NAGLU

Summary

NAGLU (N-acetyl-alpha-glucosaminidase, HGNC:7632) is a protein-coding gene on chromosome 17q21.2, encoding Alpha-N-acetylglucosaminidase (P54802). Involved in the degradation of heparan sulfate.

This gene encodes an enzyme that degrades heparan sulfate by hydrolysis of terminal N-acetyl-D-glucosamine residues in N-acetyl-alpha-D-glucosaminides. Defects in this gene are the cause of mucopolysaccharidosis type IIIB (MPS-IIIB), also known as Sanfilippo syndrome B. This disease is characterized by the lysosomal accumulation and urinary excretion of heparan sulfate.

Source: NCBI Gene 4669 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mucopolysaccharidosis type 3B (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 7
• Clinical variants (ClinVar): 1,228 total — 108 pathogenic, 93 likely-pathogenic
• Phenotypes (HPO): 41
• Druggable target: yes
• MANE Select transcript: NM_000263

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7632
Approved symbol	NAGLU
Name	N-acetyl-alpha-glucosaminidase
Location	17q21.2
Locus type	gene with protein product
Status	Approved
Aliases	NAG
Ensembl gene	ENSG00000108784
Ensembl biotype	protein_coding
OMIM	609701
Entrez	4669

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 8 protein_coding

ENST00000225927, ENST00000586516, ENST00000590358, ENST00000591587, ENST00000592454, ENST00000904921, ENST00000933285, ENST00000963429

RefSeq mRNA: 1 — MANE Select: NM_000263 NM_000263

CCDS: CCDS11427

Canonical transcript exons

ENST00000225927 — 6 exons

Exon	Start	End
ENSE00000726103	42540950	42541206
ENSE00001296761	42543028	42544449
ENSE00001299709	42536241	42536655
ENSE00002379758	42537398	42537545
ENSE00003598890	42538670	42538755
ENSE00003618662	42538339	42538485

Expression profiles

Bgee: expression breadth ubiquitous, 268 present calls, max score 96.11.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.9315 / max 104.1237, expressed in 1810 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
160953	20.9315	1810

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	96.11	gold quality
body of pancreas	UBERON:0001150	93.15	gold quality
mucosa of stomach	UBERON:0001199	92.84	gold quality
right lobe of liver	UBERON:0001114	92.81	gold quality
metanephros cortex	UBERON:0010533	92.51	gold quality
thoracic aorta	UBERON:0001515	92.37	gold quality
ascending aorta	UBERON:0001496	92.36	gold quality
right lobe of thyroid gland	UBERON:0001119	92.21	gold quality
right adrenal gland cortex	UBERON:0035827	91.96	gold quality
aorta	UBERON:0000947	91.78	gold quality
right adrenal gland	UBERON:0001233	91.77	gold quality
left adrenal gland	UBERON:0001234	91.68	gold quality
descending thoracic aorta	UBERON:0002345	91.63	gold quality
right coronary artery	UBERON:0001625	91.62	gold quality
left lobe of thyroid gland	UBERON:0001120	91.57	gold quality
popliteal artery	UBERON:0002250	91.52	gold quality
tibial artery	UBERON:0007610	91.51	gold quality
body of stomach	UBERON:0001161	91.50	gold quality
left adrenal gland cortex	UBERON:0035825	91.43	gold quality
left coronary artery	UBERON:0001626	91.03	gold quality
granulocyte	CL:0000094	90.99	gold quality
endocervix	UBERON:0000458	90.98	gold quality
left uterine tube	UBERON:0001303	90.89	gold quality
right ovary	UBERON:0002118	90.74	gold quality
gall bladder	UBERON:0002110	90.72	gold quality
left ovary	UBERON:0002119	90.68	gold quality
right lung	UBERON:0002167	90.68	gold quality
coronary artery	UBERON:0001621	90.52	gold quality
adrenal cortex	UBERON:0001235	90.50	gold quality
thyroid gland	UBERON:0002046	90.39	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-10290	no	120.89
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

8 targeting NAGLU, 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-4267	99.96	66.53	2368
HSA-MIR-18A-3P	99.56	65.68	1092
HSA-MIR-12117	99.50	67.57	868
HSA-MIR-4667-3P	99.26	65.45	1608
HSA-MIR-4483	98.09	64.12	1642
HSA-MIR-4308	97.56	67.13	1385
HSA-MIR-1293	96.16	64.69	916
HSA-MIR-4321	92.11	68.79	45

Literature-anchored findings (GeneRIF, showing 20)

• 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)
• The NAGLU gene in 11 Mucopolysaccharidosis type IIIB Portuguese patients, was examined, having identified five novel (M1K, W147X, G304V, S522P, and R533X) and four previously reported mutations (W168X, R234C, R565W and R643C). (PMID:18218046)
• We have identified an 1146 bp intragenic deletion of the NAGLU gene within consanguineous parents having two children affected with Sanfilippo syndrome type B. (PMID:20138557)
• This study suggests a possible role of NAGLU in susceptibility to PD while extending evidence for alpha-synuclein aggregation in the brain in lysosomal storage disorders. (PMID:22102531)
• Urinary NAG/Cr may be a useful surrogate marker for renal function in ADPKD patients. (PMID:22935351)
• The research may enrich the mutation spectrum of the NAGLU gene in the Chinese population and help us further in understanding the pathogenesis of MPS IIIB. (PMID:23380547)
• A modified recombinant NAGLU fused to the receptor-binding motif of insulin-like growth factor (IGF)-II enhances its ability to enter cells using the mannose 6-phosphate receptor, which is the receptor for IGF-II at a different binding site. (PMID:24266751)
• Plasma NAG correlates with gastrointestinal cancer outcomes. (PMID:25040106)
• Mutations in NAGLU gene is associated with idiopathic progressive cognitive decline. (PMID:25466957)
• study reports that carriers from two families of a severe pathogenic mutation in NAGLU develop a late dominant painful axonal sensory neuropathy. (PMID:25818867)
• 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)
• in the current meta-analysis, based on ten prospective studies involving 29366 participants, we evaluated the role of urinary tubular injury markers (NGAL, KIM-1 and NAG) in predicting clinical outcomes including CKD stage 3, end stage renal disease and mortality. (PMID:27907168)
• Mutation in NAGLU gene is associated with atypical mucopolysaccharidosis IIIB. (PMID:28306536)
• findings show that the NAGLU protein consists of a precursor and a mature form and that in slowly progressing mucopolysaccharidosis type IIIB patients’ fibroblasts only the precursor protein is present at 37 degrees ; culturing at lower temperatures resulted in the formation of the mature, enzymatically active form, due to higher mRNA levels and improved processing (PMID:28751108)
• Data reported the pathogenic missense mutations of NAGLU and CYP26B1 concurrent in one patient, which not only expands the phenotype and genotype spectra of NAGLU and CYP26B1, but more importantly indicates the possibility of simultaneous occurrence of two rare diseases in one patient. (PMID:29606097)
• we identified and characterised oncogenic fusion genes and their function in CRC, and implicated NAGLU-IKZF3 and RNF121-FOLR2 as novel molecular targets for personalised medicine development. (PMID:29955133)
• Structural characterization of the NAGLU, a key enzyme in the pathogenesis of Sanfilippo syndrome B, has been reported. (PMID:30802506)
• Generation of two NAGLU-mutated homozygous cell lines from healthy induced pluripotent stem cells using CRISPR/Cas9 to model Sanfilippo B syndrome. (PMID:31825816)
• Variations of urinary N-acetyl-beta-D-glucosaminidase levels and its performance in detecting acute kidney injury under different thyroid hormones levels: a prospectively recruited, observational study. (PMID:35241468)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	naglu	ENSDARG00000030156
mus_musculus	Naglu	ENSMUSG00000001751
rattus_norvegicus	Naglu	ENSRNOG00000032381
drosophila_melanogaster	Naglu	FBGN0014417
caenorhabditis_elegans		WBGENE00010722

Protein

Protein identifiers

Alpha-N-acetylglucosaminidase — P54802 (reviewed: P54802)

Alternative names: N-acetyl-alpha-glucosaminidase

All UniProt accessions (6): P54802, A0A140VJE4, K7END1, K7ENX5, K7EQH9, K7ESD7

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the degradation of heparan sulfate.

Subunit / interactions. Monomer and homodimer.

Subcellular location. Lysosome.

Tissue specificity. Liver, ovary, peripheral blood leukocytes, testis, prostate, spleen, colon, lung, placenta and kidney.

Disease relevance. Mucopolysaccharidosis 3B (MPS3B) [MIM:252920] 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. Charcot-Marie-Tooth disease, axonal, type 2V (CMT2V) [MIM:616491] An axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. CMT2V is an autosomal dominant sensory neuropathy with late onset. The main clinical feature is recurrent leg pain that progresses to constant painful paraesthesias in the feet and later the hands. As it evolves, some patients develop a mild sensory ataxia. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the glycosyl hydrolase 89 family.

RefSeq proteins (1): NP_000254* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007781	NAGLU	Family
IPR017853	GH_hydrolase_sf	Homologous_superfamily
IPR024240	NAGLU_N	Domain
IPR024732	NAGLU_C	Domain
IPR024733	NAGLU_tim-barrel	Domain
IPR029018	Hex-like_dom2	Homologous_superfamily

Pfam: PF05089, PF12971, PF12972

Enzyme classification (BRENDA):

• EC 3.2.1.50 — alpha-N-acetylglucosaminidase (BRENDA: 13 organisms, 49 substrates, 17 inhibitors, 31 Km, 8 kcat entries)

Substrate kinetics (BRENDA)

20 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
4-METHYLUMBELLIFERYL 2-ACETAMIDO-2-DEOXY-ALPHA-D	1.07–5.34	2
4-NITROPHENYL-N-ACETYL-ALPHA-D-GLUCOSAMINIDE	4.3–7.8	2
N-ACETYL-ALPHA-D-GLUC-1,4-(1-METHOXYPHENYL)GAL	0.2–0.28	2
2,4-DINITROPHENYL-ALPHA-N-ACETYL-D-GLUCOSAMINIDE	0.74	1
4-METHYLUMBELLIFERYL N-ACETYL-ALPHA-D-GLUCOSAMIN	0.0046	1
4-NITROPHENYL-ALPHA-N-ACETYL-D-GLUCOSAMINIDE	1.1	1
CHITOBIOSE	0.0006	1
CHITOTETRAOSE	0.003	1
CHITOTRIOSE	0.0008	1
METHYLUMBELLIFERYL-N-ACETYL-ALPHA-D-GLUCOSAMINID	0.22	1
METHYLUMBELLIFERYL-N-ACETYLGLUCOSAMINE	0.001	1
METHYLUMBELLIFERYL-N-ACETYLGLUCOSAMINE-6-SULFATE	0.0035	1
N-ACETYL-ALPHA-D-GLUCOSE-(1->4)-BETA-D-GLUCURONI	2.19	1
O-(ALPHA-ACETAMIDO-2-DEOXY-D-GLUCOPYRANOSYL)-(1-	0.0166	1
O-NITROPHENYL-ALPHA-N-ACETYLGLUCOSAMINIDE	0.08	1

UniProt features (140 total): sequence variant 72, helix 35, strand 17, glycosylation site 6, turn 5, chain 2, sequence conflict 2, signal peptide 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4XWH	X-RAY DIFFRACTION	2.32

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P54802-F1	97.19	0.97

Functional residue map

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

Glycosylation sites (6): 261, 272, 435, 503, 526, 532

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-2024096	HS-GAG degradation
R-HSA-2206282	MPS IIIB - Sanfilippo syndrome B
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: 436 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_CIRCADIAN_RHYTHM, AHRARNT_01, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_METENCEPHALON_DEVELOPMENT, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_EPIDERMIS_MORPHOGENESIS, GOBP_BEHAVIOR, GOBP_VACUOLE_ORGANIZATION, GOBP_CARDIAC_LEFT_VENTRICLE_MORPHOGENESIS, GOBP_VESICLE_LOCALIZATION

GO Biological Process (66): ganglioside metabolic process (GO:0001573), microglial cell activation (GO:0001774), liver development (GO:0001889), endothelium development (GO:0003158), mitral valve morphogenesis (GO:0003183), left ventricular cardiac muscle tissue morphogenesis (GO:0003220), superoxide metabolic process (GO:0006801), autophagy (GO:0006914), cytoplasm organization (GO:0007028), Golgi organization (GO:0007030), lysosome organization (GO:0007040), nervous system development (GO:0007399), determination of adult lifespan (GO:0008340), response to wounding (GO:0009611), microglia differentiation (GO:0014004), lipid catabolic process (GO:0016042), protein processing (GO:0016485), nerve development (GO:0021675), cerebellar Purkinje cell layer development (GO:0021680), heparan sulfate proteoglycan catabolic process (GO:0030200), heparin proteoglycan metabolic process (GO:0030202), glycosaminoglycan metabolic process (GO:0030203), adult behavior (GO:0030534), hair follicle morphogenesis (GO:0031069), response to lipopolysaccharide (GO:0032496), collagen metabolic process (GO:0032963), toll-like receptor 4 signaling pathway (GO:0034142), response to disaccharide (GO:0034285), cellular response to oxidative stress (GO:0034599), maintenance of blood-brain barrier (GO:0035633), exploration behavior (GO:0035640), aorta morphogenesis (GO:0035909), hormone metabolic process (GO:0042445), middle ear morphogenesis (GO:0042474), amyloid precursor protein metabolic process (GO:0042982), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), locomotor rhythm (GO:0045475), retinal rod cell development (GO:0046548), astrocyte activation (GO:0048143), cardiac muscle cell development (GO:0055013)

GO Molecular Function (4): alpha-N-acetylglucosaminidase activity (GO:0004561), iron ion sequestering activity (GO:0140315), hydrolase activity (GO:0016787), hydrolase activity, acting on glycosyl bonds (GO:0016798)

GO Cellular Component (5): lysosome (GO:0005764), membrane (GO:0016020), lysosomal lumen (GO:0043202), extracellular exosome (GO:0070062), vacuole (GO:0005773)

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
catabolic process	2
anatomical structure development	2
ceramide metabolic process	1
glycosphingolipid metabolic process	1
leukocyte activation involved in inflammatory response	1
macrophage activation	1
glial cell activation	1
gland development	1
hepaticobiliary system development	1
epithelium development	1
mitral valve development	1
atrioventricular valve morphogenesis	1
cardiac left ventricle morphogenesis	1
ventricular cardiac muscle tissue morphogenesis	1
reactive oxygen species metabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
cellular component organization	1
organelle organization	1
endomembrane system organization	1
lytic vacuole organization	1
system development	1
multicellular organismal process	1
response to stress	1
central nervous system development	1
glial cell differentiation	1
macrophage differentiation	1
lipid metabolic process	1
proteolysis	1
protein maturation	1
nervous system development	1
cerebellar cortex development	1
proteoglycan catabolic process	1
heparan sulfate proteoglycan metabolic process	1
hexosaminidase activity	1
iron ion binding	1
metal ion sequestering activity	1
catalytic activity	1
hydrolase activity	1
lytic vacuole	1

Protein interactions and networks

STRING

1008 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NAGLU	SGSH	P51688	988
NAGLU	HGSNAT	Q68CP4	981
NAGLU	GNS	P15586	958
NAGLU	IDUA	P35475	775
NAGLU	HSD17B1	P14061	763
NAGLU	LAMP2	P13473	749
NAGLU	GALNS	P34059	711
NAGLU	DHRS11	Q6UWP2	682
NAGLU	IDS	P22304	664
NAGLU	LAMP1	P11279	642
NAGLU	GLB1	P16278	587
NAGLU	SUMF1	Q8NBK3	586
NAGLU	MAN2B1	O00754	585
NAGLU	GUSB	P08236	570
NAGLU	ARSB	P15848	565

IntAct

95 interactions, top by confidence:

A	B	Type	Score
FBXO6	MAN2B1	psi-mi:“MI:0914”(association)	0.640
OSBPL5	NAGLU	psi-mi:“MI:0914”(association)	0.640
CANX	PGRMC1	psi-mi:“MI:0914”(association)	0.570
PRG3	ZNF324	psi-mi:“MI:0914”(association)	0.530
LIPH	LRP5	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
LGALS1	PODXL	psi-mi:“MI:0914”(association)	0.530
CLGN	NPC1	psi-mi:“MI:0914”(association)	0.530
DUSP13	NAGLU	psi-mi:“MI:0915”(physical association)	0.400
SCGB2A2	GXYLT2	psi-mi:“MI:0914”(association)	0.350
SUSD4	CCDC85C	psi-mi:“MI:0914”(association)	0.350
PLAUR	DDX11L8	psi-mi:“MI:0914”(association)	0.350
LGALS9	PODXL	psi-mi:“MI:0914”(association)	0.350
AVP	B4GALT5	psi-mi:“MI:0914”(association)	0.350
TAZ	MANBA	psi-mi:“MI:0914”(association)	0.350
LYPD4	DPYSL4	psi-mi:“MI:0914”(association)	0.350
INSL5	LAMA5	psi-mi:“MI:0914”(association)	0.350
SLAMF1	RTCA	psi-mi:“MI:0914”(association)	0.350
LYZL1	MANBA	psi-mi:“MI:0914”(association)	0.350
IFNE	NAGLU	psi-mi:“MI:0914”(association)	0.350
LYZL2	MANBA	psi-mi:“MI:0914”(association)	0.350
DNASE2B		psi-mi:“MI:0914”(association)	0.350
	HSPA12A	psi-mi:“MI:0914”(association)	0.350

BioGRID (97): NAGLU (Affinity Capture-MS), NAGLU (Affinity Capture-MS), NAGLU (Affinity Capture-MS), NAGLU (Affinity Capture-MS), NAGLU (Affinity Capture-MS), NAGLU (Affinity Capture-MS), NAGLU (Affinity Capture-MS), NAGLU (Affinity Capture-MS), TMED10 (Co-fractionation), TMED4 (Co-fractionation), TMED9 (Co-fractionation), NAGLU (Affinity Capture-MS), NAGLU (Affinity Capture-MS), NAGLU (Affinity Capture-MS), NAGLU (Affinity Capture-MS)

ESM2 similar proteins: A0JNU3, A6QNR0, O18835, O35632, O77695, O88202, O97524, P04066, P06760, P06865, P07686, P08236, P10253, P12265, P16444, P17164, P22412, P29416, P31429, P31430, P43477, P48300, P54802, P70699, P79403, Q0V8R6, Q12891, Q14697, Q3SZM7, Q3U4H6, Q4FAT7, Q4QR99, Q4R4N7, Q5R5N6, Q5R7A9, Q5RC84, Q5RFI5, Q60HF8, Q641X3, Q6AYS4

Diamond homologs: P54802, Q9FNA3

SIGNOR signaling

1 interactions.

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

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 116 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	15	4.7×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
ERAD pathway	6	11.2×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1228 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	108
Likely pathogenic	93
Uncertain significance	390
Likely benign	484
Benign	25

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1067431	NM_000263.4(NAGLU):c.457G>A (p.Glu153Lys)	Pathogenic
1068849	NM_000263.4(NAGLU):c.1453dup (p.Val485fs)	Pathogenic
1069834	NC_000017.10:g.(?40690347)(40690783_?)del	Pathogenic
1070682	NM_000263.4(NAGLU):c.454C>T (p.Arg152Ter)	Pathogenic
1071435	NM_000263.4(NAGLU):c.432G>A (p.Trp144Ter)	Pathogenic
1075574	NM_000263.4(NAGLU):c.1162C>T (p.Gln388Ter)	Pathogenic
1076452	NM_000263.4(NAGLU):c.603G>A (p.Trp201Ter)	Pathogenic
1323321	NM_000263.4(NAGLU):c.765-1G>C	Pathogenic
1343458	NM_000263.4(NAGLU):c.410_413del (p.Thr137fs)	Pathogenic
1356379	NM_000263.4(NAGLU):c.640dup (p.Leu214fs)	Pathogenic
1376432	NM_000263.4(NAGLU):c.820del (p.Ser274fs)	Pathogenic
1377108	NM_000263.4(NAGLU):c.1773del (p.Leu591_Leu592insTer)	Pathogenic
1384177	NM_000263.4(NAGLU):c.713del (p.Met238fs)	Pathogenic
1405883	NM_000263.4(NAGLU):c.387C>G (p.Tyr129Ter)	Pathogenic
1409649	NM_000263.4(NAGLU):c.1570C>T (p.Gln524Ter)	Pathogenic
1429252	NM_000263.4(NAGLU):c.441G>A (p.Trp147Ter)	Pathogenic
1432786	NM_000263.4(NAGLU):c.525G>A (p.Trp175Ter)	Pathogenic
1451661	NM_000263.4(NAGLU):c.317_323del (p.Ser106fs)	Pathogenic
1451924	NM_000263.4(NAGLU):c.1815_1821dup (p.Glu608fs)	Pathogenic
1454495	NM_000263.4(NAGLU):c.607C>T (p.Arg203Ter)	Pathogenic
1456411	NM_000263.4(NAGLU):c.308G>A (p.Trp103Ter)	Pathogenic
1456478	NM_000263.4(NAGLU):c.953_957del (p.Gln318fs)	Pathogenic
1456581	NM_000263.4(NAGLU):c.1336del (p.Glu446fs)	Pathogenic
1459502	NC_000017.10:g.(?40688281)(40693234_?)del	Pathogenic
1459884	NM_000263.4(NAGLU):c.623_626dup (p.Trp210fs)	Pathogenic
1503288	NM_000263.4(NAGLU):c.1682T>G (p.Leu561Arg)	Pathogenic
1560	NM_000263.4(NAGLU):c.2021G>A (p.Arg674His)	Pathogenic
1561	NM_000263.4(NAGLU):c.1876C>T (p.Arg626Ter)	Pathogenic
1564	NM_000263.4(NAGLU):c.507_516del (p.Ser169fs)	Pathogenic
1565	NM_000263.4(NAGLU):c.1927C>T (p.Arg643Cys)	Pathogenic

SpliceAI

831 predictions. Top by Δscore:

Variant	Effect	Δscore
17:42537542:GCGG:G	donor_gain	1.0000
17:42538333:CCTCA:C	acceptor_loss	1.0000
17:42538334:CTCA:C	acceptor_loss	1.0000
17:42538335:TCA:T	acceptor_loss	1.0000
17:42538336:CA:C	acceptor_loss	1.0000
17:42538337:AGGTG:A	acceptor_loss	1.0000
17:42538338:G:GA	acceptor_loss	1.0000
17:42538338:GGT:G	acceptor_gain	1.0000
17:42538481:TGCAG:T	donor_loss	1.0000
17:42538483:CAGGT:C	donor_loss	1.0000
17:42538484:AG:A	donor_loss	1.0000
17:42538485:GGT:G	donor_loss	1.0000
17:42538486:G:T	donor_loss	1.0000
17:42538487:T:A	donor_loss	1.0000
17:42538667:CA:C	acceptor_loss	1.0000
17:42538668:A:AG	acceptor_gain	1.0000
17:42538669:G:GG	acceptor_gain	1.0000
17:42538669:GC:G	acceptor_gain	1.0000
17:42538669:GCA:G	acceptor_gain	1.0000
17:42538669:GCAC:G	acceptor_gain	1.0000
17:42538669:GCACC:G	acceptor_gain	1.0000
17:42538671:ACCG:A	acceptor_gain	1.0000
17:42538753:CAGG:C	donor_loss	1.0000
17:42538754:AGGT:A	donor_loss	1.0000
17:42538756:GTG:G	donor_loss	1.0000
17:42538757:T:G	donor_loss	1.0000
17:42541027:T:TA	acceptor_gain	1.0000
17:42541028:G:A	acceptor_gain	1.0000
17:42541204:CAG:C	donor_loss	1.0000
17:42541205:AGGT:A	donor_loss	1.0000

AlphaMissense

4779 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:42543210:T:C	F402L	0.995
17:42543212:C:A	F402L	0.995
17:42543212:C:G	F402L	0.995
17:42543221:C:G	C405W	0.994
17:42543233:C:A	N409K	0.994
17:42543233:C:G	N409K	0.994
17:42537416:T:A	N134K	0.993
17:42537416:T:G	N134K	0.993
17:42543045:T:A	W347R	0.993
17:42543045:T:C	W347R	0.993
17:42543359:C:A	N451K	0.993
17:42543359:C:G	N451K	0.993
17:42538724:T:C	F245L	0.991
17:42538726:C:A	F245L	0.991
17:42538726:C:G	F245L	0.991
17:42543089:G:C	W361C	0.991
17:42543089:G:T	W361C	0.991
17:42541125:T:C	F314L	0.990
17:42541127:C:A	F314L	0.990
17:42541127:C:G	F314L	0.990
17:42541132:A:T	E316V	0.990
17:42537429:A:C	S139R	0.989
17:42537431:C:A	S139R	0.989
17:42537431:C:G	S139R	0.989
17:42537422:C:G	C136W	0.988
17:42543062:G:C	W352C	0.988
17:42543062:G:T	W352C	0.988
17:42543344:G:C	E446D	0.988
17:42543344:G:T	E446D	0.988
17:42543700:G:C	R565P	0.987

dbSNP variants (sampled 300 via entrez): RS1000024720 (17:42544707 T>C), RS1000105157 (17:42540333 C>T), RS1000781222 (17:42538418 T>G), RS1001284586 (17:42538219 G>A), RS1001399434 (17:42535555 T>TGCC), RS1001772880 (17:42535123 G>A,T), RS1001825267 (17:42534924 G>A), RS1001890770 (17:42539509 T>C), RS1001958678 (17:42541397 G>A), RS1002240231 (17:42539840 C>T), RS1002286212 (17:42536299 G>A,T), RS1002385973 (17:42539185 G>A), RS1002456491 (17:42541703 G>C), RS1002561522 (17:42542772 G>T), RS1002570461 (17:42538525 G>A)

Disease associations

OMIM: gene MIM:609701 | disease phenotypes: MIM:252920, MIM:616491, MIM:108600, MIM:607014, MIM:118220

GenCC curated gene-disease

Disease	Classification	Inheritance
mucopolysaccharidosis type 3B	Definitive	Autosomal recessive
Charcot-Marie-Tooth disease axonal type 2V	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
mucopolysaccharidosis type 3B	Definitive	AR

Mondo (10): mucopolysaccharidosis type 3B (MONDO:0009656), Charcot-Marie-Tooth disease axonal type 2V (MONDO:0014665), spastic ataxia (MONDO:0017845), lysosomal storage disease (MONDO:0002561), mucopolysaccharidosis (MONDO:0019249), hypertrichosis (MONDO:0019280), intellectual disability (MONDO:0001071), cardiomyopathy (MONDO:0004994), mucopolysaccharidosis type 3 (MONDO:0018937), Charcot-Marie-Tooth disease (MONDO:0015626)

Orphanet (10): Autosomal dominant Charcot-Marie-Tooth disease type 2V (Orphanet:447964), Sanfilippo syndrome type B (Orphanet:79270), Spastic ataxia (Orphanet:316226), Lysosomal disease (Orphanet:68366), Mucopolysaccharidosis (Orphanet:79213), Rare disorder with hypertrichosis (Orphanet:79365), Rare cardiomyopathy (Orphanet:167848), Mucopolysaccharidosis type 3 (Orphanet:581), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

41 total (30 of 41 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000250	Dense calvaria
HP:0000280	Coarse facial features
HP:0000365	Hearing impairment
HP:0000639	Nystagmus
HP:0000664	Synophrys
HP:0000718	Aggressive behavior
HP:0000752	Hyperactivity
HP:0000900	Thickened ribs
HP:0000943	Dysostosis multiplex
HP:0001007	Hirsutism
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001265	Hyporeflexia
HP:0001324	Muscle weakness
HP:0001387	Joint stiffness
HP:0001640	Cardiomegaly
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:0002344	Progressive neurologic deterioration
HP:0002360	Sleep disturbance
HP:0002495	Impaired vibratory sensation
HP:0002788	Recurrent upper respiratory tract infections
HP:0002936	Distal sensory impairment
HP:0003309	Ovoid thoracolumbar vertebrae

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST003825_2	Systolic blood pressure change trajectory	1.000000e-06
GCST004131_42	Inflammatory bowel disease	2.000000e-17
GCST004132_58	Crohn’s disease	2.000000e-11
GCST004133_53	Ulcerative colitis	1.000000e-10
GCST006979_818	Heel bone mineral density	5.000000e-10
GCST010043_34	Asthma	4.000000e-12
GCST010244_290	Triglyceride levels	4.000000e-15

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0006944	systolic blood pressure change measurement
EFO:0009270	heel bone mineral density
EFO:0004530	triglyceride measurement

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D009202	Cardiomyopathies	C14.280.238
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
D006983	Hypertrichosis	C17.800.329.875
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D016464	Lysosomal Storage Diseases	C16.320.565.595; C18.452.648.595
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
C564815	Spastic Ataxia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5465292 (SINGLE PROTEIN)

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
bisphenol A	decreases expression, increases expression	2
cobaltous chloride	decreases expression	2
entinostat	affects cotreatment, increases expression	2
bisphenol S	increases expression, decreases methylation	2
Tobacco Smoke Pollution	decreases expression	2
Cadmium Chloride	decreases expression	2
GSK-J4	decreases expression	1
2,4,6-tribromophenol	increases expression	1
deoxynivalenol	decreases expression	1
decabromobiphenyl ether	increases expression	1
sodium arsenite	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
yessotoxin	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
jinfukang	increases expression	1
PP242	decreases expression	1
Sunitinib	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Catechin	affects cotreatment, decreases expression	1
Doxorubicin	increases expression	1
Ivermectin	decreases expression	1
Naled	affects expression	1
Quercetin	increases expression	1
Selenium	increases expression	1
Smoke	increases expression	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5381432	Binding	Stabilization of mutated NAGLU in Sanfilippo-B patient derived human fibroblast cells assessed as increase in NAGLU activity using 4-methylumbelliferyl-N-acetyl-alpha-D-glucosaminide as substrate at 20 uM cells pretreated for 2 hrs with sub	N-Substituted l-Iminosugars for the Treatment of Sanfilippo Type B Syndrome. — J Med Chem

Cellosaurus cell lines

20 cell lines: 9 induced pluripotent stem cell, 6 finite cell line, 4 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0L90	GM00156	Finite cell line	Male
CVCL_0L94	GM00737	Finite cell line	Male
CVCL_0M01	GM01426	Finite cell line	Female
CVCL_0M04	GM02552	Finite cell line	Female
CVCL_0M05	GM02931	Finite cell line	Female
CVCL_A4XV	SDQLCHi041-A	Induced pluripotent stem cell	Male
CVCL_B3VM	WG0421	Finite cell line
CVCL_B5TP	NCATS-CL7568	Induced pluripotent stem cell	Female
CVCL_B5TQ	NCATS-CL7569	Induced pluripotent stem cell	Male
CVCL_B5TR	TRNDi042-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05492799	PHASE4	ENROLLING_BY_INVITATION	Safety, Tolerability and Efficacy of ICV AX 250 Treatment in MPS IIIB -OLE
NCT05494593	PHASE4	WITHDRAWN	A Study of ELAPRASE in Treatment-naïve Participants With Hunter Syndrome (Mucopolysaccharidosis [MPS] II)
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
NCT07579910	PHASE3	NOT_YET_RECRUITING	Intracerebroventricular Tralesinidase Alfa in Children With Mucopolysaccharidosis Type IIIB
NCT00654433	PHASE3	TERMINATED	ALD-101 Adjuvant Therapy of Unrelated Umbilical Cord Blood Transfusion (UCBT) in Patients With Inherited Metabolic Diseases
NCT04283227	PHASE3	ACTIVE_NOT_RECRUITING	OTL-200 in Patients With Late Juvenile Metachromatic Leukodystrophy (MLD)
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)
NCT01212172	PHASE3	COMPLETED	Comparison of Efficacy, Safety and Tolerability of Two Different 810 nm Diode Lasers for Hair Reduction
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
NCT03784287	PHASE2	UNKNOWN	A Treatment Extension Study of Mucopolysaccharidosis Type IIIB
NCT03392987	PHASE2	COMPLETED	A Safety and Efficacy Study of Cryopreserved OTL-200 for Treatment of Metachromatic Leukodystrophy (MLD)
NCT06130228	PHASE2	UNKNOWN	Nutritional Therapy in Late-onset Pompe Disease
NCT01043640	PHASE2	COMPLETED	Allogeneic Bone Marrow Transplant for Inherited Metabolic Disorders
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.
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
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
NCT00215527	PHASE1	TERMINATED	Intrathecal Enzyme Replacement Therapy for Spinal Cord Compression in Mucopolysaccharidosis (MPS) I
NCT00744692	PHASE1	COMPLETED	Reduced Intensity Conditioning for Umbilical Cord Blood Transplant in Pediatric Patients With Non-Malignant Disorders
NCT00786968	PHASE1	TERMINATED	Extension Study of Intrathecal Enzyme Replacement Therapy for MPS I
NCT01003912	PHASE1	WITHDRAWN	Fetal Umbilical Cord Blood (UCB) Transplant for Lysosomal Storage Diseases
NCT00580736	PHASE1	COMPLETED	Optical Clearing of the Skin in Conjunction With Laser Treatments
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)
NCT02618512	PHASE1/PHASE2	TERMINATED	A Open Label Study in Previously Studied, SBC-103 Treatment Naïve MPS IIIB Subjects to Investigate the Safety, Pharmacokinetics, and Pharmacodynamics/Efficacy of SBC-103 Administered Intravenously
NCT02754076	PHASE1/PHASE2	COMPLETED	A Treatment Study of Mucopolysaccharidosis Type IIIB
NCT03300453	PHASE1/PHASE2	COMPLETED	Intracerebral Gene Therapy in Children With Sanfilippo Type B Syndrome
NCT01509768	Not specified	COMPLETED	Natural History Study of Patients With Mucopolysaccharidosis Type IIIB (MPS IIIB, Sanfilippo Syndrome Type B)
NCT01873911	Not specified	COMPLETED	Neurobehavioral Phenotypes in MPS III
NCT02037880	Not specified	COMPLETED	Natural History Studies of Mucopolysaccharidosis III