GALNS

Summary

GALNS (galactosamine (N-acetyl)-6-sulfatase, HGNC:4122) is a protein-coding gene on chromosome 16q24.3, encoding N-acetylgalactosamine-6-sulfatase (P34059).

This gene encodes N-acetylgalactosamine-6-sulfatase which is a lysosomal exohydrolase required for the degradation of the glycosaminoglycans, keratan sulfate, and chondroitin 6-sulfate. Sequence alterations including point, missense and nonsense mutations, as well as those that affect splicing, result in a deficiency of this enzyme. Deficiencies of this enzyme lead to Morquio A syndrome, a lysosomal storage disorder.

Source: NCBI Gene 2588 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mucopolysaccharidosis type 4A (Definitive, ClinGen)
• GWAS associations: 2
• Clinical variants (ClinVar): 1,392 total — 129 pathogenic, 122 likely-pathogenic
• Phenotypes (HPO): 50
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_000512

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4122
Approved symbol	GALNS
Name	galactosamine (N-acetyl)-6-sulfatase
Location	16q24.3
Locus type	gene with protein product
Status	Approved
Aliases	GAS, GALNAC6S, GalN6S
Ensembl gene	ENSG00000141012
Ensembl biotype	protein_coding
OMIM	612222
Entrez	2588

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 8 protein_coding, 4 retained_intron, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000268695, ENST00000561812, ENST00000562593, ENST00000562831, ENST00000562931, ENST00000564263, ENST00000565364, ENST00000566563, ENST00000567525, ENST00000567779, ENST00000568311, ENST00000568613, ENST00000569433, ENST00000862787, ENST00000862788, ENST00000928281, ENST00000951737

RefSeq mRNA: 3 — MANE Select: NM_000512 NM_000512, NM_001323543, NM_001323544

CCDS: CCDS10970

Canonical transcript exons

ENST00000268695 — 14 exons

Exon	Start	End
ENSE00001297222	88813734	88814525
ENSE00001315284	88856758	88856947
ENSE00003467116	88822589	88822710
ENSE00003495626	88840992	88841094
ENSE00003508678	88836201	88836267
ENSE00003542074	88824767	88824869
ENSE00003551274	88826702	88826838
ENSE00003633720	88837622	88837765
ENSE00003662360	88841897	88841971
ENSE00003674355	88842706	88842829
ENSE00003675766	88831998	88832101
ENSE00003677250	88818007	88818124
ENSE00003685681	88835725	88835849
ENSE00003690107	88835213	88835352

Expression profiles

Bgee: expression breadth ubiquitous, 258 present calls, max score 97.41.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.6304 / max 669.3664, expressed in 1804 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
158585	19.4659	1803
158584	0.0952	22
158583	0.0693	50

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	97.41	gold quality
sperm	CL:0000019	93.61	gold quality
male germ cell	CL:0000015	93.12	gold quality
right testis	UBERON:0004534	92.52	gold quality
left testis	UBERON:0004533	92.39	gold quality
stromal cell of endometrium	CL:0002255	91.66	gold quality
small intestine Peyer’s patch	UBERON:0003454	91.25	gold quality
pituitary gland	UBERON:0000007	90.76	gold quality
adenohypophysis	UBERON:0002196	90.72	gold quality
bronchial epithelial cell	CL:0002328	90.50	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	90.43	gold quality
right adrenal gland	UBERON:0001233	90.34	gold quality
blood	UBERON:0000178	90.33	gold quality
testis	UBERON:0000473	90.28	gold quality
cervix squamous epithelium	UBERON:0006922	90.20	silver quality
right adrenal gland cortex	UBERON:0035827	90.20	gold quality
small intestine	UBERON:0002108	90.11	gold quality
granulocyte	CL:0000094	90.06	gold quality
endocervix	UBERON:0000458	90.06	gold quality
epithelium of bronchus	UBERON:0002031	90.05	gold quality
left uterine tube	UBERON:0001303	89.93	gold quality
bone marrow cell	CL:0002092	89.92	gold quality
bronchus	UBERON:0002185	89.79	gold quality
left adrenal gland cortex	UBERON:0035825	89.55	gold quality
ectocervix	UBERON:0012249	89.53	gold quality
transverse colon	UBERON:0001157	89.40	gold quality
left adrenal gland	UBERON:0001234	89.34	gold quality
right hemisphere of cerebellum	UBERON:0014890	89.27	gold quality
right lobe of thyroid gland	UBERON:0001119	89.25	gold quality
skin of abdomen	UBERON:0001416	89.13	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.38

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1

miRNA regulators (miRDB)

32 targeting GALNS, 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-6778-3P	99.96	67.29	2693
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-452-5P	99.65	69.63	1762
HSA-MIR-4676-3P	99.65	69.31	1733
HSA-MIR-892C-3P	99.65	69.38	1745
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-3171	99.49	69.06	776
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-7113-3P	98.75	65.71	1120
HSA-MIR-3138	98.41	67.53	744
HSA-MIR-4469	97.93	65.81	1319
HSA-MIR-7113-5P	97.88	67.33	1735
HSA-MIR-204-3P	97.80	66.84	1656
HSA-MIR-4646-5P	97.70	66.84	1692
HSA-MIR-4287	97.55	67.24	1247
HSA-MIR-4685-3P	97.55	67.35	1255
HSA-MIR-4640-5P	97.42	66.33	1543
HSA-MIR-4726-5P	97.24	65.67	1299
HSA-MIR-212-5P	96.83	67.43	950
HSA-MIR-4330	95.44	66.39	993
HSA-MIR-122-3P	94.51	65.61	75
HSA-MIR-764	94.16	64.85	656
HSA-MIR-3197	94.02	63.47	85

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• 6-bp deletion in exon 1 of GALNS gene. (PMID:11524742)
• Beside mutations, one previously identified E477 polymorphism and one novel W520 polymorphism were found among Turkish MPS IVA patients. (PMID:12442278)
• Mutation 1374delT introduces premature termination of GALNS, causing mucopolysaccharidosis IVA. (PMID:12721840)
• Ten novel mutations in GALNS in Italian Mucopolysaccharidosis IVA patients. (PMID:15241807)
• 26 novel mutations within the GALNS gene are associated with mucopolysaccharidosis IVA. A genotype/phenotype correlation was defined in some mutations. (PMID:16287098)
• GALNS mutations in six severe Mucopolysaccharidosis type IVA (MPS IVA) patients from four unrelated Tunisian families. (PMID:16378744)
• effect of repeated intra-articular injections (IA INJ) of recombinant human acetylgalactosamine-4-sulfatase on degenerative joint disease in an animal model. (PMID:17544310)
• In mucopolysaccharidosis IVA ‘attenuated’ mutant enzymes are heterogeneous in molecular phenotypes, including biochemical properties and tertiary structure. (PMID:17876718)
• modification of expression of the lysosomal sulfatases ASB and GALNS regulates the content of CSs. (PMID:18285341)
• This paper focuses on the study of the GALNS gene and mRNAs in two severe forms of Morquio A patients’ fibroblasts. (PMID:18710657)
• Results describe the quantitative relationship between the mutant N-acetylgalactosamine-6-sulfatase and the occurrence of mucopolysaccharidosis IVA. (PMID:19373925)
• Deficiency in N-acetylgalactosamine-6-sulfate sulfatase has an impact on the phenotypic properties of chondrocytes, resulting in the formation of cartilage that is more prone to degeneration. (PMID:19394256)
• GALNS mutations are associated with Mucopolysaccharidosis IVA. (PMID:20574428)
• Mucopolysaccharidosis type IVA or Morquio A syndrome is characterized by the lack of N-acetylgalactosamine-6-sulfate-sulfatase and the accumulation of keratan sulfate and chondroitin-6-sulfate in the lysosomes. (PMID:21251309)
• Screening of mutations and polymorphisms in GALNS gene provide useful information on genotype/phenotype correlations. (PMID:22078177)
• Comparison of the structure of GALNS to paralogous sulfatases shows a wide variety of active-site geometries in the family but strict conservation of the catalytic machinery (PMID:22940367)
• missense mutation in GALNS is associated with a severe form of mucopolysaccharidosis type IVA. (PMID:23313879)
• Novel mutations in the GALNS gene associated with mucopolysaccharidosis IVA in Korean patients. (PMID:23401410)
• Here we present 53 mutations including 19 novel mutations in GALNS gene in a cohort of 55 patients (PMID:23876334)
• GALNS gene 5 new mutations: p.N177S, p.G290R, p.F306S, p.W520X, p.W403_T404delinsCS in the mucopolysaccharidosis IVA patients in South China (PMID:24035930)
• 2 unrelated Turkish patients had 2 homozygous known mutations: p.L390X in exon 11 and p.W141R in exon 4. The p L390X mutation was associated with 4 novel polymorphisms in intron 2, intron 5 and intron 6 and a known polymorphism in exon 7. (PMID:24411403)
• Molecular analysis of 163 patients with Morquio A identified 99 unique mutations in the GALNS gene believed to negatively impact GALNS protein function. (PMID:24726177)
• A review of mutations in the GALNS gene associated with Morquio A syndrome. (PMID:25137622)
• The goals were to analyze and characterize the secondary structure, regions of intrinsic disorder and physicochemical characteristics of three classes of mutations described in the enzyme N-acetylgalactosamine-6-sulfatase. (PMID:25501214)
• A new GALNS intronic lesion was characterized: c.245-11C>G causing m-RNA defects, although identified outside the GT/AG splice pair. (PMID:25545067)
• Enzyme replacement therapy (ERT) with recombinant human GALNS (elosulfase alfa, Vimizim(R), BioMarin Pharmaceutical Inc., Novato, CA) has recently been approved as a treatment option for Morquio A. Elosulfase alfa enzyme replacement therapy associated with long-term endurance improvements in Morquio A. (PMID:27380995)
• Clinical evaluation and biochemical GALNS enzyme activity determination were carried out for the patients from four unrelated Egyptian families. Sequence analysis revealed four novel mutations; three nonsense mutations (p.Q12X, p.Q220X, p.Y254X) and one missense mutation, p.D40G. All four patients were offspring of consanguineous marriages and were homozygous for the corresponding mutation. (PMID:27825773)
• Missense mutation of GALNS is associated with mucopolysaccharidosis type IV A. (PMID:28397226)
• Currently, urinary and blood chondroitin-6-sulfate and keratan sulfate, the enzyme activity of GALNS, and GALNS molecular analysis are used for diagnosis and prognosis of clinical phenotype in Mucopolysaccharidosis IVA(MPS IVA). MPS IVA can be diagnosed with unique characters although this disorder relates closely to other disorders in some characteristics (PMID:29779902)
• Mis-splicing of the GALNS gene resulting from deep intronic mutations has been determined as a cause of Morquio a disease in three unrelated patients. (PMID:30305043)
• he aim of our work was to analyze the aforementioned anthropometric parameters, including correlation to molecular data (causative GALNS mutations). (PMID:30927141)
• Insights into the initial and follow-up clinical features and height values that contribute to the differential diagnosis of the severe and intermediate phenotypes in Mucopolysaccharidosis IV A in early childhood. Eleven mutations in GALNS gene in which one of them is novel (c.416G>A) were associated with the severe phenotype and three mutations (c.1038C>A, c.850T>G, c.752G>A) lead to the attenuated phenotype. (PMID:30980944)
• Natural history of the oldest known females with mucopolysaccharidosis type IVA (Morquio A syndrome). (PMID:32216080)
• Long-term outcomes of patients with mucopolysaccharidosis VI treated with galsulfase enzyme replacement therapy since infancy. (PMID:33775523)
• Demographic, clinical, and ancestry characterization of a large cluster of mucopolysaccharidosis IV A in the Brazilian Northeast region. (PMID:34076347)
• Molecular basis of mucopolysaccharidosis IVA (Morquio A syndrome): A review and classification of GALNS gene variants and reporting of 68 novel variants. (PMID:34387910)
• The youngest pair of siblings with Mucopolysaccharidosis type IVA to receive enzyme replacement therapy to date: A case report. (PMID:34472180)
• Investigation of GALNS variants and genotype-phenotype correlations in a large cohort of patients with mucopolysaccharidosis type IVA. (PMID:35212421)
• The GALNS p.P77R variant is a probable Gujarati-Indian founder mutation causing Mucopolysaccharidosis IVA syndrome. (PMID:35729508)
• Exome Sequencing Identifies a Biallelic GALNS Variant (p.Asp233Asn) Causing Mucopolysaccharidosis Type IVA in a Pakistani Consanguineous Family. (PMID:36292628)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	galns	ENSDARG00000051853
mus_musculus	Galns	ENSMUSG00000015027
rattus_norvegicus	Galns	ENSRNOG00000014461
drosophila_melanogaster	CG18278	FBGN0033836
drosophila_melanogaster	CG7408	FBGN0036765
drosophila_melanogaster	CG7402	FBGN0036768
drosophila_melanogaster	CG32191	FBGN0052191
drosophila_melanogaster	CG30059	FBGN0260475

Paralogs (16): ARSD (ENSG00000006756), IDS (ENSG00000010404), ARSF (ENSG00000062096), ARSA (ENSG00000100299), STS (ENSG00000101846), ARSB (ENSG00000113273), GNS (ENSG00000135677), SULF1 (ENSG00000137573), ARSG (ENSG00000141337), ARSL (ENSG00000157399), ARSK (ENSG00000164291), ARSJ (ENSG00000180801), SGSH (ENSG00000181523), ARSI (ENSG00000183876), SULF2 (ENSG00000196562), ARSH (ENSG00000205667)

Protein

Protein identifiers

N-acetylgalactosamine-6-sulfatase — P34059 (reviewed: P34059)

Alternative names: Chondroitinsulfatase, Galactose-6-sulfate sulfatase, N-acetylgalactosamine-6-sulfate sulfatase

All UniProt accessions (6): P34059, H3BNU2, H3BP66, H3BSU9, H3BV24, Q6MZF5

UniProt curated annotations — full annotation on UniProt →

Subunit / interactions. Homodimer.

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 4A (MPS4A) [MIM:253000] A form of mucopolysaccharidosis type 4, an autosomal recessive lysosomal storage disease characterized by intracellular accumulation of keratan sulfate and chondroitin-6-sulfate. Key clinical features include short stature, skeletal dysplasia, dental anomalies, and corneal clouding. Intelligence is normal and there is no direct central nervous system involvement, although the skeletal changes may result in neurologic complications. There is variable severity, but patients with the severe phenotype usually do not survive past the second or third decade of life. 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_000503, NP_001310472, NP_001310473 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000917	Sulfatase_N	Domain
IPR017850	Alkaline_phosphatase_core_sf	Homologous_superfamily
IPR024607	Sulfatase_CS	Conserved_site
IPR035626	GALNS	Family
IPR050738	Sulfatase	Family

Pfam: PF00884, PF14707

Enzyme classification (BRENDA):

• EC 3.1.6.12 — N-acetylgalactosamine-4-sulfatase (BRENDA: 9 organisms, 42 substrates, 40 inhibitors, 19 Km, 1 kcat entries)
• EC 3.1.6.4 — N-acetylgalactosamine-6-sulfatase (BRENDA: 13 organisms, 39 substrates, 31 inhibitors, 14 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
P-NITROCATECHOL SULFATE	1.3–3.9	5
4-METHYLUMBELLIFERYL SULFATE	0.06–5.6	3
NITROCATECHOL SULFATE	0.8–3.6	3
UDP-N-ACETYLGALACTOSAMINE 4-SULFATE	0.013–0.43	2
O-(BETA-D-6-SULFO-2-ACETAMIDO-2-DEOXYGALACTOSYL)	0.012–0.015	2
O-(BETA-D-SULFOGALACTOSYL)-(1-4)-1,5-ANHYDRO-D-M	0.05–0.096	2
N-ACETYLGALACTOSAMINE 4-SULFATE-(BETA-GLUCURONOS	0.03	1
N-ACETYLGALACTOSAMINE 4-SULFATE-(BETA-GLUCURONOS	0.049	1
N-ACETYLGALACTOSAMINE 4-SULFATE-(BETA-GLUCURONOS	0.064	1
N-ACETYLGALACTOSAMINE 4-SULFATE-BETA-GLUCURONOSY	0.027	1
NITROCATECHOL 4-SULFATE	1.86	1
4-METHYLUMBELLIFERYL SULFATE	4.4	1
GALACTOSAMINE 6-SULFATE	0.008	1
GALACTOSE 6-SULFATE	0.013	1
GALNAC-4-SO4-(GLCUA-GALNAC-4-SO4)2	0.03	1

UniProt features (213 total): sequence variant 149, strand 22, helix 19, turn 7, binding site 5, disulfide bond 3, glycosylation site 2, active site 2, signal peptide 1, chain 1, modified residue 1, region of interest 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
4FDI	X-RAY DIFFRACTION	2.2
4FDJ	X-RAY DIFFRACTION	2.81

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P34059-F1	96.04	0.95

Functional residue map

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

Catalytic / active sites (2): 79 (nucleophile); 142

Ligand- & substrate-binding residues (5): 39; 40; 79 (via 3-oxoalanine); 288; 289

Post-translational modifications (1): 79

Disulfide bonds (3): 308–419, 489–518, 501–507

Glycosylation sites (2): 204, 423

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-2022857	Keratan sulfate degradation
R-HSA-2206290	MPS IV - Morquio syndrome A
R-HSA-6798695	Neutrophil degranulation

MSigDB gene sets: 306 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, GOCC_SECRETORY_GRANULE, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, KEGG_LYSOSOME, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, NIKOLSKY_BREAST_CANCER_16Q24_AMPLICON, MODULE_379, MODULE_88, WANG_CISPLATIN_RESPONSE_AND_XPC_DN, ROSS_AML_WITH_PML_RARA_FUSION, MODULE_242, GOBP_CHONDROITIN_SULFATE_PROTEOGLYCAN_METABOLIC_PROCESS, GOBP_PROTEIN_CATABOLIC_PROCESS

GO Biological Process (1): chondroitin sulfate proteoglycan catabolic process (GO:0030207)

GO Molecular Function (6): N-acetylgalactosamine-4-sulfatase activity (GO:0003943), arylsulfatase activity (GO:0004065), sulfuric ester hydrolase activity (GO:0008484), N-acetylgalactosamine-6-sulfatase activity (GO:0043890), metal ion binding (GO:0046872), hydrolase activity (GO:0016787)

GO Cellular Component (5): extracellular region (GO:0005576), azurophil granule lumen (GO:0035578), lysosomal lumen (GO:0043202), extracellular exosome (GO:0070062), lysosome (GO:0005764)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Keratan sulfate/keratin metabolism	1
Mucopolysaccharidoses	1
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
sulfuric ester hydrolase activity	3
vacuolar lumen	2
proteoglycan catabolic process	1
chondroitin sulfate proteoglycan metabolic process	1
hydrolase activity, acting on ester bonds	1
cation binding	1
catalytic activity	1
cellular anatomical structure	1
secretory granule lumen	1
azurophil granule	1
lysosome	1
extracellular vesicle	1
lytic vacuole	1

Protein interactions and networks

STRING

1304 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GALNS	GLB1	P16278	970
GALNS	SUMF1	Q8NBK3	920
GALNS	APRT	P07741	857
GALNS	IDUA	P35475	772
GALNS	NEU1	Q99519	770
GALNS	ZNF276	Q8N554	766
GALNS	CTSA	P10619	734
GALNS	CDK10	Q15131	725
GALNS	NAGLU	P54802	711
GALNS	SPG7	Q9UQ90	647
GALNS	HGSNAT	Q68CP4	639
GALNS	GUSB	P08236	613
GALNS	CYBA	P13498	589
GALNS	GM2A	P17900	566
GALNS	ADK	P55263	495

IntAct

99 interactions, top by confidence:

A	B	Type	Score
CRIPTO	AIP	psi-mi:“MI:0914”(association)	0.640
ERLIN2	HSPA5	psi-mi:“MI:0914”(association)	0.640
PLAUR	PLAU	psi-mi:“MI:0914”(association)	0.560
PSG8	PEX7	psi-mi:“MI:0914”(association)	0.530
DEFA1	MANBA	psi-mi:“MI:0914”(association)	0.530
PRG3	ZNF324	psi-mi:“MI:0914”(association)	0.530
ARSA	ZBTB43	psi-mi:“MI:0914”(association)	0.530
WNT16	WNT11	psi-mi:“MI:0914”(association)	0.530
ALPG	ALPP	psi-mi:“MI:0914”(association)	0.530
CMA1	MANBA	psi-mi:“MI:0914”(association)	0.530
ISLR	BCKDK	psi-mi:“MI:0914”(association)	0.530
GALNS	CLGN	psi-mi:“MI:0914”(association)	0.530
PLAUR	XRCC3	psi-mi:“MI:0914”(association)	0.530
DNASE2B	ARSA	psi-mi:“MI:0914”(association)	0.530
GALNS	FBXO21	psi-mi:“MI:0914”(association)	0.530
OLFM2	ZSWIM8	psi-mi:“MI:0914”(association)	0.350
PRG2	ZSWIM8	psi-mi:“MI:0914”(association)	0.350
ISLR	DDX11L8	psi-mi:“MI:0914”(association)	0.350
PLAUR	DDX11L8	psi-mi:“MI:0914”(association)	0.350
PTPRK	MANBA	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
LYZL2	MANBA	psi-mi:“MI:0914”(association)	0.350
P2RX5	NOP56	psi-mi:“MI:0914”(association)	0.350

BioGRID (112): GALNS (Affinity Capture-MS), GALNS (Affinity Capture-MS), GALNS (Affinity Capture-MS), GALNS (Affinity Capture-MS), GALNS (Affinity Capture-MS), GALNS (Affinity Capture-MS), GALNS (Affinity Capture-MS), GALNS (Affinity Capture-MS), GALNS (Affinity Capture-MS), ATXN2L (Co-fractionation), GALNS (Affinity Capture-MS), GALNS (Affinity Capture-MS), GALNS (Affinity Capture-MS), GALNS (Affinity Capture-MS), GALNS (Affinity Capture-MS)

ESM2 similar proteins: A4FV98, A6NKP2, A6QLY2, O18735, O43488, O75382, O75648, O77485, O77486, O88676, P04626, P23764, P25325, P34059, P52848, Q02353, Q0VD18, Q10836, Q10981, Q10982, Q28113, Q32KH5, Q32KJ6, Q3U129, Q3UHN9, Q4R766, Q571E4, Q5I0D5, Q5RB73, Q5RJL2, Q6AYT7, Q6P988, Q7RTV5, Q7Z4H8, Q8CIW5, Q8K093, Q8N2K0, Q8WNQ7, Q96AZ1, Q96SL4

Diamond homologs: P08842, P14000, P15289, P15589, P20713, P34059, P50427, P50428, P50473, P51689, P51690, P54793, Q08DD1, Q32KH5, Q32KH8, Q32KH9, Q32KJ6, Q32KJ9, Q3TYD4, Q571E4, Q5FYA8, Q5FYB0, Q60HH5, Q8BM89, Q8WNQ7, Q9X759, T2KMG4, T2KN90, P22304, P31447, Q08890, Q32KI9, Q32KJ8, Q5FYB1, Q96EG1, P33727, P50430, Q32KH7, Q8A2F6, Q8A2H2

SIGNOR signaling

1 interactions.

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

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 121 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
Post-translational modification: synthesis of GPI-anchored proteins	7	14.7×	8e-05
Neutrophil degranulation	18	5.2×	2e-06
Innate Immune System	14	4.5×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

1392 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	129
Likely pathogenic	122
Uncertain significance	351
Likely benign	459
Benign	97

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1030834	NM_000512.5(GALNS):c.1365-1G>C	Pathogenic
1048189	NM_000512.5(GALNS):c.320-1G>T	Pathogenic
1048204	NM_000512.5(GALNS):c.708del (p.His236fs)	Pathogenic
1048228	NM_000512.5(GALNS):c.1142del (p.Pro381fs)	Pathogenic
1048237	NM_000512.5(GALNS):c.1420C>T (p.Gln474Ter)	Pathogenic
1048248	NM_000512.5(GALNS):c.29G>A (p.Trp10Ter)	Pathogenic
1048253	NM_000512.5(GALNS):c.85C>T (p.Gln29Ter)	Pathogenic
1048272	NM_000512.5(GALNS):c.334del (p.Glu112fs)	Pathogenic
1048275	NM_000512.5(GALNS):c.376G>T (p.Glu126Ter)	Pathogenic
1048291	NM_000512.5(GALNS):c.551G>A (p.Trp184Ter)	Pathogenic
1048294	NM_000512.5(GALNS):c.758+1G>C	Pathogenic
1048316	NM_000512.5(GALNS):c.974G>A (p.Trp325Ter)	Pathogenic
1048321	NM_000512.5(GALNS):c.1168del (p.Thr389_Leu390insTer)	Pathogenic
1048322	NM_000512.5(GALNS):c.1177_1178insT (p.Ala393fs)	Pathogenic
1048350	NM_000512.5(GALNS):c.1240C>T (p.Gln414Ter)	Pathogenic
1048356	NM_000512.5(GALNS):c.1259del (p.Pro420fs)	Pathogenic
1048366	NC_000016.10:g.(?88813734)(88856758_?)del	Pathogenic
1048368	NC_000016.10:g.(?88813734)(88841972_88842705)del	Pathogenic
1048370	NM_000512.5(GALNS):c.120+1G>A	Pathogenic
1048371	NM_000512.5:c.(120+1_121-1)_(244+1_245-1)del	Pathogenic
1048376	NM_000512.5(GALNS):c.121-1G>A	Pathogenic
1048392	NM_000512.5(GALNS):c.244+1G>T	Pathogenic
1048398	NM_000512.5(GALNS):c.422G>A (p.Trp141Ter)	Pathogenic
1048400	NM_000512.5(GALNS):c.422+2_422+8del	Pathogenic
1048412	NM_000512.5(GALNS):c.567-1G>T	Pathogenic
1048416	NM_000512.5(GALNS):c.604del (p.Glu202fs)	Pathogenic
1048421	NM_000512.5(GALNS):c.841_867del (p.Thr281_Asn289del)	Pathogenic
1048422	NM_000512.5(GALNS):c.863del (p.Asp288fs)	Pathogenic
1048435	NM_000512.5(GALNS):c.1012C>T (p.Gln338Ter)	Pathogenic
1048458	NM_000512.5(GALNS):c.442C>T (p.Gln148Ter)	Pathogenic

SpliceAI

3139 predictions. Top by Δscore:

Variant	Effect	Δscore
16:88818120:CAAAG:C	acceptor_gain	1.0000
16:88818125:C:CC	acceptor_gain	1.0000
16:88824766:CCTGT:C	donor_gain	1.0000
16:88824865:TAGGC:T	acceptor_gain	1.0000
16:88824866:AGGCC:A	acceptor_loss	1.0000
16:88824868:GCC:G	acceptor_loss	1.0000
16:88824869:CCTG:C	acceptor_loss	1.0000
16:88824870:C:CC	acceptor_gain	1.0000
16:88824870:CTGT:C	acceptor_loss	1.0000
16:88824871:T:G	acceptor_loss	1.0000
16:88826834:CTCAC:C	acceptor_gain	1.0000
16:88826835:TCAC:T	acceptor_gain	1.0000
16:88826836:CAC:C	acceptor_gain	1.0000
16:88826836:CACC:C	acceptor_gain	1.0000
16:88826838:CCTGA:C	acceptor_loss	1.0000
16:88835208:CTCA:C	donor_loss	1.0000
16:88835209:TCAC:T	donor_loss	1.0000
16:88835210:CAC:C	donor_loss	1.0000
16:88835211:A:AC	donor_gain	1.0000
16:88835211:AC:A	donor_gain	1.0000
16:88835212:C:CT	donor_gain	1.0000
16:88835212:CC:C	donor_gain	1.0000
16:88835212:CCT:C	donor_gain	1.0000
16:88835212:CCTT:C	donor_gain	1.0000
16:88835212:CCTTG:C	donor_gain	1.0000
16:88840985:GACTT:G	donor_loss	1.0000
16:88840986:ACTTA:A	donor_loss	1.0000
16:88840987:CTT:C	donor_loss	1.0000
16:88840989:TA:T	donor_loss	1.0000
16:88840990:A:AC	donor_gain	1.0000

AlphaMissense

3425 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:88835248:T:A	D288V	0.999
16:88856759:T:A	D40V	0.999
16:88856762:T:A	D39V	0.999
16:88835248:T:G	D288A	0.998
16:88835249:C:G	D288H	0.998
16:88835251:G:C	S287W	0.998
16:88840993:A:G	W141R	0.998
16:88840993:A:T	W141R	0.998
16:88856762:T:G	D39A	0.998
16:88856763:C:G	D39H	0.998
16:88832070:C:A	K310N	0.997
16:88832070:C:G	K310N	0.997
16:88856759:T:G	D40A	0.997
16:88835244:G:C	N289K	0.996
16:88835244:G:T	N289K	0.996
16:88835248:T:C	D288G	0.996
16:88835249:C:A	D288Y	0.996
16:88840994:C:A	K140N	0.996
16:88840994:C:G	K140N	0.996
16:88842713:G:C	C79W	0.996
16:88856761:G:C	D39E	0.996
16:88856761:G:T	D39E	0.996
16:88824812:C:A	K399N	0.995
16:88824812:C:G	K399N	0.995
16:88835242:C:A	G290V	0.995
16:88837765:C:A	W141C	0.995
16:88837765:C:G	W141C	0.995
16:88841968:C:A	R83M	0.995
16:88842714:C:T	C79Y	0.995
16:88856760:C:G	D40H	0.995

dbSNP variants (sampled 300 via entrez): RS1000034156 (16:88820394 G>A), RS1000039383 (16:88851166 C>T), RS1000143533 (16:88846556 G>A), RS1000147330 (16:88826996 G>A), RS1000174044 (16:88853606 G>A), RS1000194502 (16:88842132 C>G,T), RS1000226453 (16:88853422 A>G), RS1000358661 (16:88848024 T>G), RS1000436702 (16:88830181 A>C), RS1000468499 (16:88818454 G>A,T), RS1000501046 (16:88818646 C>T), RS1000559372 (16:88851024 CT>C), RS1000571810 (16:88840302 A>C,G), RS1000610275 (16:88815181 C>T), RS1000703074 (16:88822087 C>T)

Disease associations

OMIM: gene MIM:612222 | disease phenotypes: MIM:253000

GenCC curated gene-disease

Disease	Classification	Inheritance
mucopolysaccharidosis type 4A	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
mucopolysaccharidosis type 4A	Definitive	AR

Mondo (4): mucopolysaccharidosis type 4A (MONDO:0009659), mucopolysaccharidosis type 4 (MONDO:0018938), congenital portosystemic shunt (MONDO:0018811), skeletal dysplasia (MONDO:0018230)

Orphanet (4): Mucopolysaccharidosis type 4A (Orphanet:309297), Mucopolysaccharidosis type 4 (Orphanet:582), Congenital portosystemic shunt (Orphanet:480531), Primary bone dysplasia (Orphanet:364526)

HPO phenotypes

50 total (30 of 50 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000154	Wide mouth
HP:0000280	Coarse facial features
HP:0000303	Mandibular prognathia
HP:0000365	Hearing impairment
HP:0000470	Short neck
HP:0000670	Carious teeth
HP:0000683	Grayish enamel
HP:0000687	Widely spaced teeth
HP:0000768	Pectus carinatum
HP:0000884	Prominent sternum
HP:0000904	Flaring of rib cage
HP:0000926	Platyspondyly
HP:0000939	Osteoporosis
HP:0000943	Dysostosis multiplex
HP:0001223	Pointed proximal second through fifth metacarpals
HP:0001249	Intellectual disability
HP:0001270	Motor delay
HP:0001382	Joint hypermobility
HP:0001654	Abnormal heart valve morphology
HP:0002091	Restrictive ventilatory defect
HP:0002240	Hepatomegaly
HP:0002318	Cervical myelopathy
HP:0002515	Waddling gait
HP:0002650	Scoliosis
HP:0002673	Coxa valga
HP:0002788	Recurrent upper respiratory tract infections
HP:0002808	Kyphosis
HP:0002857	Genu valgum

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST003479_9	Hair color	1.000000e-07
GCST008098_1	Atypical femoral fracture in phosphonate treatment	9.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009958	response to bisphosphonate
EFO:0009960	atypical femoral fracture

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523218 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — 3.1.-.- Ester bond enzymes

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, increases methylation, affects expression	4
Air Pollutants	affects expression, increases abundance, increases expression	2
Smoke	decreases expression, increases abundance, increases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	increases expression	1
benzo(e)pyrene	increases methylation	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
nickel sulfate	increases expression	1
1-hydroxypyrene	affects cotreatment, decreases methylation	1
yessotoxin	increases expression	1
CGP 52608	affects binding, increases reaction	1
PP242	decreases expression	1
bisphenol AF	increases expression	1
Temozolomide	decreases expression	1
Sunitinib	increases expression	1
Acetaminophen	increases expression	1
Benzo(a)pyrene	increases methylation	1
Coumestrol	affects cotreatment, decreases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Diazinon	increases methylation	1
Methapyrilene	increases methylation	1
Ozone	affects expression, increases abundance	1
Potassium Dichromate	increases expression	1
Rotenone	decreases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Tretinoin	increases expression	1
Urethane	increases expression	1

ChEMBL screening assays

15 unique, capped per target: 15 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4365116	Binding	Inhibition of recombinant human GALNS expressed in Pichia pastoris at 10 uM using 4-methylumbelliferyl-beta-D-galactopyranoside-6-sulfate as substrate measured after 18 hrs by fluorescence assay relative to control	Identification of Ezetimibe and Pranlukast as Pharmacological Chaperones for the Treatment of the Rare Disease Mucopolysaccharidosis Type IVA. — J Med Chem

Cellosaurus cell lines

5 cell lines: 3 cancer cell line, 1 finite cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_9W81	GM01361	Finite cell line	Male
CVCL_D5EP	HeLa::TMEM192-3xHA GALNS KO	Cancer cell line	Female
CVCL_E1Y0	HAP1 GALNS (-) 1	Cancer cell line	Male
CVCL_E1Y1	HAP1 GALNS (-) 2	Cancer cell line	Male
CVCL_UL24	TRNDi005-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01275066	PHASE3	COMPLETED	A Double-Blind Study to Evaluate the Efficacy and Safety of BMN 110 in Patients With Mucopolysaccharidosis IVA (Morquio A Syndrome)
NCT01415427	PHASE3	COMPLETED	Long-Term Efficacy and Safety Extension Study of BMN 110 in Patients With Mucopolysaccharidosis IVA (Morquio A Syndrome)
NCT01515956	PHASE2	COMPLETED	Study of BMN 110 in Pediatric Patients < 5 Years of Age With Mucopolysaccharidosis IVA (Morquio A Syndrome)
NCT01609062	PHASE2	TERMINATED	Safety and Exercise Study of Two Doses of BMN 110 for Morquio A Syndrome
NCT01697319	PHASE2	TERMINATED	Efficacy and Safety Study of BMN 110 for Morquio A Syndrome Patients Who Have Limited Ambulation
NCT03632213	PHASE2	UNKNOWN	Evaluation of Losartan on Cardiovascular Disease in Patients With Mucopolysaccharidoses IV A and VI
NCT04532047	PHASE1	RECRUITING	PEARL (PrEnAtal Enzyme Replacement Therapy for Lysosomal Storage Disorders)
NCT00884949	PHASE1/PHASE2	COMPLETED	A Study to Evaluate the Safety, Tolerability and Efficacy of BMN 110 in Subjects With Mucopolysaccharidosis IVA
NCT01242111	PHASE1/PHASE2	TERMINATED	A Study to Evaluate the Long-Term Efficacy and Safety of BMN 110 in Patients With Mucopolysaccharidosis IVA (Morquio A Syndrome)
NCT05845749	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Safety and Efficacy of Voxzogo for Growth Deficits in MPS IVA and VI
NCT00787995	Not specified	TERMINATED	A Clinical Assessment Study of Subjects With Mucopolysaccharidosis IVA (Morquio Syndrome)
NCT01457456	Not specified	WITHDRAWN	Biomarker for Morquio Disease (BioMorquio)
NCT01733615	Not specified	TERMINATED	Discovering New Biomarkers For Monitoring Disease Progression in Patients With Mucopolysaccharidosis IVA
NCT01858103	Not specified	APPROVED_FOR_MARKETING	BMN 110 US Expanded Access Program
NCT01920828	Not specified	COMPLETED	Gait Analysis in MPS IVA
NCT01961518	Not specified	COMPLETED	Screening an Orthopedic Population for Mildly-affected Individuals With Morquio Syndrome A and Maroteaux-Lamy Syndrome
NCT02153255	Not specified	WITHDRAWN	Dynamic Gait Analysis in Children With Mucopolysaccharidosis Type IVa
NCT02294877	Not specified	COMPLETED	A Multicenter, Multinational, Observational Morquio A Registry Study (MARS)
NCT05284006	Not specified	RECRUITING	Non-invasive Functional Assessment and Pathogenesis of Morquio A
NCT07361536	Not specified	RECRUITING	Cardiac Structure and Function in MPS
NCT01675674	Not specified	TERMINATED	Study to Detect Unrecognized Mucopolysaccharidosis in Children Visiting Rheumatology, Hand or Skeletal Dysplasia Clinics
NCT01752296	Not specified	COMPLETED	Psychological Concomitants of Morquio Syndrome (The MAP Study)
NCT01870375	Not specified	COMPLETED	Longitudinal Studies of Brain Structure and Function in MPS Disorders
NCT03150069	Not specified	COMPLETED	Pregnancy With Morquio Syndrome - What Are Patients’ Perspectives and Has ERT Changed Them?
NCT03333200	Not specified	RECRUITING	Longitudinal Study of Neurodegenerative Disorders
NCT03872713	Not specified	COMPLETED	Establishment of Human Cellular Disease Models for Morquio Disease
NCT06036693	Not specified	RECRUITING	MPS (RaDiCo Cohort) (RaDiCo-MPS)
NCT06041906	Not specified	ENROLLING_BY_INVITATION	International Registry of Congenital Portosystemic Shunt (IRCPSS)
NCT07314814	Not specified	NOT_YET_RECRUITING	Genetic Hallmarks of Patients With Congenital Portosystemic Shunts and Portopulmonary Hypertension
NCT00001754	Not specified	COMPLETED	Study of Skeletal Disorders and Short Stature
NCT02762318	Not specified	TERMINATED	Identification and Characterization of Bone-related Genetic Variants in Families
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT05247645	Not specified	RECRUITING	Data Collection of Patients With Rare Bone Diseases
NCT05876416	Not specified	RECRUITING	Decoding the Genetic Landscape of Skeletal Diseases
NCT05991609	Not specified	ACTIVE_NOT_RECRUITING	Extreme Morphology and Metabolic Health
NCT06002373	Not specified	UNKNOWN	Assessment of Artificial Intelligence for Treatment Decision Recommendation of Adult Skeletal Class III Patients