xanthinuria type I

Summary

xanthinuria type I (MONDO:0010209) is a disease caused by XDH (GenCC Strong), with 4 cohort genes.

At a glance

• Causal gene: XDH (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 453

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	xanthinuria type I
Mondo ID	MONDO:0010209
MeSH	C562584
OMIM	278300
Orphanet	93601
DOID	DOID:0070452
SNOMED CT	72682008
UMLS	C0268118
MedGen	82771
GARD	0005621
Is cancer (heuristic)	no

Also known as: isolated xanthine oxidase deficiency · type 1 xanthinuria · XAN1 · xanthine dehydrogenase deficiency · xanthine oxidase deficiency · xanthine oxidoreductase deficiency · xanthinuria type 1 · xanthinuria type I · xanthinuria, type 1 · xanthinuria, type I · XDH deficiency · XO deficiency · XOR deficiency

Data availability: 453 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › xanthinuria › hereditary xanthinuria › xanthinuria type I

Related subtypes (1): xanthinuria type II

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

453 retrieved; paginated sample, class counts are floors:

296 uncertain significance, 49 conflicting classifications of pathogenicity, 28 likely pathogenic, 27 benign/likely benign, 23 likely benign, 19 benign, 8 pathogenic, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1027672	NM_000379.4(XDH):c.2751del (p.Gln919fs)	XDH	Pathogenic	criteria provided, single submitter
1369362	NM_000379.4(XDH):c.2164A>T (p.Lys722Ter)	XDH	Pathogenic	criteria provided, multiple submitters, no conflicts
1457782	NM_000379.4(XDH):c.641del (p.Pro214fs)	XDH	Pathogenic	criteria provided, multiple submitters, no conflicts
2415430	NM_000379.4(XDH):c.751C>T (p.Gln251Ter)	XDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2731116	NM_000379.4(XDH):c.2473C>T (p.Arg825Ter)	XDH	Pathogenic	criteria provided, multiple submitters, no conflicts
2954	NM_000379.4(XDH):c.682C>T (p.Arg228Ter)	XDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2955	NM_000379.4(XDH):c.2567del (p.Thr856fs)	XDH	Pathogenic	no assertion criteria provided
3586448	NM_000379.4(XDH):c.2890dup (p.Thr964fs)	XDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
579351	NM_000379.4(XDH):c.2274del (p.Glu760fs)	XDH	Pathogenic	criteria provided, multiple submitters, no conflicts
635517	NM_000379.4(XDH):c.3520-1G>C	XDH	Pathogenic	no assertion criteria provided
641114	NM_000379.4(XDH):c.140dup (p.Cys48fs)	XDH	Pathogenic	criteria provided, multiple submitters, no conflicts
812692	NM_000145.4(FSHR):c.1121T>A (p.Ile374Asn)	FSHR	Likely pathogenic	criteria provided, single submitter
2446438	Single allele	SRD5A2	Likely pathogenic	no assertion criteria provided
1179049	NM_000379.4(XDH):c.2198-2A>C	XDH	Likely pathogenic	criteria provided, single submitter
2145159	NM_000379.4(XDH):c.565-1G>A	XDH	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2585395	NM_000379.4(XDH):c.3352-2A>G	XDH	Likely pathogenic	criteria provided, single submitter
2956	NM_000379.4(XDH):c.445C>T (p.Arg149Cys)	XDH	Likely pathogenic	criteria provided, single submitter
3064756	NM_000379.4(XDH):c.793+1G>A	XDH	Likely pathogenic	criteria provided, single submitter
3234992	NM_000379.4(XDH):c.676C>T (p.Gln226Ter)	XDH	Likely pathogenic	criteria provided, single submitter
3236186	NM_000379.4(XDH):c.849G>A (p.Trp283Ter)	XDH	Likely pathogenic	criteria provided, single submitter
3586414	NM_000379.4(XDH):c.3853C>T (p.Gln1285Ter)	XDH	Likely pathogenic	criteria provided, single submitter
3586417	NM_000379.4(XDH):c.3774+2T>A	XDH	Likely pathogenic	criteria provided, single submitter
3586438	NM_000379.4(XDH):c.3331_3333delinsCTGGGAA (p.Ser1111fs)	XDH	Likely pathogenic	criteria provided, single submitter
3586459	NM_000379.4(XDH):c.2631+1G>A	XDH	Likely pathogenic	criteria provided, single submitter
3586462	NM_000379.4(XDH):c.2581G>T (p.Glu861Ter)	XDH	Likely pathogenic	criteria provided, single submitter
3586470	NM_000379.4(XDH):c.2371C>T (p.Arg791Ter)	XDH	Likely pathogenic	criteria provided, single submitter
3586479	NM_000379.4(XDH):c.2044dup (p.Ala682fs)	XDH	Likely pathogenic	criteria provided, single submitter
3586484	NM_000379.4(XDH):c.1885del (p.Val629fs)	XDH	Likely pathogenic	criteria provided, single submitter
3586513	NM_000379.4(XDH):c.1242_1242+6del	XDH	Likely pathogenic	criteria provided, single submitter
3586520	NM_000379.4(XDH):c.1039-1G>C	XDH	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 6 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
SORD	Strong	Autosomal recessive	xanthinuria type I	8
XDH	Strong	Autosomal recessive	xanthinuria type I	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SORD	Orphanet:700508	Distal muscle weakness-foot deformity-elevated sorbitol level-hereditary motor neuropathy
XDH	Orphanet:93601	Xanthinuria type I
SRD5A2	Orphanet:1331	Familial prostate cancer
SRD5A2	Orphanet:753	46,XY difference of sex development due to 5-alpha-reductase 2 deficiency
FSHR	Orphanet:243	46,XX gonadal dysgenesis
FSHR	Orphanet:64739	Ovarian hyperstimulation syndrome

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SORD	HGNC:11184	ENSG00000140263	Q00796	Sorbitol dehydrogenase	gencc,clinvar
XDH	HGNC:12805	ENSG00000158125	P47989	Xanthine dehydrogenase/oxidase	gencc,clinvar
SRD5A2	HGNC:11285	ENSG00000277893	P31213	3-oxo-5-alpha-steroid 4-dehydrogenase 2	clinvar
FSHR	HGNC:3969	ENSG00000170820	P23945	Follicle-stimulating hormone receptor	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SORD	Sorbitol dehydrogenase	Polyol dehydrogenase that catalyzes the reversible NAD(+)-dependent oxidation of various sugar alcohols.
XDH	Xanthine dehydrogenase/oxidase	Key enzyme in purine degradation.
SRD5A2	3-oxo-5-alpha-steroid 4-dehydrogenase 2	Converts testosterone (T) into 5-alpha-dihydrotestosterone (DHT) and progesterone or corticosterone into their corresponding 5-alpha-3-oxosteroids.
FSHR	Follicle-stimulating hormone receptor	G protein-coupled receptor for follitropin, the follicle-stimulating hormone.

Protein-family classification

Druggable: 4 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	3	9.0×	0.004
GPCR	1	6.0×	0.157

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SORD	Enzyme (other)	yes	1.1.1.14	ADH_Zn_CS, GroES-like_sf, ADH-like_C
XDH	Enzyme (other)	yes	1.17.1.4	Ald_Oxase/Xan_DH_a/b, 2Fe-2S_ferredoxin-type, Mopterin_DH_FAD-bd
SRD5A2	Enzyme (other)	yes	1.3.1.22	3-oxo-5_a-steroid_4-DH_C, 3-oxo-5-alpha-steroid_4-DH, SRD5A/TECR
FSHR	GPCR	yes		GPCR_Rhodpsn, LRRNT, Gphrmn_rcpt_fam

Expression context

Cohort genes with no expression data: 0.

4 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left lobe of thyroid gland	1
right lobe of thyroid gland	1
thyroid gland	1
ileal mucosa	1
jejunal mucosa	1
palpebral conjunctiva	1
bronchial epithelial cell	1
corpus epididymis	1
epithelium of bronchus	1
apex of heart	1
lower esophagus mucosa	1
male germ line stem cell (sensu Vertebrata) in testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SORD	199	ubiquitous	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
XDH	169	broad	marker	jejunal mucosa, ileal mucosa, palpebral conjunctiva
SRD5A2	66	tissue_specific	marker	corpus epididymis, bronchial epithelial cell, epithelium of bronchus
FSHR	98	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, lower esophagus mucosa, apex of heart

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SORD	3,915
XDH	2,141
FSHR	1,667
SRD5A2	1,103

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FSHR	P23945	5
SORD	Q00796	3
XDH	P47989	2
SRD5A2	P31213	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 4 evidence-associated genes (4 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Fructose biosynthesis	1	713.8×	0.009	SORD
Formation of xylulose-5-phosphate	1	475.8×	0.009	SORD
Androgen biosynthesis	1	259.6×	0.009	SRD5A2
Purine catabolism	1	259.6×	0.009	XDH
Hormone ligand-binding receptors	1	237.9×	0.009	FSHR
Butyrophilin (BTN) family interactions	1	219.6×	0.009	XDH
Metabolism of steroid hormones	1	129.8×	0.012	SRD5A2
Azathioprine ADME	1	124.1×	0.012	XDH
Metabolism of steroids	1	34.4×	0.038	SRD5A2
G alpha (s) signalling events	1	18.3×	0.064	FSHR
Metabolism of lipids	1	7.9×	0.132	SRD5A2
Metabolism	1	2.9×	0.302	SRD5A2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
hypoxanthine catabolic process	1	4213.0×	0.002	XDH
xanthine catabolic process	1	4213.0×	0.002	XDH
phthalate metabolic process	1	4213.0×	0.002	SRD5A2
regulation of acetylcholine metabolic process	1	4213.0×	0.002	FSHR
primary ovarian follicle growth	1	2106.5×	0.002	FSHR
D-sorbitol catabolic process	1	2106.5×	0.002	SORD
guanine catabolic process	1	2106.5×	0.002	XDH
inosine catabolic process	1	2106.5×	0.002	XDH
deoxyinosine catabolic process	1	2106.5×	0.002	XDH
deoxyguanosine catabolic process	1	2106.5×	0.002	XDH
regulation of platelet-derived growth factor receptor signaling pathway	1	2106.5×	0.002	FSHR
biphenyl metabolic process	1	2106.5×	0.002	SRD5A2
dibenzo-p-dioxin metabolic process	1	2106.5×	0.002	SRD5A2
xylitol catabolic process	1	2106.5×	0.002	SORD
xylitol metabolic process	1	2106.5×	0.002	SORD
male gonad development	2	78.0×	0.002	SRD5A2, FSHR
deoxyadenosine catabolic process	1	1404.3×	0.003	XDH
follicle-stimulating hormone signaling pathway	1	1404.3×	0.003	FSHR
GMP catabolic process	1	1404.3×	0.003	XDH
response to biphenyl	1	1404.3×	0.003	SRD5A2
adenosine catabolic process	1	1053.2×	0.003	XDH
obsolete regulation of protein kinase A signaling	1	1053.2×	0.003	FSHR
response to follicle-stimulating hormone	1	1053.2×	0.003	SRD5A2
dAMP catabolic process	1	1053.2×	0.003	XDH
fructose biosynthetic process	1	1053.2×	0.003	SORD
IMP catabolic process	1	842.6×	0.003	XDH
regulation of hormone metabolic process	1	842.6×	0.003	FSHR
obsolete D-glucuronate catabolic process to D-xylulose 5-phosphate	1	702.2×	0.004	SORD
dGMP catabolic process	1	702.2×	0.004	XDH
Sertoli cell proliferation	1	702.2×	0.004	FSHR

Therapeutics

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 3 · Phased (≥1): 3 · Undrugged: 1

Druggability breadth: 4 of 4 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
SORD	EPALRESTAT
XDH	FEBUXOSTAT
SRD5A2	FINASTERIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
XDH	16	4
SRD5A2	5	4
SORD	2	4
FSHR	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
EPALRESTAT	4	SORD
FEBUXOSTAT	4	XDH
ALLOPURINOL	4	XDH
INDOMETHACIN	4	XDH
THIOGUANINE	4	XDH
FINASTERIDE	4	SRD5A2
QUERCETIN	3	SORD, XDH
RUTIN	3	XDH
ADENINE	3	XDH
GAMOLENIC ACID	3	SRD5A2
TOPIROXOSTAT	2	XDH
LUTEOLIN	2	XDH
ISOQUERCETIN	2	XDH
FISETIN	2	XDH
BROPIRIMINE	2	XDH
GENISTEIN	2	XDH
BAICALEIN	2	XDH
OXYPURINOL	2	XDH
EPRISTERIDE	2	SRD5A2
TUROSTERIDE	2	SRD5A2
BEXLOSTERIDE	2	SRD5A2
KAEMPFEROL	1	XDH

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
XDH	184	Binding:184
SRD5A2	119	Binding:115, Functional:4
FSHR	43	Functional:26, Binding:17
SORD	17	Binding:16, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SORD	1.1.1.14	L-iditol 2-dehydrogenase
XDH	1.17.1.4, 1.17.3.2	xanthine dehydrogenase, xanthine oxidase
SRD5A2	1.3.1.22, 1.3.99.5	3-oxo-5alpha-steroid 4-dehydrogenase (NADP+), 3-oxo-5alpha-steroid 4-dehydrogenase (acceptor)

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
XDH	184
SRD5A2	119

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

22 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
EPALRESTAT	4	SORD
FEBUXOSTAT	4	XDH
ALLOPURINOL	4	XDH
INDOMETHACIN	4	XDH
THIOGUANINE	4	XDH
FINASTERIDE	4	SRD5A2
QUERCETIN	3	SORD, XDH
RUTIN	3	XDH
ADENINE	3	XDH
GAMOLENIC ACID	3	SRD5A2
TOPIROXOSTAT	2	XDH
LUTEOLIN	2	XDH
ISOQUERCETIN	2	XDH
FISETIN	2	XDH
BROPIRIMINE	2	XDH
GENISTEIN	2	XDH
BAICALEIN	2	XDH
OXYPURINOL	2	XDH
EPRISTERIDE	2	SRD5A2
TUROSTERIDE	2	SRD5A2
BEXLOSTERIDE	2	SRD5A2
KAEMPFEROL	1	XDH

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	SORD, XDH, SRD5A2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	FSHR
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
FSHR	43	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.