Hereditary renal hypouricemia

Summary

Hereditary renal hypouricemia (MONDO:0009071) is a disease with 2 cohort genes and 3 clinical trials.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 3
• Phenotypes (HPO): 16
• Clinical trials: 3

Clinical features

Signs & symptoms

Clinical features (HPO)

16 HPO clinical features (Orphanet curated; top 16 by frequency):

HPO ID	Term	Frequency
HP:0003149	Hyperuricosuria	Obligate (100%)
HP:0003537	Hypouricemia	Obligate (100%)
HP:0030973	Postexertional malaise	Very frequent (80-99%)
HP:0000091	Abnormal renal tubule morphology	Frequent (30-79%)
HP:0001919	Acute kidney injury	Frequent (30-79%)
HP:0008651	Uric acid urolithiasis independent of gout	Frequent (30-79%)
HP:0012211	Abnormal renal physiology	Frequent (30-79%)
HP:0000790	Hematuria	Occasional (5-29%)
HP:0002013	Vomiting	Occasional (5-29%)
HP:0002018	Nausea	Occasional (5-29%)
HP:0002150	Hypercalciuria	Occasional (5-29%)
HP:0003138	Increased blood urea nitrogen	Occasional (5-29%)
HP:0003418	Back pain	Occasional (5-29%)
HP:0012213	Decreased glomerular filtration rate	Occasional (5-29%)
HP:0012595	Mild proteinuria	Occasional (5-29%)
HP:0012622	Chronic kidney disease	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary renal hypouricemia
Mondo ID	MONDO:0009071
MeSH	C537757
Orphanet	94088
ICD-11	479364233
SNOMED CT	236478009
UMLS	C4551590
MedGen	1643078
GARD	0009496
Is cancer (heuristic)	no

Also known as: hypouricemia, renal

Data availability: 3 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › urinary system disorder › kidney disorder › renal tubule disorder › inherited renal tubular disease › hereditary renal hypouricemia

Related subtypes (27): cranioectodermal dysplasia, cystinuria, nephrogenic diabetes insipidus-intracranial calcification syndrome, Gitelman syndrome, nephrogenic syndrome of inappropriate antidiuresis, oculocerebrorenal syndrome, RHYNS syndrome, renal tubular acidosis, distal, 3, with or without sensorineural hearing loss, autosomal recessive proximal renal tubular acidosis, EAST syndrome, familial juvenile hyperuricemic nephropathy type 2, hyperuricemia-pulmonary hypertension-renal failure-alkalosis syndrome, Bartter syndrome, Dent disease, nephrogenic diabetes insipidus, autosomal dominant proximal renal tubular acidosis, Senior-Loken syndrome, familial primary hypomagnesemia, mitochondrial DNA depletion syndrome, hepatocerebrorenal form, Jeune syndrome, nephronophthisis, pseudohypoaldosteronism type 1, Senior-Boichis syndrome, pseudohypoparathyroidism, psychomotor regression-oculomotor apraxia-movement disorder-nephropathy syndrome, HELIX syndrome, inherited Fanconi renotubular syndrome

Subtypes (3): hypouricemia, hypercalcinuria, and decreased bone density, hypouricemia, familial renal, due to tubular hypersecretion, hypouricemia, renal

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

3 retrieved; paginated sample, class counts are floors:

1 pathogenic/likely pathogenic, 1 uncertain significance, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
305239	NM_144585.4(SLC22A12):c.1145A>T (p.Gln382Leu)	SLC22A12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3516	NM_144585.4(SLC22A12):c.269G>A (p.Arg90His)	SLC22A12	Pathogenic	criteria provided, multiple submitters, no conflicts
3068550	NM_144585.4(SLC22A12):c.237G>A (p.Pro79=)	SLC22A12	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 2 · 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
SLC22A12	Strong	Autosomal recessive	hypouricemia, renal 1	3
SLC2A9	Strong	Autosomal recessive	hypouricemia, renal, 2	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC22A12	Orphanet:94088	Hereditary renal hypouricemia
SLC2A9	Orphanet:94088	Hereditary renal hypouricemia

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC22A12	HGNC:17989	ENSG00000197891	Q96S37	Solute carrier family 22 member 12	gencc,clinvar
SLC2A9	HGNC:13446	ENSG00000109667	Q9NRM0	Solute carrier family 2, facilitated glucose transporter member 9	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC22A12	Solute carrier family 22 member 12	Electroneutral antiporter that translocates urate across the apical membrane of proximal tubular cells in exchange for monovalent organic or inorganic anions.
SLC2A9	Solute carrier family 2, facilitated glucose transporter member 9	High-capacity urate transporter, which may play a role in the urate reabsorption by proximal tubules.

Protein-family classification

Druggable: 2 · 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
Transporter	2	77.8×	2e-04

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC22A12	Transporter	yes		MFS, MFS_dom, MFS_trans_sf
SLC2A9	Transporter	yes		Sugar/inositol_transpt, MFS_sugar_transport-like, Sugar_transporter_CS

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adult mammalian kidney	1
kidney	1
kidney epithelium	1
buccal mucosa cell	1
monocyte	1
mononuclear cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC22A12	30	tissue_specific	marker	kidney epithelium, adult mammalian kidney, kidney
SLC2A9	182	broad	marker	buccal mucosa cell, monocyte, mononuclear cell

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC2A9	1,285
SLC22A12	1,033

Intra-cohort edges

A	B	Sources
SLC22A12	SLC2A9	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC22A12	Q96S37	28
SLC2A9	Q9NRM0	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective SLC2A9 causes hypouricemia renal 2 (RHUC2)	1	5710.0×	1e-03	SLC2A9
Defective SLC22A12 causes renal hypouricemia 1 (RHUC1)	1	5710.0×	1e-03	SLC22A12
Organic anion transport by SLC22 transporters	1	1142.0×	0.003	SLC22A12
R-HSA-549132	1	380.7×	0.007	SLC22A12
Cellular hexose transport	1	271.9×	0.008	SLC2A9
SLC transporter disorders	1	102.0×	0.017	SLC22A12
R-HSA-425366	1	90.6×	0.017	SLC22A12
Disorders of transmembrane transporters	1	69.6×	0.020	SLC22A12
SLC-mediated transmembrane transport	1	29.6×	0.041	SLC22A12
Transport of small molecules	1	12.6×	0.086	SLC22A12
Disease	1	6.5×	0.147	SLC22A12

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
urate transport	2	2407.4×	2e-06	SLC22A12, SLC2A9
urate metabolic process	2	1532.0×	3e-06	SLC22A12, SLC2A9
renal urate salt excretion	1	2808.7×	0.002	SLC22A12
fructose transmembrane transport	1	1053.2×	0.003	SLC2A9
hexose transmembrane transport	1	702.2×	0.003	SLC2A9
dehydroascorbic acid transport	1	601.9×	0.003	SLC2A9
D-glucose transmembrane transport	1	468.1×	0.003	SLC2A9
obsolete D-glucose import	1	421.3×	0.003	SLC2A9
obsolete organic anion transport	1	401.2×	0.003	SLC22A12
cellular homeostasis	1	401.2×	0.003	SLC22A12
cellular response to insulin stimulus	1	85.1×	0.014	SLC22A12
monoatomic ion transport	1	78.0×	0.014	SLC22A12
response to xenobiotic stimulus	1	34.5×	0.029	SLC22A12

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 0

Druggability breadth: 2 of 2 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
SLC22A12	BENZARONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC22A12	13	4
SLC2A9	1	3

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BENZARONE	4	SLC22A12
LESINURAD	4	SLC22A12
BENZBROMARONE	4	SLC22A12
SULFINPYRAZONE	4	SLC22A12
PROBENECID	4	SLC22A12
FENOFIBRIC ACID	4	SLC22A12
SHR-4640	3	SLC22A12
DOTINURAD	3	SLC22A12
CURCUMIN	3	SLC2A9
ARHALOFENATE	2	SLC22A12
PF-05089771	2	SLC22A12
VERINURAD	2	SLC22A12
PULIGINURAD	2	SLC22A12
EPAMINURAD	1	SLC22A12

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SLC22A12	108	Binding:108
SLC2A9	13	Binding:11, Functional:2

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SLC22A12	108

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

14 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)
BENZARONE	4	SLC22A12
LESINURAD	4	SLC22A12
BENZBROMARONE	4	SLC22A12
SULFINPYRAZONE	4	SLC22A12
PROBENECID	4	SLC22A12
FENOFIBRIC ACID	4	SLC22A12
SHR-4640	3	SLC22A12
DOTINURAD	3	SLC22A12
CURCUMIN	3	SLC2A9
ARHALOFENATE	2	SLC22A12
PF-05089771	2	SLC22A12
VERINURAD	2	SLC22A12
PULIGINURAD	2	SLC22A12
EPAMINURAD	1	SLC22A12

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SLC22A12
B	Phased (≥1) drug, not yet approved	1	SLC2A9
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE4	1
PHASE1/PHASE2	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04398251	PHASE4	UNKNOWN	A Randomized Clinical Trail of The Effect of Postoperative Uric Acid Control on Stone Recurrence and Renal Function in Patients With Hyperuricemia of Urolithiasis.
NCT06310967	PHASE1/PHASE2	RECRUITING	A Dose Escalation Study of IG3018 in Subjects With Hyperuricemia With or Without Chronic Kidney Disease
NCT06065852	Not specified	RECRUITING	National Registry of Rare Kidney Diseases