HGSNAT

Summary

HGSNAT (heparan-alpha-glucosaminide N-acetyltransferase, HGNC:26527) is a protein-coding gene on chromosome 8p11.21-p11.1, encoding Heparan-alpha-glucosaminide N-acetyltransferase (Q68CP4). Lysosomal acetyltransferase that acetylates the non-reducing terminal alpha-glucosamine residue of intralysosomal heparin or heparan sulfate, converting it into a substrate for luminal alpha-N-acetyl glucosaminidase.

This gene encodes a lysosomal acetyltransferase, which is one of several enzymes involved in the lysosomal degradation of heparin sulfate. Mutations in this gene are associated with Sanfilippo syndrome C, one type of the lysosomal storage disease mucopolysaccaridosis III, which results from impaired degradation of heparan sulfate.

Source: NCBI Gene 138050 — RefSeq curated summary.

At a glance

• Gene–disease (curated): inherited retinal dystrophy (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 1,365 total — 87 pathogenic, 82 likely-pathogenic
• Phenotypes (HPO): 79
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_152419

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26527
Approved symbol	HGSNAT
Name	heparan-alpha-glucosaminide N-acetyltransferase
Location	8p11.21-p11.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ32731, HGNAT
Ensembl gene	ENSG00000165102
Ensembl biotype	protein_coding
OMIM	610453
Entrez	138050

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 13 protein_coding, 4 retained_intron, 2 nonsense_mediated_decay

ENST00000379644, ENST00000517319, ENST00000519000, ENST00000519705, ENST00000520678, ENST00000520704, ENST00000521576, ENST00000522082, ENST00000523989, ENST00000524016, ENST00000902456, ENST00000902457, ENST00000902458, ENST00000902459, ENST00000902460, ENST00000902461, ENST00000902462, ENST00000902463, ENST00000967241

RefSeq mRNA: 4 — MANE Select: NM_152419 NM_001363227, NM_001363228, NM_001363229, NM_152419

CCDS: CCDS47852

Canonical transcript exons

ENST00000379644 — 18 exons

Exon	Start	End
ENSE00001127375	43193757	43193843
ENSE00001127391	43182145	43182260
ENSE00001309887	43199388	43202855
ENSE00001309984	43158575	43158711
ENSE00001503801	43178074	43178234
ENSE00001503802	43173713	43173743
ENSE00002139984	43140464	43140614
ENSE00003471440	43197672	43197742
ENSE00003479241	43170585	43170694
ENSE00003497502	43161438	43161507
ENSE00003520710	43146948	43147063
ENSE00003536498	43158923	43159044
ENSE00003537657	43192304	43192430
ENSE00003565057	43169173	43169242
ENSE00003601827	43172310	43172386
ENSE00003652173	43197840	43197952
ENSE00003676044	43191474	43191595
ENSE00003790048	43196948	43197025

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 97.11.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.3110 / max 198.6826, expressed in 1811 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
88721	17.2285	1802
88725	0.9518	556
88724	0.8133	529
88726	0.6931	298
88720	0.6243	347

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of stomach	UBERON:0001199	97.11	gold quality
right uterine tube	UBERON:0001302	96.05	gold quality
cervix squamous epithelium	UBERON:0006922	95.95	gold quality
stromal cell of endometrium	CL:0002255	95.92	gold quality
endocervix	UBERON:0000458	95.43	gold quality
left ovary	UBERON:0002119	95.30	gold quality
right ovary	UBERON:0002118	95.27	gold quality
tibial nerve	UBERON:0001323	94.72	gold quality
left uterine tube	UBERON:0001303	94.71	gold quality
body of uterus	UBERON:0009853	94.63	gold quality
skin of leg	UBERON:0001511	94.45	gold quality
gingival epithelium	UBERON:0001949	94.34	gold quality
skin of abdomen	UBERON:0001416	94.18	gold quality
hair follicle	UBERON:0002073	94.08	gold quality
subcutaneous adipose tissue	UBERON:0002190	94.05	gold quality
body of pancreas	UBERON:0001150	93.98	gold quality
ectocervix	UBERON:0012249	93.96	gold quality
skin of hip	UBERON:0001554	93.95	gold quality
zone of skin	UBERON:0000014	93.64	gold quality
squamous epithelium	UBERON:0006914	93.63	gold quality
right lung	UBERON:0002167	93.61	gold quality
right coronary artery	UBERON:0001625	93.49	gold quality
colonic epithelium	UBERON:0000397	93.45	gold quality
sural nerve	UBERON:0015488	93.39	gold quality
endometrium	UBERON:0001295	93.35	gold quality
vagina	UBERON:0000996	93.31	gold quality
synovial joint	UBERON:0002217	93.29	gold quality
urethra	UBERON:0000057	93.28	gold quality
upper leg skin	UBERON:0004262	93.28	gold quality
adenohypophysis	UBERON:0002196	93.20	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-7249	no	39.70
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

101 targeting HGSNAT, 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-3613-3P	100.00	76.36	7965
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 18)

• gene encoding the enzyme deficient in mucopolysaccharidosis IIIC was identified as HGSNAT; mutational analyses identified a splice-junction mutation that accounted for three mutant alleles, and a single base-pair insertion accounted for the fourth (PMID:16960811)
• 2.6-cM interval between D8S1051 and D8S1831 and identification of TMEM76, which encodes a 73-kDa protein with predicted multiple transmembrane domains and glycosylation sites, as the gene that causes MPS IIIC when it is mutated (PMID:17033958)
• mutational analysis of HGSNAT in Italian Sanfilippo C syndrome patients resulted in identification of 9 alleles (8 novel)– 3 splice-site mutations, 3 frameshift deletions resulting in premature stop codons, 1 nonsense mutation & 2 missense mutations (PMID:17397050)
• three patients with mucopolysaccharidosis IIIC harbored two different mutations c.525dupT and c.372-2A–>G (Table 1), both of which were previously unreported (PMID:18518886)
• HGSNAT misfolding may have a role in mucopolysaccharidosis III type C (PMID:19823584)
• Data suggests that mutations may function together to abolish HGSNAT activity. (PMID:20583299)
• intralysosomal oligomerization and proteolytic cleavage as two steps crucial for functional activation of HGSNAT. (PMID:20650889)
• Identification of novel HGSNAT mutations in Sanfilippo syndrome type C Spanish patients. (PMID:20825431)
• Characterization of the biosynthesis, processing and kinetic mechanism of heparin acetyl-CoA:alpha-glucosaminide N-acetyltransferase (PMID:21957468)
• Mutation id HGSNAT is associated with non-syndromic retinitis pigmentosa . (PMID:25859010)
• Promoter variants rs4523300 and rs149596192 did not have a measurable impact on HGSNAT enzyme activity in MPS IIIC patients carrying them. (PMID:27452122)
• A homozygous variant in HGSNAT identified in two siblings with Kluver-Bucy syndrome and Mucopolysaccharidosis type IIIC. (PMID:27827379)
• Study reports molecular analysis defects in the HGSNAT gene in the largest group of mucopolysaccharidosis type IIIC (MPSIIIC) patients studied so far increasing the total number of HGSNAT variants associated with MPSIIIC to 71. Additionally, some of these variants show common ancestor haplotypes; others are several founder mutations. (PMID:31228227)
• Nonsyndromic retinitis pigmentosa caused by two novel variants in the HGSNAT gene in a Chinese family. (PMID:32347150)
• A genetic and clinical study of individuals with nonsyndromic retinopathy consequent upon sequence variants in HGSNAT, the gene associated with Sanfilippo C mucopolysaccharidosis. (PMID:32770643)
• Mucopolysaccharidosis type IIIC in chinese mainland: clinical and molecular characteristics of ten patients and report of six novel variants in the HGSNAT gene. (PMID:37014526)
• Expanding the phenotypic and genotypic spectrum of patients with HGSNAT-related retinopathy. (PMID:37592806)
• Identification and characterization of novel genetic variants in the first Chinese family of mucopolysaccharidosis IIIC (Sanfilippo C syndrome). (PMID:38613342)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	hgsnat	ENSDARG00000077804
mus_musculus	Hgsnat	ENSMUSG00000037260
rattus_norvegicus	Hgsnat	ENSRNOG00000069796
drosophila_melanogaster	Hgsnat	FBGN0029737

Protein

Protein identifiers

Heparan-alpha-glucosaminide N-acetyltransferase — Q68CP4 (reviewed: Q68CP4)

Alternative names: Transmembrane protein 76

All UniProt accessions (6): E5RGH7, E5RH11, E5RJC4, E5RJN0, Q68CP4, H0YAZ0

UniProt curated annotations — full annotation on UniProt →

Function. Lysosomal acetyltransferase that acetylates the non-reducing terminal alpha-glucosamine residue of intralysosomal heparin or heparan sulfate, converting it into a substrate for luminal alpha-N-acetyl glucosaminidase.

Subunit / interactions. Homooligomer. Homooligomerization is necessary for enzyme activity.

Subcellular location. Lysosome membrane.

Tissue specificity. Widely expressed, with highest level in leukocytes, heart, liver, skeletal muscle, lung, placenta and liver.

Post-translational modifications. Undergoes intralysosomal proteolytic cleavage; occurs within the end of the first and/or the beginning of the second luminal domain and is essential for the activation of the enzyme. Glycosylated.

Disease relevance. Mucopolysaccharidosis 3C (MPS3C) [MIM:252930] A 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. The disease is caused by variants affecting the gene represented in this entry. Retinitis pigmentosa 73 (RP73) [MIM:616544] A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. A signal sequence is predicted but has been shown not to be cleaved in the endoplasmic reticulum. Intralysosomal proteolytic cleavage is faster and enzymatic activity higher than isoform 2.

Isoforms (2)

UniProt ID	Names	Canonical?
Q68CP4-1	1	yes
Q68CP4-2	2

RefSeq proteins (4): NP_001350156, NP_001350157, NP_001350158, NP_689632* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR012429	HGSNAT_cat	Domain

Pfam: PF07786

Enzyme classification (BRENDA):

• EC 2.3.1.78 — heparan-alpha-glucosaminide N-acetyltransferase (BRENDA: 3 organisms, 21 substrates, 28 inhibitors, 7 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ACETYL-COA	0.0025–0.55	4
BETA-D-GLUCOSAMINE	0.003–0.37	2

Catalyzed reactions (Rhea), 1 shown:

• alpha-D-glucosaminyl-heparan sulfate + acetyl-CoA = N-acetyl-alpha-D-glucosaminyl-heparan sulfate + CoA + H(+) (RHEA:15125)

UniProt features (121 total): sequence variant 29, helix 22, strand 16, topological domain 12, mutagenesis site 12, transmembrane region 11, turn 8, glycosylation site 3, region of interest 2, modified residue 2, chain 1, active site 1, disulfide bond 1, splice variant 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
8JL3	ELECTRON MICROSCOPY	2.59
8JL4	ELECTRON MICROSCOPY	2.68
8W4A	ELECTRON MICROSCOPY	2.69
8JL1	ELECTRON MICROSCOPY	2.8
8JKV	ELECTRON MICROSCOPY	2.87
8VKJ	ELECTRON MICROSCOPY	2.92
8VLU	ELECTRON MICROSCOPY	3.12
8VLG	ELECTRON MICROSCOPY	3.15
8VLI	ELECTRON MICROSCOPY	3.2
8TU9	ELECTRON MICROSCOPY	3.26
8VLV	ELECTRON MICROSCOPY	3.49
8VLY	ELECTRON MICROSCOPY	3.61

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q68CP4-F1	80.64	0.49

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): 297

Post-translational modifications (2): 243, 245

Disulfide bonds (1): 151–462

Glycosylation sites (3): 94, 142, 162

Mutagenesis-validated functional residues (12):

Position	Phenotype
107	loss of intralysosomal proteolytic cleavage and enzymatic activity. reduced oligomer formation.
151	loss of intralysosomal proteolytic cleavage and enzymatic activity. reduced oligomer formation.
179	loss of intralysosomal proteolytic cleavage and enzymatic activity.
236	displayed both lysosomal and plasma membrane localization, reduced intralysosomal proteolytic cleavage and enzymatic act
237	displayed both lysosomal and plasma membrane localization, reduced intralysosomal proteolytic cleavage and enzymatic act
297	loss of enzymatic activity, but correctly targeted and processed.
333	no loss of intralysosomal proteolytic cleavage and enzymatic activity.
402	no loss of intralysosomal proteolytic cleavage and enzymatic activity.
462	complete loss of intralysosomal proteolytic cleavage and enzymatic activity. reduced oligomer formation.
479	loss of intralysosomal proteolytic cleavage and enzymatic activity, retained in the endoplasmic reticulum.
633	loss of intralysosomal proteolytic cleavage and enzymatic activity, retained in the endoplasmic reticulum.
652–663	loss of intralysosomal proteolytic cleavage and enzymatic activity. localized in the plasma membrane.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-2024096	HS-GAG degradation
R-HSA-2206291	MPS IIIC - Sanfilippo syndrome C
R-HSA-6798695	Neutrophil degranulation

MSigDB gene sets: 364 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_LYSOSOMAL_TRANSPORT, GOCC_VACUOLAR_MEMBRANE, GOCC_SECRETORY_GRANULE, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, IVANOVA_HEMATOPOIESIS_MATURE_CELL, GOBP_VACUOLAR_TRANSPORT, KEGG_LYSOSOME, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GERY_CEBP_TARGETS, KESHELAVA_MULTIPLE_DRUG_RESISTANCE, GOBP_HEPARAN_SULFATE_PROTEOGLYCAN_METABOLIC_PROCESS

GO Biological Process (3): lysosomal transport (GO:0007041), heparan sulfate proteoglycan catabolic process (GO:0030200), protein complex oligomerization (GO:0051259)

GO Molecular Function (3): heparan-alpha-glucosaminide N-acetyltransferase activity (GO:0015019), acyltransferase activity (GO:0016746), transferase activity (GO:0016740)

GO Cellular Component (7): lysosomal membrane (GO:0005765), plasma membrane (GO:0005886), specific granule membrane (GO:0035579), lysosomal lumen (GO:0043202), tertiary granule membrane (GO:0070821), lysosome (GO:0005764), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Heparan sulfate/heparin (HS-GAG) metabolism	1
Mucopolysaccharidoses	1
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
lysosome	2
secretory granule membrane	2
vacuolar transport	1
proteoglycan catabolic process	1
heparan sulfate proteoglycan metabolic process	1
protein-containing complex assembly	1
N-acetyltransferase activity	1
transferase activity	1
catalytic activity	1
lytic vacuole membrane	1
membrane	1
cell periphery	1
specific granule	1
vacuolar lumen	1
tertiary granule	1
lytic vacuole	1
cellular anatomical structure	1

Protein interactions and networks

STRING

840 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HGSNAT	NAGLU	P54802	981
HGSNAT	SGSH	P51688	810
HGSNAT	ESCO1	Q5FWF5	803
HGSNAT	ESCO2	Q56NI9	802
HGSNAT	GNS	P15586	757
HGSNAT	GALNS	P34059	639
HGSNAT	IDUA	P35475	614
HGSNAT	MFSD8	Q8NHS3	546
HGSNAT	GLB1	P16278	520
HGSNAT	IDS	P22304	520
HGSNAT	POMK	Q9H5K3	519
HGSNAT	FNTA	P49354	503
HGSNAT	ARSG	Q96EG1	499
HGSNAT	ARSB	P15848	496
HGSNAT	BLOC1S1	P78537	496

IntAct

11 interactions, top by confidence:

A	B	Type	Score
NRN1	SLC1A1	psi-mi:“MI:0914”(association)	0.530
JMJD4	SPTLC1	psi-mi:“MI:0914”(association)	0.350
	NPC1	psi-mi:“MI:0914”(association)	0.350
Npc1	ESYT2	psi-mi:“MI:0914”(association)	0.350
ASIC4	UPK3BL1	psi-mi:“MI:0914”(association)	0.350
ENTPD2	ATP2A1	psi-mi:“MI:0914”(association)	0.350
C15orf32	NPC1	psi-mi:“MI:0914”(association)	0.350
MFSD10	NDUFS8	psi-mi:“MI:0914”(association)	0.350
MST1R	SHTN1	psi-mi:“MI:2364”(proximity)	0.270
HGSNAT	metG	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (12): HGSNAT (Affinity Capture-MS), HGSNAT (Affinity Capture-MS), TRABD (Affinity Capture-MS), SLC1A5 (Affinity Capture-MS), HGSNAT (Affinity Capture-RNA), HGSNAT (Affinity Capture-MS), HGSNAT (Affinity Capture-MS), HGSNAT (Affinity Capture-MS), HGSNAT (Affinity Capture-MS), HGSNAT (Proximity Label-MS), MCAM (Co-fractionation), HGSNAT (Affinity Capture-MS)

ESM2 similar proteins: A0A8C2M425, A1L1J9, A1L504, B0BNG2, D3ZBP4, F1MH07, O08984, O75908, O77759, O88496, O88908, P38435, P70606, Q07175, Q0P4Y8, Q32LM8, Q3U9G9, Q3UDW8, Q5KR61, Q5RF50, Q5RKL5, Q5T197, Q5T1A1, Q5ZKZ9, Q643R3, Q658P3, Q68CP4, Q6NVG1, Q767L9, Q7TNJ2, Q7TPN3, Q7TQM4, Q7ZWN0, Q8BKF1, Q8C3X8, Q8CI59, Q8IUH8, Q8IZY2, Q8R1J1, Q8TDZ2

Diamond homologs: Q3UDW8, Q68CP4

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1365 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	87
Likely pathogenic	82
Uncertain significance	446
Likely benign	598
Benign	50

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069082	NM_152419.3(HGSNAT):c.1508dup (p.Leu504fs)	Pathogenic
1073137	NM_152419.3(HGSNAT):c.376G>T (p.Glu126Ter)	Pathogenic
1074147	NM_152419.3(HGSNAT):c.1348del (p.Asp450fs)	Pathogenic
1075807	NM_152419.3(HGSNAT):c.682_740del (p.Pro228fs)	Pathogenic
1076291	NM_152419.3(HGSNAT):c.884_885insTATTTTTTTTTATTTTTTTNNNNNNNNNNTGTTAGCCAGGATGGTCTCGATCTCCTGACCTCATGATCCACCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACCGCGCCCGGCCGGATCTTCCATTTTTCT (p.Leu295_Ser296insIlePhePheTyrPhePheXaaXaaXaaXaaLeuAlaArgMetValSerIleSerTer)	Pathogenic
1076551	NM_152419.3(HGSNAT):c.133dup (p.Arg45fs)	Pathogenic
1076934	NM_152419.3(HGSNAT):c.1054_1055insATCAATTTCTAATGGGATTTCCAGAGTTGAAAAAGACAAATATTCAGCTTTAGGAAGCACAGTTGAGTCCTGAGCAGTACAAATAAAAATATAGGCTGGGCACAGTGGCTCACATGTGTAATCCCAGCACTTTCGGAGGCTGAGGTGGGTGGATTGCTGGAGTCCAGCAGTTTGAAAACAGCCTGAGCAACATGGCAAGACCCCATCTCTACAAAAAATACAACAATTATCCGGGCATGGTGGCACAAGCCCGTAGTCCCAGCTACTCAGGAAGCTGAGGTGGATCGCTTGAGCCCGGGAGGTGGAGGTTGCAGTGAGCCAAGATCACACCATTGCACTCCACACTGAATGACAGAGTGAGACTGTCTTAATAAAAAATATGAGTCAGCGTATAAGTTAAAAGGAGTTTTAAAAGATACTAATCCAAAAGAAGGCAGAAAAGGAGAAACATAATAGACTTACCAGCCCAATTTAAAAGTCAGGGATTATAAACATGAATTGAAGAAGTGAGACCCAGTTA (p.Leu352delinsTyrGlnPheLeuMetGlyPheProGluLeuLysLysThrAsnIleGlnLeuTer)	Pathogenic
1230	NM_152419.3(HGSNAT):c.493+1G>A	Pathogenic
1231	NM_152419.3(HGSNAT):c.1345dup (p.Asp449fs)	Pathogenic
1233	NM_152419.3(HGSNAT):c.962T>G (p.Leu321Ter)	Pathogenic
1235	NM_152419.3(HGSNAT):c.525dup (p.Val176fs)	Pathogenic
1236	NM_152419.3(HGSNAT):c.372-2A>G	Pathogenic
1238	NM_152419.3(HGSNAT):c.1553C>T (p.Ser518Phe)	Pathogenic
1323056	NM_152419.3(HGSNAT):c.1542+2T>C	Pathogenic
1352962	NM_152419.3(HGSNAT):c.719del (p.Leu240fs)	Pathogenic
1412507	NM_152419.3(HGSNAT):c.87_100dup (p.Gln34fs)	Pathogenic
1453420	NM_152419.3(HGSNAT):c.1245C>A (p.Cys415Ter)	Pathogenic
1453457	NM_152419.3(HGSNAT):c.1464+1del	Pathogenic
1453856	NM_152419.3(HGSNAT):c.781G>T (p.Gly261Ter)	Pathogenic
1455195	NM_152419.3(HGSNAT):c.1610del (p.Leu537fs)	Pathogenic
1458656	NC_000008.10:g.(?43024296)(43024405_?)del	Pathogenic
1458765	NM_152419.3(HGSNAT):c.1034_1049del (p.Ile345fs)	Pathogenic
1459479	NC_000008.10:g.(?42977230)(43002226_?)del	Pathogenic
1977688	NM_152419.3(HGSNAT):c.1691dup (p.Leu566fs)	Pathogenic
1992944	NM_152419.3(HGSNAT):c.1139del (p.Cys380fs)	Pathogenic
2002352	NM_152419.3(HGSNAT):c.244C>T (p.Gln82Ter)	Pathogenic
2007566	NM_152419.3(HGSNAT):c.10del (p.Ala4fs)	Pathogenic
2018296	NM_152419.3(HGSNAT):c.959del (p.Leu320fs)	Pathogenic
2020759	NM_152419.3(HGSNAT):c.969C>A (p.Cys323Ter)	Pathogenic
2082727	NM_152419.3(HGSNAT):c.932del (p.Leu311fs)	Pathogenic

SpliceAI

3325 predictions. Top by Δscore:

Variant	Effect	Δscore
8:43147064:G:GG	donor_gain	1.0000
8:43158573:A:AG	acceptor_gain	1.0000
8:43158574:G:GG	acceptor_gain	1.0000
8:43158574:GT:G	acceptor_gain	1.0000
8:43158574:GTGC:G	acceptor_gain	1.0000
8:43158692:G:GT	donor_gain	1.0000
8:43158701:G:GT	donor_gain	1.0000
8:43158701:GAA:G	donor_gain	1.0000
8:43158704:G:GG	donor_gain	1.0000
8:43158919:GTAG:G	acceptor_loss	1.0000
8:43158921:A:AC	acceptor_loss	1.0000
8:43159040:CCTTC:C	donor_gain	1.0000
8:43159041:CTTC:C	donor_gain	1.0000
8:43159042:TTC:T	donor_gain	1.0000
8:43159043:TC:T	donor_gain	1.0000
8:43159044:CGTA:C	donor_loss	1.0000
8:43159045:G:C	donor_loss	1.0000
8:43159045:G:GG	donor_gain	1.0000
8:43159046:T:G	donor_loss	1.0000
8:43161432:TTCTA:T	acceptor_loss	1.0000
8:43161433:TCTA:T	acceptor_loss	1.0000
8:43161434:CTA:C	acceptor_loss	1.0000
8:43161435:TA:T	acceptor_loss	1.0000
8:43161436:A:AG	acceptor_gain	1.0000
8:43161436:AGCT:A	acceptor_gain	1.0000
8:43161436:AGCTG:A	acceptor_loss	1.0000
8:43161437:G:GC	acceptor_gain	1.0000
8:43161437:G:GT	acceptor_loss	1.0000
8:43161437:GCT:G	acceptor_gain	1.0000
8:43161437:GCTG:G	acceptor_gain	1.0000

AlphaMissense

4112 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000044193 (8:43187525 C>A,T), RS1000145976 (8:43141239 C>G,T), RS1000199847 (8:43161840 C>G,T), RS1000212295 (8:43155921 G>A), RS1000241712 (8:43200188 T>C), RS1000310298 (8:43159497 A>G), RS1000388607 (8:43168042 C>T), RS1000392387 (8:43147303 C>A,T), RS1000464797 (8:43195126 G>A), RS1000475380 (8:43199948 T>G), RS1000515161 (8:43154799 G>T), RS1000534071 (8:43159899 C>T), RS1000648590 (8:43159546 C>T), RS1000658770 (8:43151371 G>A), RS1000675848 (8:43158188 TC>T)

Disease associations

OMIM: gene MIM:610453 | disease phenotypes: MIM:252930, MIM:616544, MIM:607014, MIM:615249, MIM:616094, MIM:268000

GenCC curated gene-disease

Disease	Classification	Inheritance
mucopolysaccharidosis type 3C	Definitive	Autosomal recessive
mucopolysaccharidosis type 3	Definitive	Autosomal recessive
retinitis pigmentosa 73	Strong	Autosomal recessive
retinitis pigmentosa	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
inherited retinal dystrophy	Definitive	AR
mucopolysaccharidosis type 3C	Definitive	AR

Mondo (11): mucopolysaccharidosis type 3C (MONDO:0009657), retinitis pigmentosa 73 (MONDO:0014687), inherited retinal dystrophy (MONDO:0019118), mucopolysaccharidosis type 3 (MONDO:0018937), mucopolysaccharidosis (MONDO:0019249), muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 12 (MONDO:0014101), limb-girdle muscular dystrophy due to POMK deficiency (MONDO:0014489), retinitis pigmentosa (MONDO:0019200), retinal disorder (MONDO:0005283), intellectual disability (MONDO:0001071), synovial plica syndrome (MONDO:0001468)

Orphanet (8): Mucopolysaccharidosis type 3 (Orphanet:581), Retinitis pigmentosa (Orphanet:791), Sanfilippo syndrome type C (Orphanet:79271), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Mucopolysaccharidosis (Orphanet:79213), Limb-girdle muscular dystrophy due to POMK deficiency (Orphanet:445110), Walker-Warburg syndrome (Orphanet:899), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

79 total (30 of 79 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000232	Everted lower lip vermilion
HP:0000250	Dense calvaria
HP:0000268	Dolichocephaly
HP:0000280	Coarse facial features
HP:0000365	Hearing impairment
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000501	Glaucoma
HP:0000505	Visual impairment
HP:0000510	Rod-cone dystrophy
HP:0000512	Abnormal electroretinogram
HP:0000543	Optic disc pallor
HP:0000546	Retinal degeneration
HP:0000551	Color vision defect
HP:0000563	Keratoconus
HP:0000602	Ophthalmoplegia
HP:0000603	Central scotoma
HP:0000613	Photophobia
HP:0000618	Blindness
HP:0000622	Blurred vision
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000662	Nyctalopia
HP:0000664	Synophrys
HP:0000752	Hyperactivity
HP:0000842	Hyperinsulinemia
HP:0000900	Thickened ribs
HP:0000943	Dysostosis multiplex
HP:0000998	Hypertrichosis

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST009391_2069	Metabolite levels	8.000000e-06
GCST010988_294	Adult body size	2.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010346	cholesteryl ester 18:3 measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
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
D012164	Retinal Diseases	C11.768
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	4
Acetaminophen	increases expression	3
sodium arsenite	affects cotreatment, decreases expression, increases abundance	2
mercuric bromide	decreases expression, affects cotreatment	2
entinostat	decreases expression, affects cotreatment	2
Arsenic	affects cotreatment, decreases expression, increases abundance	2
Tretinoin	decreases expression, increases expression	2
Aflatoxin B1	increases expression, decreases methylation	2
aristolochic acid I	decreases expression	1
FR900359	decreases phosphorylation	1
methylmercuric chloride	decreases expression	1
bisphenol A	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
pentanal	decreases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
14-deoxy-11,12-didehydroandrographolide	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	increases expression, affects cotreatment	1
Vorinostat	decreases expression	1
Cadmium	decreases expression, increases abundance	1
Carbamazepine	affects expression	1
Cisplatin	affects cotreatment, increases expression	1
Folic Acid	decreases expression	1

Cellosaurus cell lines

16 cell lines: 16 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A3MY	HPS2871	Induced pluripotent stem cell	Female
CVCL_A3MZ	HPS2872	Induced pluripotent stem cell	Female
CVCL_A3NA	HPS2873	Induced pluripotent stem cell	Female
CVCL_A3NB	HPS2874	Induced pluripotent stem cell	Female
CVCL_A3NC	HPS2875	Induced pluripotent stem cell	Female
CVCL_A9W5	SFC6-iPS#4.6	Induced pluripotent stem cell	Female
CVCL_A9W6	SFC6-iPS#4.7	Induced pluripotent stem cell	Female
CVCL_A9W7	SFC7-iPS#4.8	Induced pluripotent stem cell	Female
CVCL_A9W8	SFC7-iPS#4.9	Induced pluripotent stem cell	Female
CVCL_UP23	HPS2870	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
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
NCT00000114	PHASE3	COMPLETED	Randomized Trial of Vitamin A and Vitamin E Supplementation for Retinitis Pigmentosa
NCT00000116	PHASE3	COMPLETED	Randomized Trial of DHA for Retinitis Pigmentosa Patients Receiving Vitamin A
NCT00346333	PHASE3	COMPLETED	Clinical Trial of Lutein for Patients With Retinitis Pigmentosa Receiving Vitamin A
NCT01786395	PHASE3	TERMINATED	Phase III Efficacy and Safety Clinical Study of UF-021 for Treatment of Retinitis Pigmentosa
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT04636853	PHASE3	COMPLETED	CB-PRP in Retinitis Pigmentosa and Dry Age-related Macular Degeneration
NCT05537220	PHASE3	ACTIVE_NOT_RECRUITING	Oral N-acetylcysteine for Retinitis Pigmentosa
NCT05800301	PHASE3	COMPLETED	Management of Retinitis Pigmentosa Via Combination of Wharton’s Jelly-derived Mesenchymal Stem Cells and Magnovision
NCT05926583	PHASE3	ACTIVE_NOT_RECRUITING	A Study of AAV5-hRKp.RPGR for the Treatment of Japanese Participants With X-linked Retinitis Pigmentosa
NCT06388200	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Study Of OCU400 Gene Therapy for the Treatment Of Retinitis Pigmentosa
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT07290530	PHASE3	NOT_YET_RECRUITING	24-Month Trial of NPI-001 for the Preservation of Photoreceptors in Retinitis Pigmentosa Associated With Usher Syndrome
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)
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.
NCT00100230	PHASE2	COMPLETED	DHA and X-Linked Retinitis Pigmentosa
NCT00447980	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Participants With Early Stage Retinitis Pigmentosa
NCT00447993	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Patients With Late Stage Retinitis Pigmentosa
NCT01233609	PHASE2	COMPLETED	Trial of Oral Valproic Acid for Retinitis Pigmentosa
NCT01399515	PHASE2	COMPLETED	Efficacy and Safety of Oral Valproic Acid for Retinitis Pigmentosa
NCT01530659	PHASE2	COMPLETED	Retinal Imaging in CNTF -Releasing Encapsulated Cell Implant Treated Patients for Early-stage Retinitis Pigmentosa
NCT01560715	PHASE2	COMPLETED	Autologous Bone Marrow-Derived Stem Cells Transplantation For Retinitis Pigmentosa
NCT02609165	PHASE2	COMPLETED	Nerve Growth Factor Eye Drops Treatment in Patients With Retinitis Pigmentosa and Cystoid Macular Edema
NCT02661711	PHASE2	COMPLETED	Aflibercept for Macular Oedema With Underlying Retinitis Pigmentosa (AMOUR) Study
NCT02804360	PHASE2	UNKNOWN	Intravitreal Dexamethasone Implant in Retinitis Pigmentosa-related Macular Edema- a Retrospective Study
NCT02837640	PHASE2	UNKNOWN	Studying a Potential Protective Effect of L-Dopa on Retinitis Pigmentosa
NCT03073733	PHASE2	COMPLETED	Safety and Efficacy of Intravitreal Injection of Human Retinal Progenitor Cells in Adults With Retinitis Pigmentosa
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04356716	PHASE2	COMPLETED	Sildenafil for Treatment of Choroidal Ischemia
NCT04604899	PHASE2	COMPLETED	Safety of Repeat Intravitreal Injection of Human Retinal Progenitor Cells (jCell) in Adult Subjects With Retinitis Pigmentosa
NCT04763369	PHASE2	UNKNOWN	Investigation of Therapeutic Efficacy and Safety of UMSCs for the Management of Retinitis Pigmentosa (RP)
NCT04864496	PHASE2	UNKNOWN	Effects of Treatment With N- Acetylcysteine on Visual Outcomes in Patients With Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT05085964	PHASE2	TERMINATED	An Open-Label Extension Study to Evaluate Safety & Tolerability of QR-421a in Subjects With Retinitis Pigmentosa