.9424	341
200812	0.8113	357
200781	0.3812	135
200788	0.3699	157
200793	0.2052	64

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right frontal lobe	UBERON:0002810	98.86	gold quality
cortical plate	UBERON:0005343	97.93	gold quality
descending thoracic aorta	UBERON:0002345	97.48	gold quality
right coronary artery	UBERON:0001625	97.39	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.35	gold quality
nucleus accumbens	UBERON:0001882	97.31	gold quality
thoracic aorta	UBERON:0001515	97.24	gold quality
ascending aorta	UBERON:0001496	97.20	gold quality
cingulate cortex	UBERON:0003027	97.09	gold quality
islet of Langerhans	UBERON:0000006	97.06	gold quality
anterior cingulate cortex	UBERON:0009835	97.04	gold quality
aorta	UBERON:0000947	96.97	gold quality
amygdala	UBERON:0001876	96.96	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	96.95	gold quality
popliteal artery	UBERON:0002250	96.93	gold quality
tibial artery	UBERON:0007610	96.93	gold quality
cerebellar hemisphere	UBERON:0002245	96.64	gold quality
cerebellar cortex	UBERON:0002129	96.54	gold quality
prefrontal cortex	UBERON:0000451	96.30	gold quality
mucosa of stomach	UBERON:0001199	96.22	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.11	gold quality
adenohypophysis	UBERON:0002196	95.93	gold quality
putamen	UBERON:0001874	95.90	gold quality
right uterine tube	UBERON:0001302	95.82	gold quality
caudate nucleus	UBERON:0001873	95.71	gold quality
left coronary artery	UBERON:0001626	95.66	gold quality
gall bladder	UBERON:0002110	95.28	gold quality
endocervix	UBERON:0000458	95.19	gold quality
left ovary	UBERON:0002119	95.19	gold quality
right atrium auricular region	UBERON:0006631	95.15	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-MTAB-11011	yes	1571.57
E-HCAD-6	yes	414.17
E-HCAD-35	yes	51.97
E-CURD-88	yes	41.77
E-CURD-46	yes	41.10
E-CURD-122	yes	23.60
E-GEOD-135922	yes	22.18
E-MTAB-5061	yes	14.65
E-MTAB-7316	yes	12.69
E-CURD-55	no	321.10
E-GEOD-93593	no	14.36
E-ENAD-27	no	3.90
E-GEOD-83139	no	3.59
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

227 targeting IDS, 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-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-6778-3P	99.96	67.29	2693

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• novel mutations in Italian patients with mucopolysaccharidosis type II (PMID:11462244)
• patterns of cytosine methylation in the entire IDS gene (PMID:15146464)
• Mucopolysaccharidosis type II patients with sever CNS involvement and age of onset by 3 years of age had four IDS amino acid substitutions S333L,C53X,E341K, and P480R. (PMID:15500445)
• a total of 17 identified missense, small deletion, and nonsense mutations were further characterized by transient expression studies. (PMID:15614569)
• large deletion correlated with the severe phenotype of this Hunter syndrome patient. (PMID:15909065)
• The IDS gene was analyzed in Japanese patients with mucopolysaccharidosis II. (PMID:16133661)
• IDS activity in female carriers was less than a half of the normal level (PMID:16480701)
• These findings suggest methylation patterns in the beginning of IDS genomic region are polymorphic in humans and that hypermethylation in this region in some individuals predisposes them to CpG mutations resulting in Hunter syndrome. (PMID:16617305)
• The balance between constitutive and cryptic splice sites in the IDS gene is very sensitive. (PMID:16699754)
• A new point mutation (T1140C) in exon 8 of the IDS gene was found in Hunter syndrome. (PMID:16735228)
• the IDS gene is prone to splicing mutations in Portuguese patients with mucopolysaccharidosis type II (PMID:17063374)
• analysis of iduronate-2-sulfatase enzymatic activity, protein processing and structure (PMID:17091340)
• Two novel mutations were identified in the human iduronate-2-sulfatase (IDS) gene in two patients from unrelated families with mucopolysaccharidosis type II(MPS II). (PMID:17284421)
• Identification of a novel nonsense mutation (p.Y54X) in the IDS gene of severely affected MPS II patients of African origin. (PMID:17616540)
• The molecular characterization of one novel missense mutation (p.S305P) and 1 splice site mutation (c.1006 +5G > C) associated with mucopolysaccharidosis type II was presented. (PMID:17655837)
• frame-shift deletion mutation (1062 del 16) was identified in exon 7 of the patient’s IDS gene (PMID:17657858)
• Hunter syndrome in Thailand is caused by a diverse set of defects affecting both IDS protein production and activity. (PMID:18500569)
• A new mutation, an A>T change at nucleotide 595, substitutes a premature stop codon for a lysine at amino acid 199 of the IDS enzyme. (PMID:18546295)
• IDS has a role in glucose-stimulated insulin secretion via a mechanism that involves the activation of exocytosis through phosphorylation of PKCalpha and MARCKS. (PMID:19602578)
• The results illustrated that the deletion and frame-shift mutation of c.876-877 del TC detected in IDS gene was a novel pathologic mutation,, which was the underlying cause of MPS II of this patient. (PMID:19933090)
• The in vivo correction of heritable gene lesions at the RNA level operating via a correction mechanism akin to RNA-editing, was observed for IDS mutant transcript. (PMID:20104590)
• Family members with 3 generations of X-inactivation with Hunter syndrome have 1568A>G missence mutation in the IDS gene (PMID:21062272)
• study describes a woman with mild manifestations of Hunter syndrome who gave birth to a daughter; both the mother and daughter carried the p.R443X mutation in exon 9 of the ID2S gene (PMID:21108396)
• LCR-initiated rearrangements at the IDS locus, completed with Alu-mediated recombination or non-homologous end joining (PMID:21593745)
• Two new mutations were discovered: p.K236N (c.708G>C) and p.Q80K (c.238C>A) which resulted in a severe phenotype and early death of Muccopolysaccharridosis Type II patients from Bulgaria and Macedonia. (PMID:22286622)
• genetically analyze patients with severe Hunter syndrome that showed a total deletion of the iduronate-2-sulphatase (IDS) gene (PMID:22492741)
• A report of a novel IDS nonsense mutation resulting in mucopolysaccharidosis type II in several patients from a Chinese family. (PMID:22622771)
• a novel (p.R468P) and five known (p.R88C, p.D148V, p.G224A, p.Y348X, and p.R468Q) IDS mutations were shown to result in proteins with little or no IDS activity and altered protein processing, when expressed in COS7 cells (PMID:22990955)
• Identification of a splice site mutation in the IDS gene associated with mucopolysaccharidosis type II. (PMID:23867855)
• 30 novel iduronate sulfatase mutations have been identified in mucopolysaccharidosis type II Latin American patients. (PMID:24125893)
• p.Ser142Phe and p.Ile360Tyrfs*31 mutations caused the severe disease manifestation (PMID:24780617)
• This study evaluated a novel mutation in the IDS gene among 8 male Hunter syndrome patients; there was a quantitative deficiency of NK and B cell with normal responses in other immune parameters. (PMID:25038527)
• Extensive iduronate 2-sulfatase (Hunter syndrome) (IDS) gene deletions were identified in four mucopolysaccharidosis type II (MPSII) patients. (PMID:26762690)
• Functional characterization of all the novel sequence variants identified in the study would be helpful to confirm the clinical significance and to determine the effect of these variations on the function of respective proteins (IDUA and IDS) (PMID:27146977)
• Study identified 16 novel mutations in the IDS gene and revealed that the severe type of mucopolysaccharidosis type II is strongly associated with large structural alteration of the gene. (PMID:27246110)
• A splicing mutation, c.709-1G>A, was detected in the proband, for which his mother was heterozygous. (PMID:28186595)
• Study analyzed the genotype-phenotype relationship for 17 patients with mucopolysaccharidosis II and performed expression studies for 12 variants, nine of which have not been reported previously; speculated that very low or cell-type-specific IDS residual activity is sufficient to prevent the neuronal phenotype. (PMID:28543354)
• IDS structure revealed by X-ray crystallography provides essential insight into multiple mechanisms by which pathogenic mutations interfere with enzyme function, and a compelling explanation for severe Hunter syndrome phenotypes. (PMID:28593992)
• Genetic analysis of 63 Chinese patients with mucopolysaccharidosis type II: Functional characterization of seven novel IDS variants (PMID:30639582)
• Mucopolysaccharidosis type II R468Q IDS mutant could not be refolded in the calnexin cycle.Calnexin accelerates the folding of the mucopolysaccharidosis type II mutant IDS in the endoplasmic reticulum. (PMID:31029429)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ids	ENSDARG00000071699
mus_musculus	Ids	ENSMUSG00000035847
rattus_norvegicus	Ids	ENSRNOG00000001465
drosophila_melanogaster	Ids	FBGN0035445

Paralogs (16): ARSD (ENSG00000006756), ARSF (ENSG00000062096), ARSA (ENSG00000100299), STS (ENSG00000101846), ARSB (ENSG00000113273), GNS (ENSG00000135677), SULF1 (ENSG00000137573), GALNS (ENSG00000141012), ARSG (ENSG00000141337), ARSL (ENSG00000157399), ARSK (ENSG00000164291), ARSJ (ENSG00000180801), SGSH (ENSG00000181523), ARSI (ENSG00000183876), SULF2 (ENSG00000196562), ARSH (ENSG00000205667)

Protein

Protein identifiers

Iduronate 2-sulfatase — P22304 (reviewed: P22304)

Alternative names: Alpha-L-iduronate sulfate sulfatase

All UniProt accessions (4): P22304, E5RHJ1, H0YB91, O60597

UniProt curated annotations — full annotation on UniProt →

Function. Lysosomal enzyme involved in the degradation pathway of dermatan sulfate and heparan sulfate.

Subunit / interactions. Monomer. The 58-kDa mature form is composed of two chains resulting from proteolitic processing, the 42-kDa chain and the 14-kDa chain that remain stably associated and form the 58-kDa intermediate form which is enzymatically active.

Subcellular location. Lysosome.

Tissue specificity. Liver, kidney, lung, and placenta.

Post-translational modifications. Synthesized as a 75-kDa precursor form in the endoplasmic reticulum (ER), and then processed by proteolytic cleavage through various intermediates to yield a 55-kDa mature form, with the release of an 18 kDa polypeptide. The conversion to 3-oxoalanine (also known as C-formylglycine, FGly), of a serine or cysteine residue in prokaryotes and of a cysteine residue in eukaryotes, is critical for catalytic activity.

Disease relevance. Mucopolysaccharidosis 2 (MPS2) [MIM:309900] An X-linked lysosomal storage disease characterized by intracellular accumulation of heparan sulfate and dermatan sulfate and their excretion in urine. Most children with MPS2 have a severe form with early somatic abnormalities including skeletal deformities, hepatosplenomegaly, and progressive cardiopulmonary deterioration. A prominent feature is neurological damage that presents as developmental delay and hyperactivity but progresses to intellectual disability and dementia. They die before 15 years of age, usually as a result of obstructive airway disease or cardiac failure. In contrast, those with a mild form of MPS2 may survive into adulthood, with attenuated somatic complications and often without intellectual disability. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 Ca(2+) ion per subunit.

Similarity. Belongs to the sulfatase family.

Isoforms (3)

UniProt ID	Names	Canonical?
P22304-1	1, Long	yes
P22304-2	2, Short
P22304-3	3

RefSeq proteins (3): NP_000193, NP_001160022, NP_006114 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000917	Sulfatase_N	Domain
IPR017850	Alkaline_phosphatase_core_sf	Homologous_superfamily
IPR024607	Sulfatase_CS	Conserved_site
IPR035874	IDS	Family

Pfam: PF00884

Enzyme classification (BRENDA):

• EC 3.1.6.13 — iduronate-2-sulfatase (BRENDA: 4 organisms, 25 substrates, 24 inhibitors, 17 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

7 substrates with measured Km, best-characterized 7. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
O-(ALPHA-L-IDOPYRANOSYLURONIC ACID 2-SULFATE)-(1	0.003–0.043	7
O-(ALPHA-L-IDOPYRANOSYLURONIC ACID-2-SULFATE)-(1	0.133–0.327	2
O-(ALPHA-L-IDOPYRANOSYLURONIC ACID 2-SULFATE)-(1	0.0192	1
O-(ALPHA-L-IDURONIC ACID 2-SULFATE)-(1-4)-D-O-(A	0.0014	1
O-(ALPHA-L-IDURONIC ACID 2-SULFATE)-(1-4)-D-O-(A	0.0019	1
O-(ALPHA-L-IDURONIC ACID 2-SULFATE)-(1-4)-D-O-(A	0.0025	1
O-(ALPHA-L-IDURONIC ACID 2-SULFATE)-(1-4)-D-O-(A	0.0031	1

UniProt features (211 total): sequence variant 133, helix 25, strand 21, glycosylation site 7, turn 7, binding site 5, splice variant 4, disulfide bond 2, chain 2, active site 2, signal peptide 1, propeptide 1, modified residue 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
5FQL	X-RAY DIFFRACTION	2.3
6IOZ	X-RAY DIFFRACTION	3.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P22304-F1	93.39	0.88

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 (2): 84 (nucleophile); 138

Ligand- & substrate-binding residues (5): 335; 45; 46; 84 (via 3-oxoalanine); 334

Post-translational modifications (1): 84

Disulfide bonds (2): 171–184, 422–432

Glycosylation sites (7): 115, 144, 246, 280, 325, 513, 537

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-2024096	HS-GAG degradation
R-HSA-2024101	CS/DS degradation
R-HSA-2206296	MPS II - Hunter syndrome (HS-GAG degradation)
R-HSA-9953078	MPS II - Hunter syndrome (CS/DS degradation)

MSigDB gene sets: 414 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_UP, AP1_01, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, FLECHNER_PBL_KIDNEY_TRANSPLANT_REJECTED_VS_OK_UP, YAGI_AML_WITH_INV_16_TRANSLOCATION, MODULE_45, GOZGIT_ESR1_TARGETS_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, KEGG_LYSOSOME, MOTAMED_RESPONSE_TO_ANDROGEN_UP, GRAHAM_CML_QUIESCENT_VS_NORMAL_QUIESCENT_DN, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, STARK_HYPPOCAMPUS_22Q11_DELETION_UP

GO Biological Process (4): glycosaminoglycan catabolic process (GO:0006027), heparan sulfate proteoglycan catabolic process (GO:0030200), dermatan sulfate proteoglycan catabolic process (GO:0030209), carbohydrate derivative catabolic process (GO:1901136)

GO Molecular Function (6): iduronate-2-sulfatase activity (GO:0004423), calcium ion binding (GO:0005509), protein binding (GO:0005515), sulfuric ester hydrolase activity (GO:0008484), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (2): lysosome (GO:0005764), lysosomal lumen (GO:0043202)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Mucopolysaccharidoses	2
Heparan sulfate/heparin (HS-GAG) metabolism	1
Chondroitin sulfate/dermatan sulfate metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
proteoglycan catabolic process	2
aminoglycan catabolic process	1
glycosaminoglycan metabolic process	1
heparan sulfate proteoglycan metabolic process	1
dermatan sulfate proteoglycan metabolic process	1
catabolic process	1
carbohydrate derivative metabolic process	1
sulfuric ester hydrolase activity	1
metal ion binding	1
binding	1
hydrolase activity, acting on ester bonds	1
catalytic activity	1
cation binding	1
lytic vacuole	1
lysosome	1
vacuolar lumen	1

Protein interactions and networks

STRING

924 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IDS	IDUA	P35475	814
IDS	NAGLU	P54802	664
IDS	F9	P00740	647
IDS	DIAPH2	O60879	638
IDS	TFRC	P02786	623
IDS	SUMF1	Q8NBK3	614
IDS	GLA	P06280	583
IDS	TFF2	Q03403	548
IDS	POF1B	Q8WVV4	540
IDS	HGSNAT	Q68CP4	520
IDS	AFF2	P51816	510
IDS	FIGLA	Q6QHK4	498
IDS	BMP15	O95972	491
IDS	SPP1	P10451	490
IDS	GBA1	P04062	482

IntAct

19 interactions, top by confidence:

A	B	Type	Score
ADAMTS4	MANBA	psi-mi:“MI:0914”(association)	0.530
IDS	SUMF2	psi-mi:“MI:0914”(association)	0.500
SUMF2	IDS	psi-mi:“MI:0915”(physical association)	0.500
IDS	Dlg4	psi-mi:“MI:0407”(direct interaction)	0.440
IDS	HTR6	psi-mi:“MI:0915”(physical association)	0.370
POC5		psi-mi:“MI:0914”(association)	0.350
IDS	COCH	psi-mi:“MI:0914”(association)	0.350
ACACB	TACC1	psi-mi:“MI:0914”(association)	0.350
IDS	RTCA	psi-mi:“MI:0914”(association)	0.350
PODN	LRP5	psi-mi:“MI:0914”(association)	0.350
	TBKBP1	psi-mi:“MI:0914”(association)	0.350
	PSMD12	psi-mi:“MI:0914”(association)	0.350
DISC1	IDS	psi-mi:“MI:0915”(physical association)	0.000
IDS	FOS	psi-mi:“MI:0915”(physical association)	0.000
LCOR	IDS	psi-mi:“MI:0915”(physical association)	0.000
RUNX1	IDS	psi-mi:“MI:0915”(physical association)	0.000
FTCD	IDS	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (180): TUBB8 (Affinity Capture-MS), SUMF1 (Affinity Capture-MS), HSPA5 (Affinity Capture-MS), WDR47 (Affinity Capture-MS), B3GALTL (Affinity Capture-MS), KLHL15 (Affinity Capture-MS), TAZ (Affinity Capture-MS), P3H4 (Affinity Capture-MS), XYLT2 (Affinity Capture-MS), MESDC2 (Affinity Capture-MS), COCH (Affinity Capture-MS), FBXO3 (Affinity Capture-MS), GALNT18 (Affinity Capture-MS), GUSB (Affinity Capture-MS), AP3M1 (Affinity Capture-MS)

ESM2 similar proteins: A1A4K5, O14638, P06802, P08842, P15396, P15586, P15589, P15848, P22304, P22413, P33727, P50426, P50429, P51689, P51690, P54793, P97535, P97675, Q08890, Q08C93, Q13219, Q13822, Q1LZH9, Q32KH8, Q32KH9, Q32KJ9, Q3TYD4, Q5E9H0, Q5FYA8, Q5M900, Q5NDE3, Q5R5M5, Q5ZK90, Q60HH5, Q64610, Q66PG4, Q6DYE8, Q6NRQ1, Q6P9A2, Q6UWY0

Diamond homologs: P08842, P14000, P15289, P15589, P20713, P22304, P31447, P34059, P50427, P50428, P50473, P51689, P51690, P54793, Q08890, Q08DD1, Q32KH5, Q32KH8, Q32KH9, Q32KI9, Q32KJ6, Q32KJ8, Q32KJ9, Q3TYD4, Q571E4, Q5FYA8, Q5FYB1, Q60HH5, Q8WNQ7, Q96EG1, Q9X759, T2KMG4, O69787, T2KM04, T2KN71, T2KPK5, Q0IHJ2, Q148F3, Q6UWY0, Q89YS5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1468 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	458
Likely pathogenic	219
Uncertain significance	223
Likely benign	303
Benign	44

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
10486	NM_000202.8(IDS):c.1327C>T (p.Arg443Ter)	Pathogenic
10487	NM_000202.8(IDS):c.998C>T (p.Ser333Leu)	Pathogenic
10488	NM_000202.8(IDS):c.1505G>C (p.Trp502Ser)	Pathogenic
10490	NM_000202.8(IDS):c.514C>T (p.Arg172Ter)	Pathogenic
10492	NC_000023.11:g.(?149478764)(149505354_?)del	Pathogenic
10493	NM_000202.8(IDS):c.1264T>G (p.Cys422Gly)	Pathogenic
10496	NM_000202.8(IDS):c.509_510del (p.Thr170fs)	Pathogenic
10498	NM_000202.8(IDS):c.1403G>A (p.Arg468Gln)	Pathogenic
10500	NM_000202.8(IDS):c.1403G>T (p.Arg468Leu)	Pathogenic
10501	NM_000202.8(IDS):c.349_351del (p.Ser117del)	Pathogenic
1065181	NM_000202.8(IDS):c.205_206insAAACTGGCAT (p.Ser69Ter)	Pathogenic
1065312	NM_000202.8(IDS):c.737del (p.Asn246fs)	Pathogenic
1065331	NM_000202.8(IDS):c.1375G>T (p.Glu459Ter)	Pathogenic
1065348	NM_000202.8(IDS):c.356del (p.Ile119fs)	Pathogenic
1068596	NC_000023.10:g.(?148571835)(148582578_?)del	Pathogenic
1068822	NM_000202.8(IDS):c.1115del (p.Glu372fs)	Pathogenic
1072737	NM_000202.8(IDS):c.507+1G>A	Pathogenic
1072897	NM_000202.8(IDS):c.594_595del (p.Asp198fs)	Pathogenic
1074140	NM_000202.8(IDS):c.361C>T (p.Gln121Ter)	Pathogenic
1076526	NM_000202.8(IDS):c.458G>A (p.Trp153Ter)	Pathogenic
1323089	NM_000202.8(IDS):c.1589T>A (p.Leu530Ter)	Pathogenic
1360889	NM_000202.8(IDS):c.1216_1217del (p.Leu406fs)	Pathogenic
1432854	NM_000202.8(IDS):c.1561dup (p.Glu521fs)	Pathogenic
1453829	NM_000202.8(IDS):c.1224dup (p.Thr409fs)	Pathogenic
1455705	NM_000202.8(IDS):c.1589dup (p.Leu530fs)	Pathogenic
1455709	NM_000202.8(IDS):c.1123G>T (p.Glu375Ter)	Pathogenic
149240	GRCh38/hg38 Xq28(chrX:149474154-149506155)x0	Pathogenic
1709792	NM_000202.8(IDS):c.867del (p.Val290fs)	Pathogenic
1709794	NM_000202.8(IDS):c.880-2A>T	Pathogenic
1710487	NM_000202.8(IDS):c.1277_1450del (p.Ser426_Asp484delinsTyr)	Pathogenic

SpliceAI

1908 predictions. Top by Δscore:

Variant	Effect	Δscore
X:149490312:A:AC	donor_gain	1.0000
X:149490313:C:CC	donor_gain	1.0000
X:149490313:CCATG:C	donor_loss	1.0000
X:149490436:TTCCG:T	acceptor_gain	1.0000
X:149490437:TCCG:T	acceptor_gain	1.0000
X:149490438:CCG:C	acceptor_gain	1.0000
X:149490438:CCGC:C	acceptor_gain	1.0000
X:149490439:CG:C	acceptor_gain	1.0000
X:149490439:CGC:C	acceptor_gain	1.0000
X:149490440:GCTG:G	acceptor_loss	1.0000
X:149490440:GCTGC:G	acceptor_loss	1.0000
X:149490441:C:CC	acceptor_gain	1.0000
X:149490441:CT:C	acceptor_loss	1.0000
X:149490444:CAAAT:C	acceptor_gain	1.0000
X:149490447:A:AC	acceptor_gain	1.0000
X:149490448:T:C	acceptor_gain	1.0000
X:149490448:T:TC	acceptor_gain	1.0000
X:149496342:ATAC:A	donor_loss	1.0000
X:149496344:A:AG	donor_loss	1.0000
X:149496344:ACCTG:A	donor_loss	1.0000
X:149496345:C:A	donor_loss	1.0000
X:149496345:CCTG:C	donor_loss	1.0000
X:149496513:ATTC:A	acceptor_gain	1.0000
X:149496514:TTC:T	acceptor_gain	1.0000
X:149496515:TC:T	acceptor_gain	1.0000
X:149496516:CC:C	acceptor_gain	1.0000
X:149496516:CCT:C	acceptor_gain	1.0000
X:149496517:C:CC	acceptor_gain	1.0000
X:149496517:C:T	acceptor_gain	1.0000
X:149496518:T:C	acceptor_gain	1.0000

AlphaMissense

3604 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:149487065:T:A	K347I	0.999
X:149503469:G:C	S87R	0.999
X:149503469:G:T	S87R	0.999
X:149503471:T:G	S87R	0.999
X:149487064:T:A	K347N	0.998
X:149487064:T:G	K347N	0.998
X:149487072:A:G	W345R	0.998
X:149487072:A:T	W345R	0.998
X:149503478:G:C	C84W	0.998
X:149503480:A:G	C84R	0.998
X:149490319:T:A	D334V	0.997
X:149503467:C:G	R88P	0.997
X:149503479:C:T	C84Y	0.997
X:149504260:T:A	D46V	0.997
X:149504263:T:A	D45V	0.997
X:149487096:A:G	W337R	0.996
X:149487096:A:T	W337R	0.996
X:149498130:G:C	H229D	0.996
X:149503316:G:C	H138Q	0.996
X:149503316:G:T	H138Q	0.996
X:149503326:T:A	K135I	0.996
X:149504257:A:G	L47P	0.996
X:149482895:A:G	W502R	0.995
X:149482895:A:T	W502R	0.995
X:149482928:A:G	S491P	0.995
X:149490314:C:A	G336W	0.995
X:149490316:T:G	H335P	0.995
X:149490319:T:C	D334G	0.995
X:149490319:T:G	D334A	0.995
X:149490320:C:G	D334H	0.995

dbSNP variants (sampled 300 via entrez): RS1000801232 (X:149476689 A>C,G), RS1000863873 (X:149479090 C>T), RS1000924923 (X:149484552 C>T), RS1000977041 (X:149502593 C>A,T), RS1001264868 (X:149493769 G>A), RS1001741605 (X:149479923 G>A,C), RS1001821842 (X:149498252 A>C), RS1002301494 (X:149477342 T>G), RS1002321708 (X:149494390 G>A), RS1002393188 (X:149494677 G>A,C), RS1002488876 (X:149477798 G>A), RS1002934620 (X:149481016 C>A), RS1002984608 (X:149498619 A>G), RS1003015445 (X:149498890 T>C), RS1003283472 (X:149489902 G>C)

Disease associations

OMIM: gene MIM:300823 | disease phenotypes: MIM:309900, MIM:252900, MIM:616487

GenCC curated gene-disease

Disease	Classification	Inheritance
mucopolysaccharidosis type 2	Definitive	X-linked
mucopolysaccharidosis type 2, severe form	Supportive	X-linked
mucopolysaccharidosis type 2, attenuated form	Supportive	X-linked

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
mucopolysaccharidosis type 2	Definitive	XL

Mondo (5): mucopolysaccharidosis type 2 (MONDO:0010674), mucopolysaccharidosis type 3A (MONDO:0009655), mucopolysaccharidosis type 2, severe form (MONDO:0016315), epidermolysis bullosa simplex with nail dystrophy (MONDO:0014661), mucopolysaccharidosis type 2, attenuated form (MONDO:0016316)

Orphanet (5): Mucopolysaccharidosis type 2 (Orphanet:580), Mucopolysaccharidosis with skin involvement (Orphanet:79388), Mucopolysaccharidosis type 3 (Orphanet:581), Sanfilippo syndrome type A (Orphanet:79269), Mucopolysaccharidosis type 2, severe form (Orphanet:217085)

HPO phenotypes

53 total (30 of 53 shown, HPO-id order):

HPO	Term
HP:0000023	Inguinal hernia
HP:0000158	Macroglossia
HP:0000179	Thick lower lip vermilion
HP:0000238	Hydrocephalus
HP:0000256	Macrocephaly
HP:0000268	Dolichocephaly
HP:0000280	Coarse facial features
HP:0000365	Hearing impairment
HP:0000403	Recurrent otitis media
HP:0000470	Short neck
HP:0000508	Ptosis
HP:0000684	Delayed eruption of teeth
HP:0000687	Widely spaced teeth
HP:0000943	Dysostosis multiplex
HP:0000998	Hypertrichosis
HP:0001085	Papilledema
HP:0001171	Split hand
HP:0001250	Seizure
HP:0001371	Flexion contracture
HP:0001419	X-linked recessive inheritance
HP:0001433	Hepatosplenomegaly
HP:0001537	Umbilical hernia
HP:0001609	Hoarse voice
HP:0001635	Congestive heart failure
HP:0001654	Abnormal heart valve morphology
HP:0001744	Splenomegaly
HP:0001761	Pes cavus
HP:0002014	Diarrhea
HP:0002099	Asthma
HP:0002159	Heparan sulfate excretion in urine

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST000579_39	Cognitive performance	4.000000e-06
GCST010172_11	Idiopathic downbeat nystagmus	4.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0003926	neuropsychological test

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D016532	Mucopolysaccharidosis II	C10.597.606.360.455.750; C16.320.322.500.750; C16.320.400.525.750; C16.320.565.202.715.645; C16.320.565.595.600.645; C17.300.550.575.645; C18.452.648.202.715.645; C18.452.648.595.600.645

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, affects cotreatment, increases expression	6
methylmercuric chloride	increases expression, affects cotreatment	4
trichostatin A	affects cotreatment, increases expression	3
sodium arsenite	affects expression, increases expression	3
Tretinoin	increases expression, decreases expression	3
mercuric bromide	increases expression, affects cotreatment	2
Benzo(a)pyrene	affects methylation, increases expression	2
Formaldehyde	decreases expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Smoke	decreases expression	2
Tobacco Smoke Pollution	increases expression, affects expression	2
Aflatoxin B1	increases expression	2
Cadmium Chloride	increases expression	2
aristolochic acid I	increases expression	1
testosterone enanthate	affects expression	1
chloroacetaldehyde	increases expression	1
triphenyl phosphate	affects expression	1
methylselenic acid	increases expression	1
beta-lapachone	increases expression	1
cobaltous chloride	increases expression	1
potassium chromate(VI)	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
nickel sulfate	decreases expression	1
beta-methylcholine	affects expression	1
yessotoxin	increases expression	1
chromium hexavalent ion	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
NSC 689534	increases expression, affects binding	1

Cellosaurus cell lines

17 cell lines: 8 induced pluripotent stem cell, 4 cancer cell line, 2 conditionally immortalized cell line, 1 finite cell line, 1 transformed cell line, 1 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_B1U6	Abcam HeLa IDS KO	Cancer cell line	Female
CVCL_B5V3	TRNDi008-B	Induced pluripotent stem cell	Male
CVCL_B7SH	CSSi014-A	Induced pluripotent stem cell	Male
CVCL_D2PI	LUHMES IDS KO clone 13	Conditionally immortalized cell line	Female
CVCL_D2PJ	LUHMES IDS KO clone 18	Conditionally immortalized cell line	Female
CVCL_DX33	HAP1 FAM20B (-) IDS (-) 1	Cancer cell line	Male
CVCL_DX34	HAP1 FAM20B (-) IDS (-) 2	Cancer cell line	Male
CVCL_E4EB	PNUSCRi005-A	Induced pluripotent stem cell	Male
CVCL_IJ23	MPSII-1.3	Induced pluripotent stem cell	Male
CVCL_IJ24	MPSII-2.5	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00607386	PHASE4	COMPLETED	Safety and Clinical Outcomes in Hunter Syndrome Patients 5 Years of Age and Younger Receiving Idursulfase Therapy
NCT02455622	PHASE4	COMPLETED	Long-term Evaluation on Height and Weight in Patients With MPS II Who Started Treatment at < 6 Years of Age
NCT05058391	PHASE4	COMPLETED	A Study of Elaprase in Children and Adults With Hunter Syndrome (Mucopolysaccharidosis II) in India
NCT05494593	PHASE4	WITHDRAWN	A Study of ELAPRASE in Treatment-naïve Participants With Hunter Syndrome (Mucopolysaccharidosis [MPS] II)
NCT01645189	PHASE3	COMPLETED	Safety and Efficacy of Hunterase
NCT03920540	PHASE3	COMPLETED	A Study of GC1111 in Hunter Syndrom Patients
NCT07236606	PHASE3	SUSPENDED	RGX-121-3102 Gene Therapy in Participants With MPS II (Hunter Syndrome)
NCT07344376	PHASE3	COMPLETED	An Extension Study to Assess the Long-term Safety and Efficacy of Hunterase (Idursulfase Beta)
NCT04360265	PHASE3	ENROLLING_BY_INVITATION	Follow-up Study of AAV-Mediated Gene Transfer (UX111; Previously Known as ABO-102) for MPS Type IIIA
NCT01043640	PHASE2	COMPLETED	Allogeneic Bone Marrow Transplant for Inherited Metabolic Disorders
NCT02171104	PHASE2	ACTIVE_NOT_RECRUITING	MT2013-31: Allo HCT for Metabolic Disorders and Severe Osteopetrosis
NCT04532047	PHASE1	RECRUITING	PEARL (PrEnAtal Enzyme Replacement Therapy for Lysosomal Storage Disorders)
NCT04539340	PHASE1	COMPLETED	A Multi-cohort Study of the Tolerance, Safety, and Pharmacokinetics of GNR-055 in Healthy Volunteers
NCT05422482	PHASE1	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Safety, Tolerability, PK and PD of Intracerebroventricular GC1123 in Patients with MPS Ⅱ
NCT06475404	PHASE1	COMPLETED	A Study of the Tolerance, Safety, and Pharmacokinetics of GNR-055 in Healthy Volunteers
NCT06567769	PHASE1	RECRUITING	Phase 1 Study of GC1130A in Patients With Sanfilippo Syndrome Type A (MPS IIIA)
NCT00630747	PHASE2/PHASE3	COMPLETED	Extension of Study TKT024 Evaluating Long-Term Safety and Clinical Outcomes in MPS II Patients Receiving Idursulfase
NCT02055118	PHASE2/PHASE3	COMPLETED	Study of Intrathecal Idursulfase-IT Administered in Conjunction With Elaprase® in Pediatric Patients With Hunter Syndrome and Early Cognitive Impairment
NCT02412787	PHASE2/PHASE3	COMPLETED	Study of Long Term Safety and Clinical Outcomes of Idursulfase IT and Elaprase Treatment in Pediatric Participants Who Have Completed Study HGT-HIT-094
NCT03566043	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	CAMPSIITE™ RGX-121 Gene Therapy in Subjects With MPS II (Hunter Syndrome)
NCT05208281	PHASE2/PHASE3	RECRUITING	A Multi-cohort Study of Safety, Efficacy, PK and PD of GNR-055 in Patients With Mucopolysaccharidosis Type II
NCT06031259	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	Extension Study of Idursulfase-IT Along With Elaprase in Children and Adults With Hunter Syndrome and Cognitive Impairment
NCT00920647	PHASE1/PHASE2	COMPLETED	A Safety and Dose Ranging Study of Idursulfase (Intrathecal) Administration Via an Intrathecal Drug Delivery Device in Pediatric Patients With Hunter Syndrome Who Have Central Nervous System Involvement and Are Receiving Treatment With Elaprase®
NCT01372228	PHASE1/PHASE2	TERMINATED	Phase I/II Pilot Study of Mixed Chimerism to Treat Inherited Metabolic Disorders
NCT01506141	PHASE1/PHASE2	COMPLETED	An Extension Study of HGT-HIT-045 Evaluating Long-Term Safety and Clinical Outcomes of Idursulfase-IT in Conjunction With Elaprase in Pediatric Participants With Hunter Syndrome and Cognitive Impairment
NCT02437253	PHASE1/PHASE2	COMPLETED	Effects of Adalimumab in Mucopolysaccharidosis Types I, II and VI
NCT03041324	PHASE1/PHASE2	TERMINATED	Ascending Dose Study of Genome Editing by the Zinc Finger Nuclease (ZFN) Therapeutic SB-913 in Subjects With MPS II
NCT04571970	PHASE1/PHASE2	COMPLETED	RGX-121 Gene Therapy in Children 5 Years of Age and Over With MPS II (Hunter Syndrome)
NCT00882921	Not specified	COMPLETED	An Observational Study Evaluating Anti-Idursulfase Serum Antibody Response in Hunter Syndrome Patients
NCT00937794	Not specified	COMPLETED	Screening Study to Identify Pediatric Patients With Hunter Syndrome Who Demonstrate Evidence of Central Nervous System (CNS) Involvement and Who Are Currently Receiving Treatment With Elaprase®
NCT01330277	Not specified	TERMINATED	Biomarkers for Hunter Syndrome
NCT01449240	Not specified	COMPLETED	Collection and Study of Cerebrospinal Fluid in Patients With Hunter Syndrome
NCT01822184	Not specified	COMPLETED	Observational Study to Evaluate Neurodevelopmental Status in Pediatric Patients With Hunter Syndrome (MPS II)
NCT01870375	Not specified	COMPLETED	Longitudinal Studies of Brain Structure and Function in MPS Disorders
NCT01938014	Not specified	COMPLETED	Lysosomal Storage Disease: Health, Development, and Functional Outcome Surveillance in Preschool Children
NCT02044692	Not specified	UNKNOWN	The Long-term Safety Study of Idursulfase-beta in Hunter Syndrome(Mucopolysaccharidosis II) Patients
NCT03161171	Not specified	COMPLETED	Parental Coping With Challenging Behavior in Mucopolysaccharidosis Type I-III
NCT03292887	Not specified	COMPLETED	Hunter Outcome Survey (HOS)
NCT03333200	Not specified	RECRUITING	Longitudinal Study of Neurodegenerative Disorders
NCT03582449	Not specified	COMPLETED	Intensive Pharmacovigilance Program for Elaprase (SHP ELA-701)