Dent disease

Summary

Dent disease (MONDO:0015612) is a disease with 2 cohort genes and 10 clinical trials.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 5
• Phenotypes (HPO): 40
• Clinical trials: 10

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		250	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

40 HPO clinical features (Orphanet curated; top 40 by frequency):

HPO ID	Term	Frequency
HP:0000083	Renal insufficiency	Very frequent (80-99%)
HP:0000092	Renal tubular atrophy	Very frequent (80-99%)
HP:0000093	Proteinuria	Very frequent (80-99%)
HP:0000097	Focal segmental glomerulosclerosis	Very frequent (80-99%)
HP:0000114	Proximal tubulopathy	Very frequent (80-99%)
HP:0000117	Renal phosphate wasting	Very frequent (80-99%)
HP:0000787	Nephrolithiasis	Very frequent (80-99%)
HP:0000790	Hematuria	Very frequent (80-99%)
HP:0002150	Hypercalciuria	Very frequent (80-99%)
HP:0002757	Recurrent fractures	Very frequent (80-99%)
HP:0003355	Aminoaciduria	Very frequent (80-99%)
HP:0003076	Glycosuria	Very frequent (80-99%)
HP:0003109	Hyperphosphaturia	Very frequent (80-99%)
HP:0003126	Low-molecular-weight proteinuria	Very frequent (80-99%)
HP:0003149	Hyperuricosuria	Very frequent (80-99%)
HP:0005576	Tubulointerstitial fibrosis	Very frequent (80-99%)
HP:0005574	Non-acidotic proximal tubulopathy	Very frequent (80-99%)
HP:0012622	Chronic kidney disease	Very frequent (80-99%)
HP:0008732	Renal hypophosphatemia	Very frequent (80-99%)
HP:0031415	High serum calcitriol	Very frequent (80-99%)
HP:0000121	Nephrocalcinosis	Frequent (30-79%)
HP:0002027	Abdominal pain	Frequent (30-79%)
HP:0002653	Bone pain	Frequent (30-79%)
HP:0003236	Elevated circulating creatine kinase concentration	Frequent (30-79%)
HP:0000518	Cataract	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001256	Intellectual disability, mild	Occasional (5-29%)
HP:0002663	Delayed epiphyseal ossification	Occasional (5-29%)
HP:0002748	Rickets	Occasional (5-29%)
HP:0002814	Abnormality of the lower limb	Occasional (5-29%)
HP:0002749	Osteomalacia	Occasional (5-29%)
HP:0002752	Sparse bone trabeculae	Occasional (5-29%)
HP:0002753	Thin bony cortex	Occasional (5-29%)
HP:0002979	Bowing of the legs	Occasional (5-29%)
HP:0003013	Bulging epiphyses	Occasional (5-29%)
HP:0010580	Enlarged epiphyses	Occasional (5-29%)
HP:0003020	Enlargement of the wrists	Occasional (5-29%)
HP:0003025	Metaphyseal irregularity	Occasional (5-29%)
HP:0003029	Enlargement of the ankles	Occasional (5-29%)
HP:0011342	Mild global developmental delay	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Dent disease
Mondo ID	MONDO:0015612
MeSH	D057973
OMIM	300009
Orphanet	1652
DOID	DOID:0050699
ICD-11	1762998355
NCIT	C123260
SNOMED CT	444645005
UMLS	C0878681
MedGen	168056
GARD	0013105
MedDRA	10069199
NORD	1040
Is cancer (heuristic)	no

Also known as: Dent disease 1 · Dent disease 2 · Dent syndrome · Dents disease · low-molecular-weight proteinuria with hypercalciuria and nephrocalcinosis · renal Fanconi syndrome with nephrocalcinosis and renal stones · X-linked recessive hypercalciuric hypophosphatemic rickets · X-linked recessive hypophosphatemic rickets · X-linked recessive nephrolithiasis

Data availability: 5 ClinVar variants · 3 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › urinary system disorder › kidney disorder › renal tubular transport disease › Dent disease

Related subtypes (8): Fanconi renotubular syndrome, renal tubular acidosis, Liddle syndrome, familial renal glucosuria, renal hypomagnesemia 3, Gitelman syndrome, Bartter syndrome, pseudohypoaldosteronism

Subtypes (2): Dent disease type 1, Dent disease type 2

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

5 retrieved; paginated sample, class counts are floors:

3 likely pathogenic, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
207999	NM_001127898.4(CLCN5):c.2119C>T (p.Arg707Ter)	CLCN5	Pathogenic	criteria provided, multiple submitters, no conflicts
4688304	NC_000023.10:g.(?49832242)(49863888_?)del	CLCN5	Pathogenic	criteria provided, single submitter
4525797	NM_001127898.4(CLCN5):c.1558-2A>G	CLCN5	Likely pathogenic	criteria provided, single submitter
1723236	NM_000276.4(OCRL):c.1580T>A (p.Val527Asp)	OCRL	Likely pathogenic	criteria provided, single submitter
1878394	NM_000276.4(OCRL):c.2582-1G>C	OCRL	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CLCN5	Orphanet:93622	Dent disease type 1
OCRL	Orphanet:534	Oculocerebrorenal syndrome of Lowe
OCRL	Orphanet:93623	Dent disease type 2

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
CLCN5	HGNC:2023	ENSG00000171365	P51795	H(+)/Cl(-) exchange transporter 5	clinvar
OCRL	HGNC:8108	ENSG00000122126	Q01968	Inositol polyphosphate 5-phosphatase OCRL	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CLCN5	H(+)/Cl(-) exchange transporter 5	Proton-coupled chloride transporter.
OCRL	Inositol polyphosphate 5-phosphatase OCRL	Catalyzes the hydrolysis of the 5-position phosphate of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) and phosphatidylinositol-3,4,5-bisphosphate (PtdIns(3,4,5)P3), with the greatest catalytic activity towards PtdIns(4,5)P2.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Antibody/Immunoglobulin	1	14.6×	0.135
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CLCN5	Other/Unknown	no		CBS_dom, ClC, Cl_channel-5
OCRL	Antibody/Immunoglobulin	yes	3.1.3.36	RhoGAP_dom, IPPc, Rho_GTPase_activation_prot

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
corpus epididymis	1
renal medulla	1
secondary oocyte	1
Brodmann (1909) area 10	1
endometrium epithelium	1
lower esophagus muscularis layer	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CLCN5	218	ubiquitous	marker	renal medulla, secondary oocyte, corpus epididymis
OCRL	225	ubiquitous	marker	endometrium epithelium, Brodmann (1909) area 10, lower esophagus muscularis layer

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
OCRL	2,269
CLCN5	1,345

Intra-cohort edges

A	B	Sources
CLCN5	OCRL	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
OCRL	Q01968	5
CLCN5	P51795	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. 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
Synthesis of IP2, IP, and Ins in the cytosol	1	380.7×	0.014	OCRL
Synthesis of PIPs at the Golgi membrane	1	317.2×	0.014	OCRL
Synthesis of IP3 and IP4 in the cytosol	1	211.5×	0.014	OCRL
Synthesis of PIPs at the plasma membrane	1	105.7×	0.015	OCRL
Golgi Associated Vesicle Biogenesis	1	100.2×	0.015	OCRL
RHOJ GTPase cycle	1	100.2×	0.015	OCRL
Stimuli-sensing channels	1	68.0×	0.019	CLCN5
RAC3 GTPase cycle	1	59.5×	0.019	OCRL
Clathrin-mediated endocytosis	1	42.6×	0.023	OCRL

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
renal system process	1	561.7×	0.011	CLCN5
inositol phosphate metabolic process	1	495.6×	0.011	OCRL
phosphatidylinositol dephosphorylation	1	324.1×	0.011	OCRL
membrane organization	1	255.3×	0.011	OCRL
chloride transport	1	227.7×	0.011	CLCN5
phosphatidylinositol biosynthetic process	1	183.2×	0.011	OCRL
monoatomic ion transmembrane transport	1	104.0×	0.016	CLCN5
endocytosis	1	47.6×	0.029	CLCN5
lipid metabolic process	1	45.8×	0.029	OCRL
cilium assembly	1	36.8×	0.030	OCRL
in utero embryonic development	1	36.0×	0.030	OCRL
signal transduction	1	8.0×	0.121	OCRL

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CLCN5	0	0
OCRL	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
OCRL	3.1.3.36	phosphoinositide 5-phosphatase

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

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	OCRL
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CLCN5

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CLCN5	0	—
OCRL	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 10.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	9
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02016235	PHASE1/PHASE2	COMPLETED	Role Of Phosphorus And FGF 23 In Patients With Dent Disease
NCT00588562	Not specified	RECRUITING	Rare Kidney Stone Consortium Patient Registry
NCT02026388	Not specified	RECRUITING	Rare Kidney Stone Consortium Biobank
NCT02780297	Not specified	RECRUITING	Prospective Research Rare Kidney Stones (ProRKS)
NCT06017193	Not specified	RECRUITING	Ultrasound for Socket Healing Evaluation
NCT06065852	Not specified	RECRUITING	National Registry of Rare Kidney Diseases
NCT01783795	Not specified	COMPLETED	Dent Disease Mutation Genotyping
NCT02022189	Not specified	COMPLETED	Review of Kidney Biopsies of Dent Disease Patients
NCT02124395	Not specified	COMPLETED	Health-related Quality of Life in Rare Kidney Stone
NCT04459013	Not specified	COMPLETED	Evaluation of the Release of Monomers From Composite Bonding Resins in Orthodontics