HEXD

Summary

HEXD (hexosaminidase D, HGNC:26307) is a protein-coding gene on chromosome 17q25.3, encoding Hexosaminidase D (Q8WVB3). Has hexosaminidase activity.

Enables beta-N-acetylhexosaminidase activity. Predicted to be involved in carbohydrate metabolic process. Located in extracellular vesicle.

Source: NCBI Gene 284004 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 154 total
• Druggable target: yes
• MANE Select transcript: NM_001330542

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26307
Approved symbol	HEXD
Name	hexosaminidase D
Location	17q25.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ23825
Ensembl gene	ENSG00000169660
Ensembl biotype	protein_coding
OMIM	616864
Entrez	284004

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 17 protein_coding, 5 retained_intron, 4 nonsense_mediated_decay

ENST00000327949, ENST00000337014, ENST00000577944, ENST00000578130, ENST00000578616, ENST00000578632, ENST00000578775, ENST00000580235, ENST00000581482, ENST00000582131, ENST00000582315, ENST00000582429, ENST00000583354, ENST00000583978, ENST00000585077, ENST00000644009, ENST00000644886, ENST00000851765, ENST00000851766, ENST00000928628, ENST00000928629, ENST00000928630, ENST00000949822, ENST00000949823, ENST00000949824, ENST00000949825

RefSeq mRNA: 4 — MANE Select: NM_001330542 NM_001330542, NM_001369487, NM_001369488, NM_173620

CCDS: CCDS42402, CCDS82231

Canonical transcript exons

ENST00000327949 — 13 exons

Exon	Start	End
ENSE00001226212	82439631	82439713
ENSE00002832609	82437168	82437363
ENSE00003458353	82433658	82433822
ENSE00003466988	82419749	82419883
ENSE00003503038	82424394	82424503
ENSE00003531873	82441165	82441266
ENSE00003540060	82436667	82436738
ENSE00003555999	82441800	82441889
ENSE00003579177	82428558	82428645
ENSE00003609729	82440997	82441075
ENSE00003639689	82435689	82435872
ENSE00003687010	82442177	82442645
ENSE00003903655	82418347	82418740

Expression profiles

Bgee: expression breadth ubiquitous, 212 present calls, max score 97.30.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.5755 / max 175.6869, expressed in 1780 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
163513	10.1798	1759
163514	1.3089	635
163517	0.0868	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	97.30	gold quality
granulocyte	CL:0000094	96.48	gold quality
body of pancreas	UBERON:0001150	96.44	gold quality
right ovary	UBERON:0002118	96.43	gold quality
adenohypophysis	UBERON:0002196	96.02	gold quality
left ovary	UBERON:0002119	95.85	gold quality
body of uterus	UBERON:0009853	95.83	gold quality
endocervix	UBERON:0000458	95.74	gold quality
right lobe of thyroid gland	UBERON:0001119	95.25	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.21	gold quality
spleen	UBERON:0002106	95.13	gold quality
right adrenal gland cortex	UBERON:0035827	94.87	gold quality
right lobe of liver	UBERON:0001114	94.84	gold quality
left uterine tube	UBERON:0001303	94.66	gold quality
right adrenal gland	UBERON:0001233	94.53	gold quality
ectocervix	UBERON:0012249	94.50	gold quality
cerebellar hemisphere	UBERON:0002245	94.49	gold quality
left lobe of thyroid gland	UBERON:0001120	94.48	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.45	gold quality
pituitary gland	UBERON:0000007	94.43	gold quality
metanephros cortex	UBERON:0010533	94.43	gold quality
cerebellar cortex	UBERON:0002129	94.28	gold quality
body of stomach	UBERON:0001161	94.01	gold quality
mucosa of transverse colon	UBERON:0004991	93.83	gold quality
popliteal artery	UBERON:0002250	93.15	gold quality
left adrenal gland cortex	UBERON:0035825	93.14	gold quality
tibial artery	UBERON:0007610	93.13	gold quality
left adrenal gland	UBERON:0001234	93.03	gold quality
minor salivary gland	UBERON:0001830	93.03	gold quality
omental fat pad	UBERON:0010414	92.99	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	11.96
E-ANND-3	yes	9.33
E-MTAB-7606	no	428.47

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 5)

• In normoalbuminuric/microalbuminuric patients with essential hypertension renal impairment measured by e-GFR is related to the increased urinary NAG activity and albumin/creatinine ratio rather than elevated concentrations of individual proteins. (PMID:21265931)
• The results suggest that, following coronary angiography and/or percutaneous coronary intervention, contrast-induced nephropathy (CIN) occurs to a certain degree and that NAG may be a useful early CIN marker. (PMID:21672370)
• Studies indicate the most studied biomarkers for acute kidney injury are neutrophil gelatinase-associated lipocalin-2, kidney injury molecule-1, IL-18, cystatin C, N-acetyl-beta-D-glucosaminidase, liver fatty-acid binding protein, and heat shock protein 72. (PMID:22515481)
• the expression and disease relevance of the HEXDC gene in humans demonstrate the expression of this novel enzyme within the joints, and suggests that its activity may significantly contribute to the overall local exoglycosidase activity. (PMID:23099419)
• The catalytically important residues are Asp148 and Glu149, with Glu149 serving as the general acid/base residue and Asp148 as the polarizing residue. HexD is inhibited by Gal-NAG-thiazoline (Ki = 420 nM). (PMID:27149221)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	hexd	ENSDARG00000061216
mus_musculus	Hexd	ENSMUSG00000039307
rattus_norvegicus	Hexd	ENSRNOG00000036667
drosophila_melanogaster	CG7985	FBGN0028499
caenorhabditis_elegans		WBGENE00012663
caenorhabditis_elegans		WBGENE00013497
caenorhabditis_elegans		WBGENE00015767
caenorhabditis_elegans	hex-4	WBGENE00021766

Protein

Protein identifiers

Hexosaminidase D — Q8WVB3 (reviewed: Q8WVB3)

Alternative names: Beta-N-acetylhexosaminidase, Beta-hexosaminidase D, Hexosaminidase domain-containing protein, N-acetyl-beta-galactosaminidase

All UniProt accessions (9): Q8WVB3, J3KRH3, J3KS46, J3KT84, J3KTD0, J3QKL0, J3QKU6, J3QLN1, J3QS29

UniProt curated annotations — full annotation on UniProt →

Function. Has hexosaminidase activity. Responsible for the cleavage of the monosaccharides N-acetylglucosamine (GlcNAc) and N-acetylgalactosamine (GalNAc) from cellular substrates. Has a preference for galactosaminide over glucosaminide substrates.

Subunit / interactions. Homodimer; disulfide-linked.

Subcellular location. Cytoplasm. Nucleus. Extracellular vesicle.

Tissue specificity. Expressed in synovial fibroblasts and synovial membranes.

Activity regulation. Inhibited by O-(2-acetamido-2-deoxy-D-glucopyranosylidene)amino N-phenylcarbamate (PUGNAc). Inhibited by galacto-NAG-thiazoline.

Induction. Expression is inhibited by TGFB1.

Similarity. Belongs to the glycosyl hydrolase 20 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8WVB3-1	1	yes
Q8WVB3-2	2

RefSeq proteins (4): NP_001317471, NP_001356416, NP_001356417, NP_775891 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR015883	GH20_cat	Domain
IPR017853	GH_hydrolase_sf	Homologous_superfamily
IPR038901	HEXDC-like	Family

Pfam: PF00728

UniProt features (8 total): mutagenesis site 3, sequence variant 2, chain 1, active site 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WVB3-F1	93.50	0.90

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): 149 (proton donor)

Mutagenesis-validated functional residues (3):

Position	Phenotype
92	decreases hexosaminidase activity.
148	loss of hexosaminidase activity.
149	decreases hexosaminidase activity. optimum ph shifts to 7.5.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 72 (showing top): GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_CARBOHYDRATE_METABOLIC_PROCESS, ACEVEDO_LIVER_CANCER_UP, NIKOLSKY_BREAST_CANCER_17Q21_Q25_AMPLICON, GOMF_HYDROLASE_ACTIVITY_ACTING_ON_GLYCOSYL_BONDS, GOMF_HYDROLASE_ACTIVITY_HYDROLYZING_O_GLYCOSYL_COMPOUNDS, GOMF_HEXOSAMINIDASE_ACTIVITY, RB_P107_DN.V1_UP, CHARAFE_BREAST_CANCER_LUMINAL_VS_BASAL_UP, GSE14386_UNTREATED_VS_IFNA_TREATED_ACT_PBMC_MS_PATIENT_UP, CEBPZ_TARGET_GENES, FOXN3_TARGET_GENES, NAB2_TARGET_GENES, RBM34_TARGET_GENES

GO Biological Process (1): carbohydrate metabolic process (GO:0005975)

GO Molecular Function (5): beta-N-acetylhexosaminidase activity (GO:0004563), hexosaminidase activity (GO:0015929), hydrolase activity, hydrolyzing O-glycosyl compounds (GO:0004553), hydrolase activity (GO:0016787), hydrolase activity, acting on glycosyl bonds (GO:0016798)

GO Cellular Component (3): nucleus (GO:0005634), cytoplasm (GO:0005737), extracellular vesicle (GO:1903561)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
primary metabolic process	1
hexosaminidase activity	1
hydrolase activity, hydrolyzing O-glycosyl compounds	1
hydrolase activity, acting on glycosyl bonds	1
catalytic activity	1
hydrolase activity	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1
extracellular region	1
vesicle	1
extracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1027 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HEXD	OGA	O60502	557
HEXD	ZNF662	Q6ZS27	491
HEXD	CTRC	Q99895	474
HEXD	YPEL5	P62699	462
HEXD	XYLB	O75191	454
HEXD	GASK1A	Q9UFP1	449
HEXD	ARMC7	Q9H6L4	399
HEXD	GLB1L	Q6UWU2	388
HEXD	ZNF646	O15015	387
HEXD	RUNX1T1	Q06455	387
HEXD	MAD1L1	Q9Y6D9	374
HEXD	ZDHHC24	Q6UX98	372
HEXD	FUCA1	P04066	369
HEXD	HEXA	P06865	363
HEXD	INTS2	Q9H0H0	359

IntAct

11 interactions, top by confidence:

A	B	Type	Score
H3-4	HEXD	psi-mi:“MI:0915”(physical association)	0.400
TUBB4A	HEXD	psi-mi:“MI:0915”(physical association)	0.000
HEXD	EEF1D	psi-mi:“MI:0915”(physical association)	0.000
HEXD	ADPRS	psi-mi:“MI:0915”(physical association)	0.000
HEXD	C7orf25	psi-mi:“MI:0915”(physical association)	0.000
HEXD	RILPL2	psi-mi:“MI:0915”(physical association)	0.000
HEXD	GDPD2	psi-mi:“MI:0915”(physical association)	0.000
HEXD	PSD	psi-mi:“MI:0915”(physical association)	0.000
HEXD	GLRX3	psi-mi:“MI:0915”(physical association)	0.000
HEXD	PRKN	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (12): HEXDC (Affinity Capture-MS), HEXDC (Affinity Capture-MS), ADPRHL2 (Two-hybrid), C7orf25 (Two-hybrid), RILPL2 (Two-hybrid), GDPD2 (Two-hybrid), PSD (Two-hybrid), GLRX3 (Two-hybrid), EEF1D (Two-hybrid), HEXDC (Two-hybrid), HEXDC (Proximity Label-MS), HEXDC (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A1L1C2, A3KNW0, A6H603, A6NFQ2, A6QLU7, A9ULG4, B1H1N7, E1BE10, E2RD63, O35405, O55230, O60294, O60906, O75771, O95479, P21709, P51839, P56201, Q0V8L6, Q149M9, Q1JPJ9, Q28DT3, Q2KJJ8, Q2TBP8, Q4R583, Q5FVH2, Q5R4Y7, Q5XIA3, Q60750, Q643R3, Q6NVG1, Q6QHF9, Q80XS7, Q865R1, Q8BG07, Q8BYR1, Q8C0L6, Q8CFX1, Q8IV08, Q8N0W3

Diamond homologs: A6QNR0, Q3U4H6, Q8WVB3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	110
Likely benign	21
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

3045 predictions. Top by Δscore:

Variant	Effect	Δscore
17:82418552:G:GT	donor_gain	1.0000
17:82419881:GAG:G	donor_gain	1.0000
17:82428553:TCCA:T	acceptor_loss	1.0000
17:82428554:CCAG:C	acceptor_loss	1.0000
17:82428556:A:AG	acceptor_gain	1.0000
17:82428557:G:GT	acceptor_gain	1.0000
17:82428557:GC:G	acceptor_gain	1.0000
17:82428557:GCC:G	acceptor_gain	1.0000
17:82428557:GCCC:G	acceptor_gain	1.0000
17:82428557:GCCCC:G	acceptor_gain	1.0000
17:82433653:CGCA:C	acceptor_loss	1.0000
17:82433655:CA:C	acceptor_loss	1.0000
17:82433656:A:AG	acceptor_gain	1.0000
17:82433656:A:C	acceptor_loss	1.0000
17:82433656:AGTTT:A	acceptor_gain	1.0000
17:82433657:G:GA	acceptor_gain	1.0000
17:82433657:GT:G	acceptor_gain	1.0000
17:82433657:GTT:G	acceptor_gain	1.0000
17:82433657:GTTT:G	acceptor_gain	1.0000
17:82433657:GTTTG:G	acceptor_gain	1.0000
17:82433821:AGG:A	donor_loss	1.0000
17:82433822:GGT:G	donor_loss	1.0000
17:82433823:G:A	donor_loss	1.0000
17:82435683:TTGCA:T	acceptor_loss	1.0000
17:82435684:TGCA:T	acceptor_loss	1.0000
17:82435685:GCAGG:G	acceptor_loss	1.0000
17:82435686:CAG:C	acceptor_loss	1.0000
17:82435687:AGGTC:A	acceptor_loss	1.0000
17:82435868:CGCAG:C	donor_loss	1.0000
17:82435869:GCAGG:G	donor_loss	1.0000

AlphaMissense

3129 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:82437221:A:C	S253R	0.995
17:82437223:T:A	S253R	0.995
17:82437223:T:G	S253R	0.995
17:82419849:A:T	K17I	0.994
17:82437232:G:C	K256N	0.994
17:82437232:G:T	K256N	0.994
17:82437363:G:T	R300M	0.994
17:82433658:T:C	F95L	0.993
17:82433660:T:A	F95L	0.993
17:82433660:T:G	F95L	0.993
17:82435830:T:A	W197R	0.993
17:82435830:T:C	W197R	0.993
17:82442259:T:A	W446R	0.992
17:82442259:T:C	W446R	0.992
17:82424446:A:T	E46V	0.991
17:82437296:T:A	W278R	0.991
17:82437296:T:C	W278R	0.991
17:82419850:A:C	K17N	0.990
17:82419850:A:T	K17N	0.990
17:82435832:G:C	W197C	0.990
17:82435832:G:T	W197C	0.990
17:82437227:T:C	F255L	0.990
17:82437229:C:A	F255L	0.990
17:82437229:C:G	F255L	0.990
17:82437219:C:A	A252D	0.989
17:82419834:T:A	V12D	0.988
17:82424448:G:C	D47H	0.987
17:82437363:G:C	R300T	0.987
17:82439655:C:G	C308W	0.987
17:82419836:C:G	H13D	0.986

dbSNP variants (sampled 300 via entrez): RS1000039022 (17:82436840 T>C), RS1000108156 (17:82424136 G>A,T), RS1000166782 (17:82430690 A>C,G), RS1000344989 (17:82429453 G>A), RS1000400317 (17:82438979 C>T), RS1000437433 (17:82418905 G>A,C), RS1000734834 (17:82438162 C>T), RS1000780530 (17:82437979 G>T), RS1000862756 (17:82418035 C>T), RS1000893041 (17:82417636 T>A,C), RS1001206717 (17:82440222 A>G), RS1001289405 (17:82417856 A>C), RS1001331255 (17:82436289 G>C), RS1001335539 (17:82418228 G>C,T), RS1001444499 (17:82436082 C>T)

Disease associations

OMIM: gene MIM:616864 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST007856_71	Colorectal cancer or advanced adenoma	7.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5169180 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	decreases expression, increases expression	2
Tobacco Smoke Pollution	decreases expression	2
Valproic Acid	increases methylation, affects expression	2
GSK-J4	decreases expression	1
afuresertib	increases expression	1
bisphenol A	decreases methylation	1
sodium arsenite	decreases expression	1
perfluorooctanoic acid	decreases expression	1
ferrous chloride	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
perfluorohexanesulfonic acid	decreases expression	1
ICG 001	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
(+)-JQ1 compound	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Bortezomib	decreases expression	1
Temozolomide	increases expression	1
Sunitinib	increases expression	1
Atrazine	decreases expression	1
Phenylmercuric Acetate	affects cotreatment, decreases expression	1
Smoke	decreases expression	1
Aflatoxin B1	increases methylation	1
Antirheumatic Agents	decreases expression	1
Okadaic Acid	decreases expression	1
Copper Sulfate	decreases expression	1
Genistein	increases expression	1
Acrylamide	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5115655	Binding	Inhibition of human recombinant beta-hexosaminidase at 10 uM pretreated with compound followed by 4-nitrophenyl Nacetyl-beta-D-glucosaminide substrate addition by fluorometer	Structure-based discovery and development of novel O-GlcNAcase inhibitors for the treatment of Alzheimer’s disease. — Eur J Med Chem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SR32	HAP1 HEXDC (-) 1	Cancer cell line	Male
CVCL_SR33	HAP1 HEXDC (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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