XDH

protein-coding

xanthine dehydrogenase

Gene summary

Xanthine dehydrogenase belongs to the group of molybdenum-containing hydroxylases involved in the oxidative metabolism of purines. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. Xanthine dehydrogenase can be converted to xanthine oxidase by reversible sulfhydryl oxidation or by irreversible proteolytic modification. Defects in xanthine dehydrogenase cause xanthinuria, may contribute to adult respiratory stress syndrome, and may potentiate influenza infection through an oxygen metabolite-dependent mechanism. [provided by RefSeq, Jan 2014]

MANE transcript

NM_000379.4

Inheritance

ClinVar variants

P:58U:465B:190

Top phenotype

Xanthinuria, type I

gnomAD constraint

pLI —, LoF o/e 0.67

Max pathogenic AF

—

Genomic locus

chr2:31,334,321-31,414,742

External References & Databases

Ensembl (ENSG00000158125)

Transcript & Mutation Effects

hg38 • Region Span ~80.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

xanthinuria type ISTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010209

Submitter: PanelApp Australia

xanthinuria type ISUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010209

Submitter: Orphanet

xanthinuria type IMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0010209

Submitter: Ambry Genetics

xanthinuria type ISTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010209

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Xanthinuria, type IAR

Manifestation: Biochemical; Musculoskeletal; Renal

Intervention: Biochemical; Renal

Rationale: Dietary measures (eg, purine restricted, increased fluid intake) and medical measures (eg, allopurinol) can be effective

Refs: 13118765; 861350; 3818951; 3339736; 754557; 9767921; 9153281

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to XDH variants in ClinVar

6 Conditions Cataloged

Xanthinuria type IITotal: 525

Hereditary xanthinuria type 1Total: 390

Inborn genetic diseasesTotal: 172

not providedTotal: 105

XDH-related disorderTotal: 76

not specifiedTotal: 52

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000379.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			21 clinvar	143 clinvar	3 clinvar	167
missense		2 clinvar	438 clinvar	41 clinvar	3 clinvar	484
nonsense	5 clinvar	11 clinvar				16
start loss						0
frameshift	11 clinvar	9 clinvar	2 clinvar			22
splice donor/acceptor (+/-2bp)	1 clinvar	19 clinvar	4 clinvar			24
Total	17	41	465	184	6	713

Highest pathogenic variant AF is 0.00092517544

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 23 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000379.4	RefSeq	NP_000370.2	36	MANE Select
ENST00000379416.4	Ensembl	ENSP00000368727.3	36	MANE Select
ENST00000879520.1	Ensembl	ENSP00000549579.1	36	Standard
ENST00000879520.2	Ensembl	ENSP00000549579.1	36	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Doxorubicin Pathway (Cancer Cell), Pharmacodynamics
Peroxisome - Homo sapiens (human)
Drug metabolism - other enzymes - Homo sapiens (human)
Doxorubicin Pathway, Pharmacokinetics
Caffeine metabolism - Homo sapiens (human)

Biological Process

negative regulation of protein phosphorylation
negative regulation of endothelial cell proliferation
purine nucleotide catabolic process
activation of cysteine-type endopeptidase activity involved in apoptotic process
lactation

Molecular Function

xanthine dehydrogenase activity
xanthine oxidase activity
iron ion binding
electron transfer activity
protein homodimerization activity

Cellular Component

extracellular space
peroxisome
cytosol
sarcoplasmic reticulum

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000379416
Coding exons: 36
Length: 80395
Individuals with no LoFs: 125419
Homozygous LoFs: 1
Heterozygous LoFs: 328
Defined: 125748
p: 0.00131

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.45	839	729	1.15	0.0000434	8729
Missense (PolyPhen)		317	281.44	1.1263		3371
Synonymous	-2.25	329	281	1.17	0.0000172	2639
Loss of Function	2.52	45	67.3	0.668	0.00000350	841

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00062	0.00062	rare
Latino/Admixed American	0.0014	0.0014	notable
Ashkenazi Jewish	0.00079	0.00079	rare
East Asian	0.00071	0.00071	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.0017	0.0017	notable
South Asian	0.0016	0.0016	notable
Other	0.00098	0.00098	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Key enzyme in purine degradation. Catalyzes the oxidation of hypoxanthine to xanthine. Catalyzes the oxidation of xanthine to uric acid. Contributes to the generation of reactive oxygen species. Has also low oxidase activity towards aldehydes (in vitro). {ECO:0000269|PubMed:17301077}.;
Disease: DISEASE: Xanthinuria 1 (XAN1) [MIM:278300]: A disorder characterized by excretion of very large amounts of xanthine in the urine and a tendency to form xanthine stones. Uric acid is strikingly diminished in serum and urine. XAN1 is due to isolated xanthine dehydrogenase deficiency. Patients can metabolize allopurinol. {ECO:0000269|PubMed:10844591, ECO:0000269|PubMed:11379872, ECO:0000269|PubMed:14551354, ECO:0000269|PubMed:9153281}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0937

Intolerance Scores

LoFtool: 0.922
RVIS EVS: 1.29
RVIS percentile EVS: 93.81

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.901

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium