XYLT1

Summary

XYLT1 (xylosyltransferase 1, HGNC:15516) is a protein-coding gene on chromosome 16p12.3, encoding Xylosyltransferase 1 (Q86Y38). Catalyzes the first step in the biosynthesis of chondroitin sulfate and dermatan sulfate proteoglycans, such as DCN.

This locus encodes a xylosyltransferase enzyme. The encoded protein catalyzes transfer of UDP-xylose to serine residues of an acceptor protein substrate. This transfer reaction is necessary for biosynthesis of glycosaminoglycan chains. Mutations in this gene have been associated with increased severity of pseudoxanthoma elasticum.

Source: NCBI Gene 64131 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Desbuquois dysplasia 2 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 12
• Clinical variants (ClinVar): 514 total — 18 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 118
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_022166

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15516
Approved symbol	XYLT1
Name	xylosyltransferase 1
Location	16p12.3
Locus type	gene with protein product
Status	Approved
Aliases	XT-I, PXYLT1
Ensembl gene	ENSG00000103489
Ensembl biotype	protein_coding
OMIM	608124
Entrez	64131

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 2 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000261381, ENST00000563403, ENST00000568226, ENST00000575674, ENST00000933757

RefSeq mRNA: 1 — MANE Select: NM_022166 NM_022166

CCDS: CCDS10569

Canonical transcript exons

ENST00000261381 — 12 exons

Exon	Start	End
ENSE00001030286	17127666	17127861
ENSE00001030290	17117646	17117979
ENSE00001030300	17134473	17134735
ENSE00001110631	17198212	17198414
ENSE00001110633	17141153	17141369
ENSE00001110634	17158829	17158909
ENSE00001110635	17258988	17259498
ENSE00001247162	17101769	17109017
ENSE00001301632	17470434	17470960
ENSE00001721825	17138355	17138531
ENSE00003512228	17358012	17358050
ENSE00003674175	17200482	17200654

Expression profiles

Bgee: expression breadth ubiquitous, 272 present calls, max score 98.13.

FANTOM5 (CAGE): breadth broad, TPM avg 0.7399 / max 31.8128, expressed in 430 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
156545	0.6294	384
156537	0.1105	66

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibia	UBERON:0000979	98.13	gold quality
cartilage tissue	UBERON:0002418	94.95	gold quality
hair follicle	UBERON:0002073	91.78	gold quality
CA1 field of hippocampus	UBERON:0003881	91.76	gold quality
choroid plexus epithelium	UBERON:0003911	90.86	gold quality
synovial joint	UBERON:0002217	90.63	gold quality
gingival epithelium	UBERON:0001949	90.46	gold quality
pigmented layer of retina	UBERON:0001782	90.26	gold quality
retina	UBERON:0000966	90.24	gold quality
entorhinal cortex	UBERON:0002728	89.36	gold quality
gingiva	UBERON:0001828	88.86	gold quality
Brodmann (1909) area 23	UBERON:0013554	88.03	gold quality
eye	UBERON:0000970	87.30	gold quality
ventricular zone	UBERON:0003053	87.02	gold quality
orbitofrontal cortex	UBERON:0004167	86.40	gold quality
palpebral conjunctiva	UBERON:0001812	86.33	gold quality
squamous epithelium	UBERON:0006914	85.83	gold quality
mucosa of sigmoid colon	UBERON:0004993	85.80	gold quality
adrenal tissue	UBERON:0018303	85.77	gold quality
superior frontal gyrus	UBERON:0002661	85.27	gold quality
layer of synovial tissue	UBERON:0007616	85.10	gold quality
epithelium of esophagus	UBERON:0001976	85.08	gold quality
Brodmann (1909) area 46	UBERON:0006483	85.08	gold quality
postcentral gyrus	UBERON:0002581	85.05	gold quality
skin of hip	UBERON:0001554	84.95	gold quality
colonic mucosa	UBERON:0000317	84.88	gold quality
jejunal mucosa	UBERON:0000399	84.53	gold quality
esophagus squamous epithelium	UBERON:0006920	84.46	gold quality
parietal lobe	UBERON:0001872	84.19	gold quality
saphenous vein	UBERON:0007318	82.80	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	81.61
E-HCAD-25	yes	26.84
E-GEOD-84465	yes	23.78
E-CURD-119	yes	16.82
E-ANND-3	no	2.65

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, JUN, SP1, SP3

miRNA regulators (miRDB)

279 targeting XYLT1, 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-5692A	100.00	74.40	6850
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4531	99.99	69.70	3181
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548P	99.98	72.25	3784

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 37)

• DXD motifs in human xylosyltransferase I are required for enzyme activity (PMID:15294915)
• Elevated XYLT1 activities in pseudoxanthoma elasticum patients is a marker of proteoglycan biosynthesis. (PMID:16133423)
• xylotransferase genes might be potential candidate genes predisposing to diabetic nephropathy in type 1 diabetic patients (PMID:16164625)
• Over 80% of the nucleotide sequence of the XT-I-cDNA is necessary for expressing a recombinant enzyme with full catalytic activity. (PMID:16225459)
• recombinant expression and cloning of active full-length xylosyltransferase I (XT-I) and characterization of subcellular localization of XT-I and XT-II (PMID:16569644)
• Variations in the XYLT-II gene are genetic co-factors in the severity of PXE. (PMID:16571645)
• Increased levels of xylosyltransferase I correlates with the formation of extracellular matrix during chondrogenic differentiation of mesenchymal stem cells. (PMID:16778156)
• The XYLT-I c.343G>T polymorphism contributes to the genetic susceptibility to development of diabetic nephropathy in type 1 diabetic patients. (PMID:17003309)
• TGF-beta(1) and mechanical stress induce xylosyltransferase I expression in cardiac fibroblasts and have impact for ECM remodeling in the dilated heart. (PMID:17635914)
• For the rate-limiting enzyme in glycosaminoglycan synthesis XT-I, maximal mRNA expression and enzyme activity were observed 10 days after osteogenic induction of mesenchymal stem cells, simultaneously to the beginning of ECM mineralization. (PMID:17980567)
• results show that XT-I polymorphisms potentially confer to the genetic susceptibility of abdominal aortic aneurysm (PMID:18294457)
• These results point to skeletal growth and tissue remodeling as a cause of the high XT activity in children (PMID:18763033)
• Data show that the xylosyltransferase I SNP is associated with a decreased glycosaminoglycan amount in the serum of healthy blood donors. (PMID:19014925)
• No statistically significant association was found between four XYLT variants and hypertension or blood pressure, suggesting that they do not play a significant role in the development of essential hypertension. (PMID:19197251)
• AP-1 Sp1 family of transcription factors are necessary for the transcriptional regulation of the XYLT1 gene. (PMID:19762916)
• Xylosyltransferase-I regulates glycosaminoglycan synthesis during the pathogenic process of human osteoarthritis (PMID:22479506)
• AP-1 and Sp3 are key regulators of IL-1beta-mediated modulation of xylosyltransferase I expression. (PMID:23223231)
• XYLT1 activity increased time-dependently in response to progressive myofibroblast transformation. (PMID:23747722)
• A family study shows that functional alterations of XYLT1 cause an autosomal recessive short stature syndrome associated with intellectual disability. (PMID:23982343)
• five distinct homozygous XYLT1 mutations may have a role in Desbuquois dysplasia type 2 (PMID:24581741)
• These results suggest that XT-1 expression is refractory to the disease process and to inhibition by inflammatory cytokines and that signaling through AP-1, Sp1, and Sp3 is important in the maintenance of XT-1 levels in NP cells. (PMID:25476526)
• Human XYLT1 promoter sequence analysis and description. (PMID:25480529)
• XYLT1 mutation is associated with short limb skeletal dysplasia. (PMID:26601923)
• Our study describes the first case of DBQD2 resulting from compound heterozygous XYLT1 mutation, expands the mutational spectrum of the disease and provides evidence that the severe growth retardation and microsomia observed in DBQD2 patients may result not only from the skeletal dysplasia itself but also from GH and IGF-1 deficiency. (PMID:27030147)
• Novel and recurrent XYLT1 mutations in two Turkish families with Desbuquois dysplasia, type 2, have been reported. (PMID:27881841)
• In conclusion, we identified two genes, DZIP1 and XYLT1, potentially associated with nonsyndromic high myopia using whole exome sequencing and subsequent mutation screening analysis. (PMID:28085539)
• Study has provided detailed mechanistic insight into the initiation of glycosaminoglycan biosynthesis by showing how the unique active-site architecture of XT1 selects particular serine residues for xylosylation. (PMID:29681470)
• Due to the decrease in XYLT1 promoter activity after Sp1 binding site mutation. (PMID:30542210)
• GGC Repeat Expansion and Exon 1 Methylation of XYLT1 Is a Common Pathogenic Variant in Baratela-Scott Syndrome (PMID:30554721)
• HEK293 cells lacking both XT-isoforms are not viable (PMID:31677793)
• Expression of xylosyltransferases I and II and their role in the pathogenesis of arthrofibrosis. (PMID:31973761)
• microRNA-145 mediates xylosyltransferase-I induction in myofibroblasts via suppression of transcription factor KLF4. (PMID:31973816)
• Activin A-Mediated Regulation of XT-I in Human Skin Fibroblasts. (PMID:32295230)
• Lysophosphatidic acid receptor 5 transactivation of TGFBR1 stimulates the mRNA expression of proteoglycan synthesizing genes XYLT1 and CHST3. (PMID:32920014)
• Development of a xylosyltransferase-I-selective UPLC MS/MS activity assay using a specific acceptor peptide. (PMID:33609631)
• Cytokine-mediated induction of human xylosyltransferase-I in systemic sclerosis skin fibroblasts. (PMID:33662666)
• SNAI1-activated long non-coding RNA LINC01711 promotes hepatic fibrosis cell proliferation and migration by regulating XYLT1. (PMID:36871637)

Cross-species orthologs

22 orthologs

Organism	Symbol	Gene ID
danio_rerio	xylt1	ENSDARG00000061248
mus_musculus	Xylt1	ENSMUSG00000030657
rattus_norvegicus	Xylt1	ENSRNOG00000056658
drosophila_melanogaster	oxt	FBGN0015360
drosophila_melanogaster	CG9164	FBGN0030634
caenorhabditis_elegans	gly-15	WBGENE00001640
caenorhabditis_elegans	gly-16	WBGENE00001641
caenorhabditis_elegans	gly-17	WBGENE00001642
caenorhabditis_elegans	gly-18	WBGENE00001643
caenorhabditis_elegans	gly-19	WBGENE00001644
caenorhabditis_elegans		WBGENE00005024
caenorhabditis_elegans		WBGENE00009148
caenorhabditis_elegans	F30A10.4	WBGENE00009263
caenorhabditis_elegans		WBGENE00011090
caenorhabditis_elegans	T09E11.6	WBGENE00011655
caenorhabditis_elegans	T09E11.9	WBGENE00011658
caenorhabditis_elegans	T27F6.1	WBGENE00012102
caenorhabditis_elegans		WBGENE00012135
caenorhabditis_elegans		WBGENE00013119
caenorhabditis_elegans	ZK1225.2	WBGENE00014236
caenorhabditis_elegans		WBGENE00019270
caenorhabditis_elegans		WBGENE00019919

Paralogs (8): XYLT2 (ENSG00000015532), WSCD2 (ENSG00000075035), GCNT2 (ENSG00000111846), GCNT7 (ENSG00000124091), GCNT3 (ENSG00000140297), GCNT4 (ENSG00000176928), WSCD1 (ENSG00000179314), GCNT1 (ENSG00000187210)

Protein

Protein identifiers

Xylosyltransferase 1 — Q86Y38 (reviewed: Q86Y38)

Alternative names: Peptide O-xylosyltransferase 1, Xylosyltransferase I

All UniProt accessions (1): Q86Y38

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the first step in the biosynthesis of chondroitin sulfate and dermatan sulfate proteoglycans, such as DCN. Transfers D-xylose from UDP-D-xylose to specific serine residues of the core protein. Required for normal embryonic and postnatal skeleton development, especially of the long bones. Required for normal maturation of chondrocytes during bone development, and normal onset of ossification.

Subunit / interactions. Monomer.

Subcellular location. Golgi apparatus membrane. Secreted.

Tissue specificity. Widely expressed. Expressed at higher level in placenta, kidney and pancreas. Weakly expressed in skeletal muscle.

Post-translational modifications. Contains 7 disulfide bonds. N-glycosylated.

Disease relevance. Desbuquois dysplasia 2 (DBQD2) [MIM:615777] A chondrodysplasia characterized by severe prenatal and postnatal growth retardation (less than -5 SD), joint laxity, short extremities, progressive scoliosis, round face, midface hypoplasia, prominent bulging eyes. The main radiologic features are short long bones with metaphyseal splay, a ‘Swedish key’ appearance of the proximal femur (exaggerated trochanter), and advance carpal and tarsal bone age. Two forms of Desbuquois dysplasia are distinguished on the basis of the presence or absence of characteristic hand anomalies: an extra ossification center distal to the second metacarpal, delta phalanx, bifid distal thumb phalanx, and phalangeal dislocations. The disease is caused by variants affecting the gene represented in this entry. Pseudoxanthoma elasticum (PXE) [MIM:264800] A multisystem disorder characterized by accumulation of mineralized and fragmented elastic fibers in the skin, vascular walls, and Burch membrane in the eye. Clinically, patients exhibit characteristic lesions of the posterior segment of the eye including peau d’orange, angioid streaks, and choroidal neovascularizations, of the skin including soft, ivory colored papules in a reticular pattern that predominantly affect the neck and large flexor surfaces, and of the cardiovascular system with peripheral and coronary arterial occlusive disease as well as gastrointestinal bleedings. The gene represented in this entry acts as a disease modifier.

Pathway. Glycan metabolism; chondroitin sulfate biosynthesis. Glycan metabolism; heparan sulfate biosynthesis.

Miscellaneous. Activity is strongly reduced in seminal plasma of infertile men.

Similarity. Belongs to the glycosyltransferase 14 family. XylT subfamily.

RefSeq proteins (1): NP_071449* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003406	Glyco_trans_14	Family
IPR024448	XylT_C	Domain
IPR043538	XYLT	Family

Pfam: PF02485, PF12529

Enzyme classification (BRENDA):

• EC 2.4.2.26 — protein xylosyltransferase (BRENDA: 8 organisms, 138 substrates, 27 inhibitors, 180 Km, 8 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
BIKUNIN	0.0006–0.0656	70
UDP-D-XYLOSE	0.0065–0.25	7
BIOTIN-NH-QEEEGSGGGQKK(5-FLUORESCEIN)-CONH2	0.0025–0.0061	3
CARTILAGE CHONDROITIN SULFATE PROTEOGLYCAN	0.11–0.19	3
HF-DEGRADED CHONDROITIN SULFATE PROTEOGLYCAN	0.0001–1.02	3
QEEEGSGGGQKK	0.0117–0.093	3
SILK FIBROIN	0.545–0.677	3
TENEGSGLTNIK	0.02–0.3905	3
BAMCAN	0.0179–0.0222	2
BFGF-PEPTIDE	0.0093–0.0137	2
FRAGMENT(1-24) OF HUMAN BASIC FIBROBLAST GROWTH	0.0208–0.0223	2
GLYPICAN-1	0.0109–0.0171	2
L-APLP2	0.0104–0.0134	2
NEUROGLYCAN C	0.0032–0.0236	2
PERLECAN-2	0.0102–0.0145	2

Catalyzed reactions (Rhea), 1 shown:

• UDP-alpha-D-xylose + L-seryl-[protein] = 3-O-(beta-D-xylosyl)-L-seryl-[protein] + UDP + H(+) (RHEA:50192)

UniProt features (132 total): mutagenesis site 32, strand 31, helix 26, sequence variant 9, turn 8, binding site 6, disulfide bond 6, compositionally biased region 5, glycosylation site 3, topological domain 2, region of interest 2, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
6FOA	X-RAY DIFFRACTION	1.87
6EJA	X-RAY DIFFRACTION	1.94
6EJ7	X-RAY DIFFRACTION	2
6EJ9	X-RAY DIFFRACTION	2.02
6EJC	X-RAY DIFFRACTION	2.06
6EJ8	X-RAY DIFFRACTION	2.09
6EJE	X-RAY DIFFRACTION	2.43
6EJB	X-RAY DIFFRACTION	2.56
6EJD	X-RAY DIFFRACTION	2.68

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86Y38-F1	82.43	0.71

Functional residue map

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

Ligand- & substrate-binding residues (6): 333; 361; 390–392; 494–495; 575; 598–599

Disulfide bonds (6): 257–285, 301–542, 561–574, 563–572, 675–927, 920–933

Glycosylation sites (3): 226, 421, 777

Mutagenesis-validated functional residues (32):

Position	Phenotype
257	no effect.
276	strongly reduced enzyme activity.
285	no effect.
301	no effect.
314	no effect.
316	no effect.
462	no effect on enzyme activity.
462	decreased enzyme activity.
471	strongly reduced enzyme activity.
494	decreased enzyme activity.
494	loss of enzyme activity.
529	loss of enzyme activity.
542	no effect.
557	no effect on enzyme activity.
561	strongly reduced enzyme activity.
562–572	loss of enzyme activity.
563	no effect.
572	strongly reduced enzyme activity.
574	strongly reduced enzyme activity.
598	strongly decreased enzyme activity; when associated with a-599.
599	decreased enzyme activity. strongly decreased enzyme activity; when associated with a-598.
675	no effect.
745	no effect.
745	abolishes enzyme activity but does not affect udp-binding.
746	strongly reduced enzyme activity but does not affect udp-binding.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1971475	Glycosaminoglycan-protein linkage region biosynthesis

MSigDB gene sets: 518 (showing top): VERHAAK_AML_WITH_NPM1_MUTATED_DN, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, BENPORATH_ES_WITH_H3K27ME3, MYOGENIN_Q6, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, LFA1_Q6, GOBP_EMBRYONIC_SKELETAL_SYSTEM_DEVELOPMENT, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, TGACCTY_ERR1_Q2, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_AMINOGLYCAN_BIOSYNTHETIC_PROCESS, GOBP_CHONDROITIN_SULFATE_PROTEOGLYCAN_BIOSYNTHETIC_PROCESS, BROWNE_HCMV_INFECTION_48HR_DN, GOBP_ANATOMICAL_STRUCTURE_MATURATION, GOBP_BONE_DEVELOPMENT

GO Biological Process (9): glycosaminoglycan biosynthetic process (GO:0006024), heparan sulfate proteoglycan biosynthetic process (GO:0015012), proteoglycan biosynthetic process (GO:0030166), ossification involved in bone maturation (GO:0043931), embryonic skeletal system development (GO:0048706), chondroitin sulfate proteoglycan biosynthetic process (GO:0050650), glycosaminoglycan-protein linkage region biosynthetic process (GO:0120532), glycoprotein biosynthetic process (GO:0009101), glycosaminoglycan metabolic process (GO:0030203)

GO Molecular Function (5): protein xylosyltransferase activity (GO:0030158), metal ion binding (GO:0046872), UDP-glycosyltransferase activity (GO:0008194), transferase activity (GO:0016740), glycosyltransferase activity (GO:0016757)

GO Cellular Component (6): Golgi cis cisterna (GO:0000137), Golgi membrane (GO:0000139), obsolete extracellular space (GO:0005615), Golgi apparatus (GO:0005794), extracellular region (GO:0005576), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Glycosaminoglycan metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein O-linked glycosylation via xylose	3
proteoglycan biosynthetic process	2
cellular anatomical structure	2
aminoglycan biosynthetic process	1
glycosaminoglycan metabolic process	1
heparan sulfate proteoglycan metabolic process	1
proteoglycan metabolic process	1
glycoprotein biosynthetic process	1
ossification	1
bone maturation	1
skeletal system development	1
chordate embryonic development	1
chondroitin sulfate proteoglycan metabolic process	1
heparan sulfate proteoglycan biosynthetic process	1
heparin proteoglycan biosynthetic process	1
chondroitin sulfate proteoglycan biosynthetic process	1
dermatan sulfate proteoglycan biosynthetic process	1
macromolecule biosynthetic process	1
glycoprotein metabolic process	1
carbohydrate derivative biosynthetic process	1
aminoglycan metabolic process	1
UDP-xylosyltransferase activity	1
catalytic activity, acting on a protein	1
cation binding	1
glycosyltransferase activity	1
catalytic activity	1
transferase activity	1
Golgi cisterna	1
Golgi apparatus	1
bounding membrane of organelle	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

676 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
XYLT1	NOMO3	P69849	918
XYLT1	ABCC6	P78420	851
XYLT1	B3GALT6	Q96L58	804
XYLT1	NOMO2	Q5JPE7	801
XYLT1	B4GALT7	Q9UBV7	797
XYLT1	B3GAT3	O94766	782
XYLT1	FAM20B	O75063	751
XYLT1	CANT1	Q8WVQ1	686
XYLT1	EXTL2	Q9UBQ6	669
XYLT1	EXTL3	O43909	650
XYLT1	UXS1	Q8NBZ7	649
XYLT1	SLC6A20	Q9NP91	644
XYLT1	CHSY1	Q86X52	633
XYLT1	CHST11	Q9NPF2	633
XYLT1	CSGALNACT1	Q8TDX6	632

IntAct

6 interactions, top by confidence:

A	B	Type	Score
ADH1C	ADH1B	psi-mi:“MI:0914”(association)	0.560
MEF2A	REV3L	psi-mi:“MI:0914”(association)	0.350
MYC	PDZD2	psi-mi:“MI:0914”(association)	0.350
MYC		psi-mi:“MI:0914”(association)	0.350
XYLT1	ANKRD17	psi-mi:“MI:0914”(association)	0.350

BioGRID (22): XYLT1 (Affinity Capture-MS), XYLT1 (Affinity Capture-MS), XYLT1 (Affinity Capture-MS), XYLT1 (Affinity Capture-RNA), NELFCD (Affinity Capture-MS), ARFIP2 (Affinity Capture-MS), NELFE (Affinity Capture-MS), USP24 (Affinity Capture-MS), FAM114A2 (Affinity Capture-MS), NELFA (Affinity Capture-MS), NELFB (Affinity Capture-MS), CDK5RAP3 (Affinity Capture-MS), ANKRD17 (Affinity Capture-MS), XYLT1 (Affinity Capture-MS), XYLT2 (Negative Genetic)

ESM2 similar proteins: A0A8C2LVE3, A0MGZ5, A0MGZ7, A4IID1, F6PTN1, O08889, O60243, O93336, P0DJQ9, P25722, P69478, P79282, P79948, Q56UJ5, Q5NVB3, Q5QQ57, Q5R621, Q5RBC3, Q659X0, Q6EV76, Q6EV77, Q6GQI7, Q6GQK9, Q6KFX9, Q6NVP8, Q76KB1, Q76KB2, Q7LFX5, Q7LGA3, Q7T3S3, Q800H9, Q80UW0, Q86Y38, Q8CHI9, Q8IZP7, Q8JHF2, Q8R3H7, Q8TDX6, Q91XQ5, Q91ZB4

Diamond homologs: Q5QQ49, Q5QQ50, Q5QQ51, Q5QQ52, Q5QQ53, Q5QQ54, Q5QQ55, Q5QQ56, Q5QQ57, Q7KVA1, Q811B1, Q86Y38, Q965Q8, Q9EPI0, Q9EPI1, Q9EPL0, Q9H1B5, A2BGL3, Q0IIY2, Q2TBF2, Q505J3, Q658N2, Q80XH4, D4AUF4, D4PHA7, E9Q649, P54867, P84675, Q8NCW0, Q8S8P3, Q9P109, Q1M0V6, Q7YQE1, Q80RC7, Q866Z4, Q866Z5, A0A1U9VX91, D4AUF1, P83097, Q8N0V5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	18
Likely pathogenic	3
Uncertain significance	238
Likely benign	179
Benign	51

Top pathogenic / likely-pathogenic (21)

Variant ID	HGVS	Classification
1073304	NC_000016.9:g.(?17564281)(17564653_?)del	Pathogenic
127234	NM_022166.4(XYLT1):c.1441C>T (p.Arg481Trp)	Pathogenic
127237	NM_022166.4(XYLT1):c.276dup (p.Pro93fs)	Pathogenic
127239	NM_022166.4(XYLT1):c.1290-2A>C	Pathogenic
1977942	NM_022166.4(XYLT1):c.2462G>A (p.Trp821Ter)	Pathogenic
2137795	NM_022166.4(XYLT1):c.2026C>T (p.Arg676Ter)	Pathogenic
2734363	NM_022166.4(XYLT1):c.-110_280del (p.Met1_Gln94del)	Pathogenic
2794457	NM_022166.4(XYLT1):c.1510G>T (p.Glu504Ter)	Pathogenic
280402	NM_022166.4(XYLT1):c.62del (p.Ala21fs)	Pathogenic
3243529	NC_000016.9:g.(?17292049)(17451927_?)del	Pathogenic
3339666	NM_022166.4(XYLT1):c.1108C>T (p.Gln370Ter)	Pathogenic
4279342	GRCh37/hg19 16p12.3(chr16:17320825-17570897)x1	Pathogenic
4715309	NM_022166.4(XYLT1):c.1245del (p.Trp416fs)	Pathogenic
619181	NM_022166.4(XYLT1):c.319G>T (p.Gly107Ter)	Pathogenic
619182	NW_019805500.1:g.472169CCG[(100-833)]	Pathogenic
619183	NM_022166.4(XYLT1):c.281_306del (p.Gln94fs)	Pathogenic
619184	NM_022166.4(XYLT1):c.1290-1G>A	Pathogenic
958408	NM_022166.4(XYLT1):c.1321C>T (p.Arg441Ter)	Pathogenic
3384002	NM_022166.4(XYLT1):c.2169dup (p.Val724fs)	Likely pathogenic
4690451	NM_022166.4(XYLT1):c.402+1G>T	Likely pathogenic
521275	NM_022166.4(XYLT1):c.2560G>T (p.Glu854Ter)	Likely pathogenic

SpliceAI

4610 predictions. Top by Δscore:

Variant	Effect	Δscore
16:17134743:C:CT	acceptor_gain	1.0000
16:17134744:A:C	acceptor_gain	1.0000
16:17134750:T:TC	acceptor_gain	1.0000
16:17138349:TCTCA:T	donor_loss	1.0000
16:17138350:CTCA:C	donor_loss	1.0000
16:17138351:TCA:T	donor_loss	1.0000
16:17138352:CA:C	donor_loss	1.0000
16:17138353:A:AC	donor_gain	1.0000
16:17138353:ACCTG:A	donor_loss	1.0000
16:17138354:C:A	donor_loss	1.0000
16:17138354:C:CC	donor_gain	1.0000
16:17138527:AAGGA:A	acceptor_gain	1.0000
16:17138528:AGGA:A	acceptor_gain	1.0000
16:17138529:GGA:G	acceptor_gain	1.0000
16:17138529:GGAC:G	acceptor_loss	1.0000
16:17138530:GA:G	acceptor_gain	1.0000
16:17138531:AC:A	acceptor_loss	1.0000
16:17138532:C:CC	acceptor_gain	1.0000
16:17138532:CTG:C	acceptor_loss	1.0000
16:17138533:T:G	acceptor_loss	1.0000
16:17141149:TCA:T	donor_loss	1.0000
16:17141150:CA:C	donor_loss	1.0000
16:17141151:A:AC	donor_gain	1.0000
16:17141151:AC:A	donor_gain	1.0000
16:17141151:ACCT:A	donor_gain	1.0000
16:17141152:C:CT	donor_gain	1.0000
16:17141152:CC:C	donor_gain	1.0000
16:17141152:CCT:C	donor_gain	1.0000
16:17141152:CCTC:C	donor_gain	1.0000
16:17141152:CCTCA:C	donor_gain	1.0000

AlphaMissense

6275 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:17117889:A:G	W772R	1.000
16:17117889:A:T	W772R	1.000
16:17117956:C:A	K749N	1.000
16:17117956:C:G	K749N	1.000
16:17134703:C:A	K599N	1.000
16:17134703:C:G	K599N	1.000
16:17134705:T:C	K599E	1.000
16:17134708:G:T	R598S	1.000
16:17134710:G:T	A597D	1.000
16:17138392:G:A	P576L	1.000
16:17138392:G:C	P576R	1.000
16:17138392:G:T	P576H	1.000
16:17138393:G:A	P576S	1.000
16:17138393:G:T	P576T	1.000
16:17138397:G:C	C574W	1.000
16:17138398:C:A	C574F	1.000
16:17138398:C:G	C574S	1.000
16:17138398:C:T	C574Y	1.000
16:17138399:A:G	C574R	1.000
16:17138399:A:T	C574S	1.000
16:17138401:C:A	G573V	1.000
16:17138401:C:T	G573D	1.000
16:17138402:C:A	G573C	1.000
16:17138402:C:G	G573R	1.000
16:17138403:G:C	C572W	1.000
16:17138404:C:A	C572F	1.000
16:17138404:C:G	C572S	1.000
16:17138404:C:T	C572Y	1.000
16:17138405:A:G	C572R	1.000
16:17138405:A:T	C572S	1.000

dbSNP variants (sampled 300 via entrez): RS1000001923 (16:17388364 C>A,G,T), RS1000005321 (16:17394285 G>A), RS1000022733 (16:17137836 T>C), RS1000032533 (16:17384548 T>A,C), RS1000032766 (16:17188805 T>C), RS1000033596 (16:17150340 G>A), RS1000039369 (16:17435600 T>C), RS1000043429 (16:17398492 C>T), RS1000044531 (16:17326272 C>G), RS1000068720 (16:17262846 C>A,T), RS1000088703 (16:17232033 C>T), RS1000089167 (16:17291478 T>C), RS1000090776 (16:17268525 T>G), RS1000108042 (16:17113301 C>G), RS1000117623 (16:17250304 T>G)

Disease associations

OMIM: gene MIM:608124 | disease phenotypes: MIM:251450, MIM:615777, MIM:264800

GenCC curated gene-disease

Disease	Classification	Inheritance
Desbuquois dysplasia 2	Strong	Autosomal recessive
Desbuquois dysplasia	Supportive	Autosomal recessive
XYLT1-congenital disorder of glycosylation	Supportive	Autosomal recessive

Mondo (5): Desbuquois dysplasia 1 (MONDO:0009629), Desbuquois dysplasia 2 (MONDO:0014343), autosomal recessive inherited pseudoxanthoma elasticum (MONDO:0009925), Desbuquois dysplasia (MONDO:0015426), XYLT1-congenital disorder of glycosylation (MONDO:0018273)

Orphanet (2): Desbuquois syndrome (Orphanet:1425), Pseudoxanthoma elasticum (Orphanet:758)

HPO phenotypes

118 total (30 of 118 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000175	Cleft palate
HP:0000193	Bifid uvula
HP:0000252	Microcephaly
HP:0000280	Coarse facial features
HP:0000286	Epicanthus
HP:0000311	Round face
HP:0000343	Long philtrum
HP:0000358	Posteriorly rotated ears
HP:0000463	Anteverted nares
HP:0000470	Short neck
HP:0000499	Abnormal eyelash morphology
HP:0000501	Glaucoma
HP:0000505	Visual impairment
HP:0000520	Proptosis
HP:0000545	Myopia
HP:0000573	Retinal hemorrhage
HP:0000592	Blue sclerae
HP:0000608	Macular degeneration
HP:0000664	Synophrys
HP:0000668	Hypodontia
HP:0000678	Dental crowding
HP:0000750	Delayed speech and language development
HP:0000767	Pectus excavatum
HP:0000768	Pectus carinatum
HP:0000774	Narrow chest
HP:0000822	Hypertension
HP:0000885	Broad ribs
HP:0000894	Short clavicles
HP:0000926	Platyspondyly

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST001819_5	Corneal astigmatism	2.000000e-06
GCST003648_1	Pathological gambling	7.000000e-06
GCST004863_72	Mosquito bite size	6.000000e-06
GCST006868_11	Type 2 diabetes	5.000000e-09
GCST006956_13	Erectile dysfunction	9.000000e-06
GCST007277_22	Tourette syndrome	9.000000e-06
GCST007326_19	Number of sexual partners	3.000000e-08
GCST008163_469	Height	5.000000e-07
GCST008760_8	Perceived sweetness of sucrose	9.000000e-06
GCST011703_23	Smoking initiation	5.000000e-08
GCST012051_6	Systolic blood pressure	6.000000e-07
GCST012616_14	Spondylosis	5.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0008378	mosquito bite reaction size measurement
EFO:0005670	smoking initiation
EFO:0006335	systolic blood pressure

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D011561	Pseudoxanthoma Elasticum	C14.907.454.530; C15.378.463.515.530; C16.131.831.766; C16.320.850.750; C17.300.766; C17.800.804.766; C17.800.827.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects cotreatment, decreases expression	5
trichostatin A	affects cotreatment, decreases expression, increases expression	3
sodium arsenite	increases abundance, decreases expression, affects cotreatment	2
bisphenol S	decreases methylation, increases expression	2
Vorinostat	affects cotreatment, decreases expression	2
Arsenic	affects methylation, affects cotreatment, decreases expression, increases abundance	2
Cisplatin	affects cotreatment, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tobacco Smoke Pollution	decreases expression, decreases methylation	2
Tretinoin	decreases expression, increases expression	2
2,4,6-tribromophenol	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
testosterone undecanoate	affects cotreatment, decreases expression	1
decabromobiphenyl ether	decreases expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1
tetrabromobisphenol A	decreases expression	1
perfluorooctanoic acid	increases expression	1
manganese chloride	increases abundance, affects cotreatment, decreases expression	1
cyanoginosin LR	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
Poly(amidoamine)	decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05832580	PHASE3	RECRUITING	The Prevention of Systemic Ectopic Mineralization in Pseudoxanthoma Elasticum
NCT01525875	PHASE2	COMPLETED	Magnesium Supplements In The Treatment Of Pseudoxanthoma Elasticum (PXE)
NCT02537054	PHASE2	COMPLETED	Intravitreal Aflibercept for Therapy of Patients With Pseudoxanthoma Elasticum (PXE)
NCT04441671	PHASE2	WITHDRAWN	Oral Pyrophosphate Absorption in PXE Disease
NCT05569252	PHASE2	COMPLETED	A Study of DS-1211b in Individuals With PseudoXanthoma Elasticum
NCT06462547	PHASE2	RECRUITING	ADAPT Study: Long-term Safety Study of INZ-701 in Patients With ENPP1 Deficiency and ABCC6 Deficiency
NCT05734196	PHASE1	RECRUITING	The ENERGY Study: Evaluation of Safety and Tolerability of INZ-701 in Infants With ENPP1 Deficiency or ABCC6 Deficiency
NCT00470977	PHASE1/PHASE2	COMPLETED	Treatment of Exudative and Vasogenic Chorioretinal Diseases Including Variants of AMD and Other CNV Related Maculopathy
NCT05030831	PHASE1/PHASE2	COMPLETED	Evaluation of Safety, Tolerability, and Efficacy of INZ-701 in Adults With ABCC6 Deficiency Causing PXE
NCT00341419	Not specified	COMPLETED	Genetic Analysis of Patients With Pseudoxanthoma Elasticum
NCT00555113	Not specified	COMPLETED	Evolution of Visual Impairment During Pseudoxanthoma Elasticum
NCT01446380	Not specified	UNKNOWN	Phenotypic Expressions in a French Pseudoxanthoma-Elasticum Cohort
NCT01446393	Not specified	COMPLETED	Functional and Structural Characterization of Arteriopathy in Pseudoxanthoma Elasticum (PXE)
NCT01731080	Not specified	UNKNOWN	Arterial Wall Calcium Load in Pseudoxanthoma Elasticum
NCT02108392	Not specified	UNKNOWN	Characterization of Pseudoxanthoma Elasticum
NCT03070860	Not specified	COMPLETED	What’s Happen Under the Calcification Process in Pseudoxanthoma Elasticum
NCT03364504	Not specified	UNKNOWN	Biological Collection of Kidney Cells
NCT03758534	Not specified	UNKNOWN	Natural History of GACI With or Without ARHR2 or PXE
NCT03813550	Not specified	UNKNOWN	Intestinal Microbiota and Vitamin K Levels in PXE Patients (IMPROVE Study)
NCT04868578	Not specified	RECRUITING	PPI Supplementation to Fight ECtopIc Calcification in PXE
NCT05025722	Not specified	COMPLETED	Pseudoxanthoma Elasticum (PXE) Natural History Biomarkers in PXE Individuals and Their Biological Non-PXE Siblings
NCT05246189	Not specified	COMPLETED	Employment of Patients With Pseudoxanthoma Elasticum
NCT05662085	Not specified	ACTIVE_NOT_RECRUITING	Progression Rate of Pseudoxanthoma Elasticum-associated Choroidal and Retinal Degeneration
NCT06636344	Not specified	RECRUITING	Impact of Optimized Recruitment and Follow-up of Patients With Pseudoxanthoma Elasticum (PXE)
NCT07006649	Not specified	RECRUITING	CHOPXE - Analysis of Choriocapillaris Flow Deficits in Patients With Pseudoxanthoma Elasticum
NCT07048106	Not specified	RECRUITING	Progression Assessment of PXE-associated Alterations
NCT07323082	Not specified	RECRUITING	Purinergic Compounds in Pseudoxanthoma Elasticum