SGSH

Summary

SGSH (N-sulfoglucosamine sulfohydrolase, HGNC:10818) is a protein-coding gene on chromosome 17q25.3, encoding N-sulphoglucosamine sulphohydrolase (P51688). Catalyzes a step in lysosomal heparan sulfate degradation.

This gene encodes the enzyme sulfamidase; one of several enzymes involved in the lysosomal degradation of heparan sulfate. Mutations in this gene are associated with the lysosomal storage disease mucopolysaccaridosis IIIA, also known as Sanfilippo syndrome A, which results from impaired degradation of heparan sulfate. Transcripts of varying sizes have been reported but their biological validity has not been determined.

Source: NCBI Gene 6448 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mucopolysaccharidosis type 3A (Definitive, ClinGen)
• Clinical variants (ClinVar): 1,324 total — 64 pathogenic, 82 likely-pathogenic
• Phenotypes (HPO): 28
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_000199

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10818
Approved symbol	SGSH
Name	N-sulfoglucosamine sulfohydrolase
Location	17q25.3
Locus type	gene with protein product
Status	Approved
Aliases	HSS, MPS3A, SFMD
Ensembl gene	ENSG00000181523
Ensembl biotype	protein_coding
OMIM	605270
Entrez	6448

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 9 protein_coding, 5 retained_intron, 3 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay

ENST00000326317, ENST00000570427, ENST00000570923, ENST00000571051, ENST00000571075, ENST00000571156, ENST00000571675, ENST00000572208, ENST00000572257, ENST00000573150, ENST00000574505, ENST00000575188, ENST00000575282, ENST00000575484, ENST00000576707, ENST00000576856, ENST00000576941, ENST00000874333, ENST00000874334, ENST00000874335

RefSeq mRNA: 3 — MANE Select: NM_000199 NM_000199, NM_001352921, NM_001352922

CCDS: CCDS11770

Canonical transcript exons

ENST00000326317 — 8 exons

Exon	Start	End
ENSE00002647697	80209276	80211011
ENSE00003465484	80217032	80217192
ENSE00003509359	80214172	80214328
ENSE00003552839	80213804	80213885
ENSE00003561418	80212071	80212274
ENSE00003636651	80215033	80215138
ENSE00003637727	80220226	80220333
ENSE00003662885	80214615	80214765

Expression profiles

Bgee: expression breadth ubiquitous, 272 present calls, max score 97.29.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.4572 / max 182.7254, expressed in 1750 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
168609	16.0297	1738
168610	5.3500	1663
168611	0.0774	33

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left adrenal gland	UBERON:0001234	97.29	gold quality
left adrenal gland cortex	UBERON:0035825	97.23	gold quality
adrenal cortex	UBERON:0001235	97.08	gold quality
right adrenal gland	UBERON:0001233	97.04	gold quality
right adrenal gland cortex	UBERON:0035827	97.04	gold quality
adrenal gland	UBERON:0002369	96.34	gold quality
granulocyte	CL:0000094	95.43	gold quality
spleen	UBERON:0002106	95.17	gold quality
stromal cell of endometrium	CL:0002255	95.15	gold quality
right uterine tube	UBERON:0001302	94.43	gold quality
right lobe of thyroid gland	UBERON:0001119	94.28	gold quality
left lobe of thyroid gland	UBERON:0001120	94.09	gold quality
metanephros cortex	UBERON:0010533	93.96	gold quality
mucosa of stomach	UBERON:0001199	93.85	gold quality
minor salivary gland	UBERON:0001830	93.81	gold quality
adenohypophysis	UBERON:0002196	93.81	gold quality
upper lobe of left lung	UBERON:0008952	93.44	gold quality
pituitary gland	UBERON:0000007	93.39	gold quality
thyroid gland	UBERON:0002046	93.27	gold quality
adrenal tissue	UBERON:0018303	93.16	gold quality
skin of leg	UBERON:0001511	93.08	gold quality
body of stomach	UBERON:0001161	93.06	gold quality
right lung	UBERON:0002167	92.94	gold quality
monocyte	CL:0000576	92.93	gold quality
mononuclear cell	CL:0000842	92.67	gold quality
skin of abdomen	UBERON:0001416	92.53	gold quality
mouth mucosa	UBERON:0003729	92.48	gold quality
prostate gland	UBERON:0002367	92.47	gold quality
small intestine Peyer’s patch	UBERON:0003454	92.41	gold quality
upper lobe of lung	UBERON:0008948	92.27	gold 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)

28 targeting SGSH, 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-4673	100.00	66.64	1490
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-6733-3P	99.54	67.80	1281
HSA-MIR-208A-5P	99.42	70.83	1913
HSA-MIR-208B-5P	99.42	70.83	1952
HSA-MIR-3182	99.40	68.15	2454
HSA-MIR-4293	99.22	65.46	1263
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-210-5P	98.57	64.37	832
HSA-MIR-6880-5P	98.08	65.59	1282
HSA-MIR-6801-3P	98.04	64.64	805
HSA-MIR-6810-3P	97.96	64.57	1023
HSA-MIR-6847-5P	97.93	66.74	1808
HSA-MIR-4639-3P	97.54	67.12	787
HSA-MIR-4671-5P	97.10	65.70	93
HSA-MIR-3116	97.07	65.78	1324
HSA-MIR-597-5P	96.82	67.57	732

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 12)

• Molecular genetics of mucopolysaccharidosis type IIIA and IIIB: Diagnostic, clinical, and biological implications (PMID:11668611)
• Sanfilippo syndrome (subtypes A and B) in Turkey: identification of novel mutations in SGSH and NAGLU (PMID:11793481)
• expression studies of four novel mutations (PMID:15146460)
• analysis of a nonsense mutation (Y40X) and two de novo missense mutations (E300V; Q307P) in heparan N-sulphatase in a mucopolysaccharidosis IIIA patient [case report] (PMID:15902564)
• By assessing the degree of developmental regression over time a group of 7 pts with a slowly progressive course of MPSIIIA were identified. In these 7 pts and in 3 other mildly affected pts missense mutation c.892T>C (p.Ser298Pro) was found on 1 allele (PMID:18407553)
• Pre-symptomatic treatment of progressive neurodegenerative disease (mucopolysaccharidosis type IIIA) via intra-cerebrospinal fluid injection of recombinant human SGSH mediates highly significant reductions in neuropathology in a canine model. (PMID:21550404)
• Processing and secretion of p.Ser298Pro sulfamidase suggests that small amounts of the newly synthesized enzyme are transported to lysosomes (PMID:21671382)
• The crystal structure of glycosylated sulfamidase provides insight into the diverse effects of pathogenic mutations on sulfamidase function in mucopolysaccharidosis type IIIA. (PMID:24816101)
• results demonstrate that a single systemic scAAVrh74-hSGSH delivery mediated efficient restoration of SGSH activity and resulted in a near complete correction of MPS IIIA molecular pathology (PMID:25592334)
• We have identified ocular features of a patient with Sanfilippo syndrome type IIIA harboring a novel SGHS mutation that were not previously known to occur in this disease - namely, a progressive retinopathy with distinctive features, cystic macular changes responsive to carbonic anhydrase inhibitors, and complex electroretinographic abnormalities consistent with postreceptoral dysfunction. (PMID:26331342)
• CSF enzyme activity levels for either SGSH (in MPS IIIA subjects) or NAGLU (in MPS IIIB) significantly differed from normal controls. Several other behavioral or functional measures were found to be uninformative in this population, including timed functional motor tests. (PMID:27590925)
• Sulfamidase activity in 238 random newborns was well elevated compared to the range of activities measured in dried blood spots from 8 patients previously confirmed to have mucopolysaccharidosis III-A. (PMID:30006231)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	sgsh	ENSDARG00000032087
mus_musculus	Sgsh	ENSMUSG00000005043
rattus_norvegicus	Sgsh	ENSRNOG00000064880
drosophila_melanogaster	Sgsh	FBGN0038660

Paralogs (16): ARSD (ENSG00000006756), IDS (ENSG00000010404), ARSF (ENSG00000062096), ARSA (ENSG00000100299), STS (ENSG00000101846), ARSB (ENSG00000113273), GNS (ENSG00000135677), SULF1 (ENSG00000137573), GALNS (ENSG00000141012), ARSG (ENSG00000141337), ARSL (ENSG00000157399), ARSK (ENSG00000164291), ARSJ (ENSG00000180801), ARSI (ENSG00000183876), SULF2 (ENSG00000196562), ARSH (ENSG00000205667)

Protein

Protein identifiers

N-sulphoglucosamine sulphohydrolase — P51688 (reviewed: P51688)

Alternative names: Sulfoglucosamine sulfamidase, Sulphamidase

All UniProt accessions (9): P51688, I3L0M2, I3L207, I3L2I6, I3L2L4, I3L3T3, I3L4B7, I3L4C9, I3NI22

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes a step in lysosomal heparan sulfate degradation.

Subcellular location. Lysosome.

Post-translational modifications. 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 3A (MPS3A) [MIM:252900] A severe form of mucopolysaccharidosis type 3, an autosomal recessive lysosomal storage disease due to impaired degradation of heparan sulfate. MPS3 is characterized by severe central nervous system degeneration, but only mild somatic disease. Onset of clinical features usually occurs between 2 and 6 years; severe neurologic degeneration occurs in most patients between 6 and 10 years of age, and death occurs typically during the second or third decade of life. MPS3A is characterized by earlier onset, rapid progression of symptoms and shorter survival. 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.

RefSeq proteins (3): NP_000190, NP_001339850, NP_001339851 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000917	Sulfatase_N	Domain
IPR017850	Alkaline_phosphatase_core_sf	Homologous_superfamily
IPR024607	Sulfatase_CS	Conserved_site
IPR032506	SGSH_C	Domain

Pfam: PF00884, PF16347

Enzyme classification (BRENDA):

• EC 3.10.1.1 — N-sulfoglucosamine sulfohydrolase (BRENDA: 5 organisms, 26 substrates, 9 inhibitors, 8 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

5 substrates with measured Km, best-characterized 5. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
HEPARAN SULFATE	0.032–0.22	2
HEPARIN	0.009–0.01	2
TETRASACCHARIDES	0.0107–0.0123	2
2-DEOXY-2-SULFAMIDO-D-GLUCOSE	0.0083	1
GLUCOSAMINE 2,6-DISULFATE	0.13	1

Catalyzed reactions (Rhea), 1 shown:

• N-sulfo-D-glucosamine + H2O = D-glucosamine + sulfate (RHEA:17881)

UniProt features (133 total): sequence variant 70, helix 19, strand 18, turn 10, glycosylation site 5, binding site 5, disulfide bond 2, signal peptide 1, chain 1, active site 1, modified residue 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
4MHX	X-RAY DIFFRACTION	2
4MIV	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P51688-F1	96.64	0.96

Functional residue map

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

Catalytic / active sites (1): 70 (nucleophile)

Ligand- & substrate-binding residues (5): 31; 32; 70 (via 3-oxoalanine); 273; 274

Post-translational modifications (1): 70

Disulfide bonds (2): 183–194, 481–495

Glycosylation sites (5): 142, 151, 264, 413, 41

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-2024096	HS-GAG degradation
R-HSA-2206307	MPS IIIA - Sanfilippo syndrome A
R-HSA-1430728	Metabolism
R-HSA-1630316	Glycosaminoglycan metabolism
R-HSA-1638091	Heparan sulfate/heparin (HS-GAG) metabolism
R-HSA-1643685	Disease
R-HSA-2206281	Mucopolysaccharidoses
R-HSA-5663084	Diseases of carbohydrate metabolism
R-HSA-5668914	Diseases of metabolism
R-HSA-71387	Metabolism of carbohydrates and carbohydrate derivatives

MSigDB gene sets: 234 (showing top): GOBP_BEHAVIOR, BHATI_G2M_ARREST_BY_2METHOXYESTRADIOL_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, KEGG_LYSOSOME, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, ONKEN_UVEAL_MELANOMA_UP, GOBP_HEPARAN_SULFATE_PROTEOGLYCAN_METABOLIC_PROCESS, KINSEY_TARGETS_OF_EWSR1_FLII_FUSION_DN, GOBP_AMINOGLYCAN_METABOLIC_PROCESS, LIAO_METASTASIS, PETROVA_ENDOTHELIUM_LYMPHATIC_VS_BLOOD_DN, GOBP_DETERMINATION_OF_ADULT_LIFESPAN, MODULE_48, HAMAI_APOPTOSIS_VIA_TRAIL_DN

GO Biological Process (4): glycosaminoglycan catabolic process (GO:0006027), determination of adult lifespan (GO:0008340), heparan sulfate proteoglycan catabolic process (GO:0030200), motor behavior (GO:0061744)

GO Molecular Function (5): sulfuric ester hydrolase activity (GO:0008484), N-sulfoglucosamine sulfohydrolase activity (GO:0016250), metal ion binding (GO:0046872), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (3): lysosome (GO:0005764), lysosomal lumen (GO:0043202), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Heparan sulfate/heparin (HS-GAG) metabolism	1
Mucopolysaccharidoses	1
Metabolism of carbohydrates and carbohydrate derivatives	1
Glycosaminoglycan metabolism	1
Diseases of carbohydrate metabolism	1
Diseases of metabolism	1
Disease	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
aminoglycan catabolic process	1
glycosaminoglycan metabolic process	1
multicellular organismal process	1
proteoglycan catabolic process	1
heparan sulfate proteoglycan metabolic process	1
behavior	1
hydrolase activity, acting on ester bonds	1
hydrolase activity, acting on sulfur-nitrogen bonds	1
cation binding	1
binding	1
catalytic activity	1
lytic vacuole	1
lysosome	1
vacuolar lumen	1
extracellular vesicle	1

Protein interactions and networks

STRING

1056 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SGSH	NAGLU	P54802	988
SGSH	MANBA	O00462	880
SGSH	HGSNAT	Q68CP4	810
SGSH	SUMF1	Q8NBK3	763
SGSH	IDUA	P35475	726
SGSH	SLC26A11	Q86WA9	616
SGSH	CLN6	Q9NWW5	608
SGSH	GLB1	P16278	567
SGSH	CLN5	O75503	564
SGSH	GUSB	P08236	553
SGSH	CLN3	Q13286	550
SGSH	PPT1	P50897	542
SGSH	ALB	P02768	527
SGSH	MFSD8	Q8NHS3	524
SGSH	CLCN6	P51797	517

IntAct

42 interactions, top by confidence:

A	B	Type	Score
SUMF1	SGSH	psi-mi:“MI:0914”(association)	0.710
SGSH	SUMF1	psi-mi:“MI:0915”(physical association)	0.710
FBXO6	MAN2B1	psi-mi:“MI:0914”(association)	0.640
SMAD2	SMAD9	psi-mi:“MI:0914”(association)	0.550
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
PLAUR	XRCC3	psi-mi:“MI:0914”(association)	0.530
SGSH	FBXO21	psi-mi:“MI:0914”(association)	0.530
PNLIPRP2	TGFB1	psi-mi:“MI:0914”(association)	0.530
SUMF2	SGSH	psi-mi:“MI:0915”(physical association)	0.400
SGSH	PCNA	psi-mi:“MI:0915”(physical association)	0.370
PLAUR	DDX11L8	psi-mi:“MI:0914”(association)	0.350
P		psi-mi:“MI:0914”(association)	0.350
DISC1	AGRN	psi-mi:“MI:0914”(association)	0.350
	VPS37C	psi-mi:“MI:0914”(association)	0.350
CANX	HLA-A	psi-mi:“MI:0914”(association)	0.350
INSL4	SGSH	psi-mi:“MI:0914”(association)	0.350
LY86	TMEM131L	psi-mi:“MI:0914”(association)	0.350
IL5RA	POTEF	psi-mi:“MI:0914”(association)	0.350
DNAJB9	POTEF	psi-mi:“MI:0914”(association)	0.350
PI15		psi-mi:“MI:0914”(association)	0.350
NAAA	HAX1	psi-mi:“MI:0914”(association)	0.350
MFAP4	QSOX1	psi-mi:“MI:0914”(association)	0.350
PRG2	QSOX1	psi-mi:“MI:0914”(association)	0.350
IDS	RTCA	psi-mi:“MI:0914”(association)	0.350
SDF2L1	MANBA	psi-mi:“MI:0914”(association)	0.350
GGH	MANBA	psi-mi:“MI:0914”(association)	0.350

BioGRID (53): SGSH (Affinity Capture-MS), SGSH (Affinity Capture-MS), SGSH (Affinity Capture-MS), SGSH (Affinity Capture-MS), SGSH (Affinity Capture-MS), SGSH (Affinity Capture-MS), SGSH (Affinity Capture-MS), SGSH (Affinity Capture-MS), SGSH (Affinity Capture-MS), SGSH (Proximity Label-MS), SGSH (Reconstituted Complex), SGSH (Affinity Capture-MS), SGSH (Affinity Capture-MS), SGSH (Affinity Capture-MS), SGSH (Affinity Capture-MS)

ESM2 similar proteins: A0A060S684, A0A075TXZ3, A0A084B9Z4, A0A0B4GDU5, A0A1L9WN42, A0A455ZJM4, A1CE56, A1CFK9, A1CTM5, B0Y7S2, B6DZC8, B6DZD1, B6DZD2, C0HLA0, D4AQ54, D4AR77, D4ASH1, D4AV38, D4AZ78, D4AZG9, H2DF87, I1RIF1, O19015, P07140, P14000, P14217, P16278, P34724, P37274, P50473, P51688, P54793, P56161, P92916, Q0INM3, Q0IZZ8, Q10723, Q10B67, Q21376, Q4WMS9

Diamond homologs: P51688, P54793, Q32KH9, Q32KJ9, Q5FYA8, Q96EG1, P08842, P14000, P15289, P15589, P34059, P50427, P50428, P50473, P51689, P51690, Q08DD1, Q0IHJ2, Q32KH0, Q32KH5, Q32KH8, Q32KJ6, Q3TYD4, Q571E4, Q60HH5, Q6UWY0, Q89YS5, Q8WNQ7, Q9C0V7, T2KMG4, T2KN71, P50429, P50430, Q0TUK6, Q32KH7, Q5FYB1, T2KM26, Q32KI9, Q32KJ8, Q8CFG0

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
TFEB	“up-regulates quantity by expression”	SGSH	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 50 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
Neutrophil degranulation	9	6.1×	2e-03
Innate Immune System	7	5.2×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
ERAD pathway	7	28.2×	2e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

1324 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	64
Likely pathogenic	82
Uncertain significance	457
Likely benign	519
Benign	40

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068595	NC_000017.10:g.(?78194005)(78194132_?)del	Pathogenic
1073350	NM_000199.5(SGSH):c.1241_1242dup (p.Thr415fs)	Pathogenic
1076318	NM_000199.5(SGSH):c.642del (p.Tyr215fs)	Pathogenic
1184569	NM_000199.5(SGSH):c.716A>G (p.Gln239Arg)	Pathogenic
1381871	NM_000199.5(SGSH):c.282_283dup (p.Val95fs)	Pathogenic
1383454	NM_000199.5(SGSH):c.250-289_463del	Pathogenic
1455207	NM_000199.5(SGSH):c.303C>A (p.Phe101Leu)	Pathogenic
1456247	NM_000199.5(SGSH):c.418G>T (p.Glu140Ter)	Pathogenic
1926896	NM_000199.5(SGSH):c.391del (p.Val131fs)	Pathogenic
1953824	NM_000199.5(SGSH):c.481A>T (p.Lys161Ter)	Pathogenic
1968702	NM_000199.5(SGSH):c.578_579delinsAA (p.Phe193Ter)	Pathogenic
198694	NM_000199.5(SGSH):c.1027dup (p.Leu343fs)	Pathogenic
2011911	NM_000199.5(SGSH):c.915G>A (p.Trp305Ter)	Pathogenic
2017325	NM_000199.5(SGSH):c.714del (p.Gln239fs)	Pathogenic
2026037	NM_000199.5(SGSH):c.1265dup (p.Trp423fs)	Pathogenic
2028783	NM_000199.5(SGSH):c.364G>C (p.Gly122Arg)	Pathogenic
2029536	NM_000199.5(SGSH):c.544dup (p.Arg182fs)	Pathogenic
2052169	NM_000199.5(SGSH):c.1276del (p.Asp426fs)	Pathogenic
2097039	NM_000199.5(SGSH):c.794_795insAGGTGCGATAAATAATAGGATGAGGCAGGAATCAAAGACAGATACTGCGACATAGGGTGCTCCGG (p.Asp265delinsGluGlyAlaIleAsnAsnArgMetArgGlnGluSerLysThrAspThrAlaThrTer)	Pathogenic
2109750	NM_000199.5(SGSH):c.790_794delinsGCCAGAAGCGGGGGGAGGGGGGGGGTTTGGTGGAAATTTTTTGTTATGATGTCTGTGTGGAAAGCGGCTGTGCAGACATTCAATTGTTATTATTATGTCCTACAAGCATTAATTAATTAACACACTTTAGTAGGTATGTTCGCCTGTAATATTGAACGTAGGTGCGATAAATAATAGGATGAGGCAGGAATCAAAGACAGATACTGCGACATAGGGTGCTCCGG (p.Asn264_Asp265delinsAlaArgSerGlyGlyArgGlyGlyValTrpTrpLysPhePheValMetMetSerValTrpLysAlaAlaValGlnThrPheAsnCysTyrTyrTyrValLeuGlnAlaLeuIleAsnTer)	Pathogenic
2128742	NM_000199.5(SGSH):c.389_392del (p.Thr130fs)	Pathogenic
2422572	NC_000017.10:g.(?78188510)(78190896_?)del	Pathogenic
2422573	NC_000017.10:g.(?78194005)(78194112_?)del	Pathogenic
2498725	NM_000199.5(SGSH):c.391_392insC (p.Val131fs)	Pathogenic
2572061	NM_000199.5(SGSH):c.221G>T (p.Arg74Leu)	Pathogenic
2704472	NM_000199.5(SGSH):c.1286del (p.His429fs)	Pathogenic
2710788	NM_000199.5(SGSH):c.1260del (p.Thr421fs)	Pathogenic
2736689	NM_000199.5(SGSH):c.120C>G (p.Tyr40Ter)	Pathogenic
2752377	NM_000199.5(SGSH):c.1418G>A (p.Trp473Ter)	Pathogenic
2754541	NM_000199.5(SGSH):c.1417del (p.Trp473fs)	Pathogenic

SpliceAI

2299 predictions. Top by Δscore:

Variant	Effect	Δscore
17:80206964:A:AG	acceptor_gain	1.0000
17:80206965:C:G	acceptor_gain	1.0000
17:80206966:A:AG	acceptor_gain	1.0000
17:80206967:A:G	acceptor_gain	1.0000
17:80206968:A:AG	acceptor_gain	1.0000
17:80206969:G:A	acceptor_loss	1.0000
17:80206969:G:GT	acceptor_gain	1.0000
17:80206969:GA:G	acceptor_gain	1.0000
17:80206969:GAA:G	acceptor_gain	1.0000
17:80206969:GAAC:G	acceptor_gain	1.0000
17:80206969:GAACA:G	acceptor_gain	1.0000
17:80207077:G:GT	donor_gain	1.0000
17:80207081:CTCAA:C	donor_gain	1.0000
17:80207086:G:GG	donor_gain	1.0000
17:80207087:T:G	donor_loss	1.0000
17:80212086:AGG:A	donor_gain	1.0000
17:80214613:A:AC	donor_gain	1.0000
17:80214614:C:CC	donor_gain	1.0000
17:80214621:T:TA	donor_gain	1.0000
17:80214763:TGC:T	acceptor_gain	1.0000
17:80214763:TGCC:T	acceptor_loss	1.0000
17:80214764:GC:G	acceptor_gain	1.0000
17:80214764:GCC:G	acceptor_loss	1.0000
17:80214765:CC:C	acceptor_gain	1.0000
17:80214766:C:CC	acceptor_gain	1.0000
17:80214766:CTGG:C	acceptor_loss	1.0000
17:80215027:CCTCA:C	donor_loss	1.0000
17:80215028:CTCA:C	donor_loss	1.0000
17:80215029:TCA:T	donor_loss	1.0000
17:80215030:CAC:C	donor_loss	1.0000

AlphaMissense

3278 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:80212202:T:A	D273V	0.998
17:80217074:G:C	S69R	0.996
17:80217074:G:T	S69R	0.996
17:80217076:T:G	S69R	0.996
17:80217077:G:C	S68R	0.996
17:80217077:G:T	S68R	0.996
17:80217079:T:G	S68R	0.996
17:80217189:T:A	D31V	0.996
17:80212197:C:A	G275W	0.995
17:80212203:C:A	D273Y	0.995
17:80212203:C:G	D273H	0.995
17:80214752:C:A	K123N	0.995
17:80214752:C:G	K123N	0.995
17:80217062:G:C	S73R	0.995
17:80217062:G:T	S73R	0.995
17:80217064:T:G	S73R	0.995
17:80217186:T:A	D32V	0.995
17:80213816:G:T	R245S	0.994
17:80217190:C:A	D31Y	0.993
17:80212196:C:T	G275E	0.992
17:80212202:T:G	D273A	0.992
17:80217061:G:T	R74S	0.992
17:80217071:G:C	C70W	0.992
17:80217190:C:G	D31H	0.992
17:80210831:C:G	R377P	0.991
17:80213810:C:G	D247H	0.991
17:80213842:A:G	L236P	0.991
17:80214294:G:C	H181D	0.991
17:80214299:T:A	D179V	0.991
17:80214753:T:G	K123T	0.991

dbSNP variants (sampled 300 via entrez): RS1000063683 (17:80200900 C>A,T), RS1000270769 (17:80219780 G>A), RS1000661013 (17:80221197 G>C,T), RS1000927635 (17:80220843 C>A,T), RS1001011996 (17:80221005 C>G,T), RS1001049181 (17:80215776 A>G), RS1001373198 (17:80211818 A>G,T), RS1001470301 (17:80221248 A>G), RS1001481135 (17:80215052 G>A), RS1001543278 (17:80215536 G>T), RS1001569174 (17:80208106 G>A,C), RS1001712764 (17:80220604 G>A,T), RS1001715896 (17:80202882 C>T), RS1001798222 (17:80206867 G>A), RS1001860912 (17:80216527 C>T)

Disease associations

OMIM: gene MIM:605270 | disease phenotypes: MIM:252900, MIM:602723, MIM:607014, MIM:120970

GenCC curated gene-disease

Disease	Classification	Inheritance
mucopolysaccharidosis type 3A	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
mucopolysaccharidosis type 3A	Definitive	AR

Mondo (11): mucopolysaccharidosis type 3A (MONDO:0009655), psoriasis 2 (MONDO:0011269), pityriasis rubra pilaris (MONDO:0100017), autoinflammatory syndrome (MONDO:0019751), mucopolysaccharidosis type 3 (MONDO:0018937), intellectual disability (MONDO:0001071), mucopolysaccharidosis (MONDO:0019249), pathologic nystagmus (MONDO:0004843), cone-rod dystrophy (MONDO:0015993), inherited retinal dystrophy (MONDO:0019118), neurodegenerative disease (MONDO:0005559)

Orphanet (8): Mucopolysaccharidosis type 3 (Orphanet:581), Sanfilippo syndrome type A (Orphanet:79269), Pityriasis rubra pilaris (Orphanet:2897), Autoinflammatory syndrome (Orphanet:93665), Mucopolysaccharidosis (Orphanet:79213), Cone rod dystrophy (Orphanet:1872), OBSOLETE: Inherited retinal disorder (Orphanet:71862), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

28 total (29 of 28 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000250	Dense calvaria
HP:0000280	Coarse facial features
HP:0000365	Hearing impairment
HP:0000664	Synophrys
HP:0000752	Hyperactivity
HP:0000900	Thickened ribs
HP:0000943	Dysostosis multiplex
HP:0001007	Hirsutism
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001387	Joint stiffness
HP:0001507	Growth abnormality
HP:0001537	Umbilical hernia
HP:0001670	Asymmetric septal hypertrophy
HP:0001744	Splenomegaly
HP:0002014	Diarrhea
HP:0002159	Heparan sulfate excretion in urine
HP:0002208	Coarse hair
HP:0002240	Hepatomegaly
HP:0002360	Sleep disturbance
HP:0002650	Scoliosis
HP:0002788	Recurrent upper respiratory tract infections
HP:0003309	Ovoid thoracolumbar vertebrae
HP:0011463	Childhood onset
HP:4000193	Reduced leukocyte N-sulfoglucosamine sulfohydrolase activity
HP:0000556	Retinal dystrophy

GWAS associations

0 associations (top):

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D000071700	Cone-Rod Dystrophies	C11.270.152; C11.768.585.658.250; C16.320.290.152
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D009083	Mucopolysaccharidoses	C16.320.565.202.715; C16.320.565.595.600; C17.300.550.575; C18.452.648.202.715; C18.452.648.595.600
D019636	Neurodegenerative Diseases	C10.574
D009759	Nystagmus, Pathologic	C10.292.562.675; C11.590.400
D010916	Pityriasis Rubra Pilaris	C17.800.859.600.685
D058499	Retinal Dystrophies	C11.768.585.658

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects expression, decreases expression, increases abundance, increases expression	3
bisphenol A	decreases expression, increases methylation	2
bisphenol S	decreases methylation, increases expression	2
Arsenic	affects methylation, increases abundance, increases expression	2
Valproic Acid	affects expression, decreases expression	2
Cyclosporine	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
butyraldehyde	decreases expression	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
2-palmitoylglycerol	increases expression	1
K 7174	increases expression	1
bisphenol B	increases expression	1
jinfukang	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
bisphenol AF	increases expression	1
Bortezomib	increases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	increases expression	1
Cadmium	increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, decreases expression	1
Gasoline	increases abundance, increases expression, affects cotreatment	1
Ivermectin	decreases expression	1
Polycyclic Aromatic Hydrocarbons	affects cotreatment, increases abundance, increases expression	1
Selenium	increases expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1

Cellosaurus cell lines

13 cell lines: 7 finite cell line, 3 cancer cell line, 3 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_0L92	GM00629	Finite cell line	Male
CVCL_0L93	GM00643	Finite cell line	Male
CVCL_0L95	GM00879	Finite cell line	Female
CVCL_0L98	GM01094	Finite cell line	Female
CVCL_0M02	GM01739	Finite cell line	Female
CVCL_0M06	GM06110	Finite cell line	Female
CVCL_B5KV	HAP1 SGSH (-) 2	Cancer cell line	Male
CVCL_D5FJ	HeLa::TMEM192-3xHA SGSH partial KO	Cancer cell line	Female
CVCL_UD89	IMEDEAi004-A	Induced pluripotent stem cell	Female
CVCL_UD90	IMEDEAi004-B	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00815633	PHASE4	TERMINATED	A Pilot Study of Alefacept for the Treatment of Pityriasis Rubra Pilaris
NCT07497620	PHASE4	NOT_YET_RECRUITING	Bimzelx (Bimekizumab) For The Treatment Of Adult Onset PRP
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT05494593	PHASE4	WITHDRAWN	A Study of ELAPRASE in Treatment-naïve Participants With Hunter Syndrome (Mucopolysaccharidosis [MPS] II)
NCT04360265	PHASE3	ENROLLING_BY_INVITATION	Follow-up Study of AAV-Mediated Gene Transfer (UX111; Previously Known as ABO-102) for MPS Type IIIA
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00654433	PHASE3	TERMINATED	ALD-101 Adjuvant Therapy of Unrelated Umbilical Cord Blood Transfusion (UCBT) in Patients With Inherited Metabolic Diseases
NCT02230566	PHASE3	COMPLETED	A Phase 3 Study of UX003 Recombinant Human Betaglucuronidase (rhGUS) Enzyme Replacement Therapy in Patients With Mucopolysaccharidosis Type 7 (MPS 7)
NCT02432144	PHASE3	COMPLETED	A Study of UX003 Recombinant Human Beta-Glucuronidase (rhGUS) Enzyme Replacement Therapy in Subjects With Mucopolysaccharidosis Type 7, Sly Syndrome (MPS 7)
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT03485976	PHASE2	COMPLETED	Ixekizumab in the Treatment of Pityriasis Rubra Pilaris (PRP)
NCT03975153	PHASE2	COMPLETED	Guselkumab in the Treatment of Pityriasis Rubra Pilaris (PRP)
NCT06444399	PHASE2	RECRUITING	Deucravacitinib (BMS-986165) for Pityriasis Rubra Pilaris
NCT00442182	PHASE2	UNKNOWN	The Efficacy and Safety of ITF2357 in AIS
NCT00383448	PHASE2	COMPLETED	HSCT for High Risk Inherited Inborn Errors
NCT02060526	PHASE2	COMPLETED	Randomized, Controlled, Open-label, Multicenter, Safety and Efficacy Study of rhHNS Administration Via an IDDD in Pediatric Patients With Early Stage MPS IIIA Disease
NCT02350816	PHASE2	TERMINATED	An Extension Study to Determine Safety and Efficacy for Pediatric Patients With MPS Type IIIA Disease Who Participated in Study HGT-SAN-093.
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT01043640	PHASE2	COMPLETED	Allogeneic Bone Marrow Transplant for Inherited Metabolic Disorders
NCT02418455	PHASE2	COMPLETED	Study of UX003 Recombinant Human Beta-Glucuronidase (rhGUS) Enzyme Replacement Treatment in Mucopolysaccharidosis Type 7, Sly Syndrome (MPS 7) Patients Less Than 5 Years of Age
NCT03632213	PHASE2	UNKNOWN	Evaluation of Losartan on Cardiovascular Disease in Patients With Mucopolysaccharidoses IV A and VI
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT06567769	PHASE1	RECRUITING	Phase 1 Study of GC1130A in Patients With Sanfilippo Syndrome Type A (MPS IIIA)
NCT03342573	PHASE1	COMPLETED	Cosentyx (Secukinumab) for the Treatment of Adult Onset Pityriasis Rubra Pilaris
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT02716246	PHASE2/PHASE3	RECRUITING	Phase I/II/III Gene Transfer Clinical Trial of scAAV9.U1a.hSGSH
NCT03612869	PHASE2/PHASE3	UNKNOWN	Study of AAVrh10-h.SGSH Gene Therapy in Patients With Mucopolysaccharidosis Type IIIA (MPS IIIA)
NCT03423186	PHASE1/PHASE2	COMPLETED	A Study to Assess the Safety and Tolerability of SOBI003 in Pediatric MPS IIIA Patients