Progressive retinal dystrophy due to retinol transport defect

Summary

Progressive retinal dystrophy due to retinol transport defect (MONDO:0014060) is a disease caused by RBP4 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: RBP4 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 9

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	progressive retinal dystrophy due to retinol transport defect
Mondo ID	MONDO:0014060
OMIM	615147
Orphanet	352718
UMLS	C3554593
MedGen	767507
GARD	0017529
Is cancer (heuristic)	no

Also known as: RDCCAS · retinal dystrophy, iris coloboma, and comedogenic acne syndrome · retinol dystrophy-iris coloboma-comedogenic acne syndrome

Data availability: 9 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › retinal disorder › retinal degeneration › inherited retinal dystrophy › progressive retinal dystrophy due to retinol transport defect

Related subtypes (104): retinal dystrophies primarily involving Bruch’s membrane, vitreoretinal dystrophy, dystrophies primarily involving the retinal pigment epithelium, retinal dystrophy in systemic or cerebroretinal lipidoses, age-related macular degeneration, helicoid peripapillary chorioretinal degeneration, Sorsby fundus dystrophy, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, pigmented paravenous retinochoroidal atrophy, retinoschisis, autosomal dominant, retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations, amaurosis-hypertrichosis syndrome, familial benign flecked retina, microcephaly and chorioretinopathy 1, ornithine aminotransferase deficiency, retinal degeneration-nanophthalmos-glaucoma syndrome, retinoschisis of fovea, Revesz syndrome, choroideremia, choroideremia-deafness-obesity syndrome, X-linked retinal dysplasia, X-linked retinoschisis, progressive bifocal chorioretinal atrophy, aceruloplasminemia, late-onset retinal degeneration, infantile cerebellar-retinal degeneration, microcornea-myopic chorioretinal atrophy, retinal dystrophy with inner retinal dysfunction and ganglion cell anomalies, macular degeneration, early-onset, cone-rod dystrophy, ectopia lentis-chorioretinal dystrophy-myopia syndrome, foveal hypoplasia-presenile cataract syndrome, MRCS syndrome, X-linked intellectual disability-limb spasticity-retinal dystrophy-diabetes insipidus syndrome, Leber congenital amaurosis, oligocone trichromacy, Oguchi disease, retinitis pigmentosa, hereditary macular dystrophy, RPE65-related recessive retinopathy, RPGR-related retinopathy, AIPL1-related retinopathy, RP2-related retinopathy, RDH5-related retinopathy, RLBP1-related retinopathy, LCA5-related retinopathy, ATF6-related retinopathy, RAB28-related retinopathy, FLVCR1-related retinopathy with or without ataxia, RPE65-related dominant retinopathy, GUCY2D retinopathy, PDE6A-related retinopathy, ELOVL4-related maculopathy, MAK-related retinopathy, KIZ-related retinopathy, TOPORS-related retinopathy, PRPF8-related retinopathy, RD3-related retinopathy, BEST1-related dominant retinopathy, BEST1-related recessive retinopathy, IMPG2-related recessive retinopathy, IMPG2-related dominant retinopathy, CACNA1F-related retinopathy, CACNA2D4-related retinopathy, CDHR1-related retinopathy, GUCA1A-related retinopathy, RHO-related retinopathy, SNRNP200-related dominant retinopathy, RDH12-related recessive retinopathy, RDH12-related dominant retinopathy, NMNAT1-related retinopathy, CNGA3-related retinopathy, EYS-related retinopathy, GNAT2-related retinopathy, IDH3B-related retinopathy, MERTK-related retinopathy, PRPF31-related retinopathy, GPR179-related retinopathy, GRM6-related retinopathy, ADAM9-related retinopathy, RP1-related recessive retinopathy, RP1-related dominant retinopathy, CERKL-related retinopathy, TRPM1-related retinopathy, CNGB1-related retinopathy, PCARE-related retinopathy, CNGA1-related retinopathy, ABCA4-related retinopathy, NYX-related retinopathy, retinal dystrophy, X-linked, Gardner-Hardcastle type, PDE6C-related retinopathy, PDE6G-related retinopathy, LRIT3-related retinopathy, IMPG1-related dominant retinopathy, IMPG1-related recessive retinopathy, TTLL5-related retinopathy, HGSNAT-related retinopathy, IMPDH1-related retinopathy, PRPH2-related retinopathy, PROM1-related retinopathy, KCNV2-related retinopathy, CRX-related retinopathy, REEP6-related retinopathy, SPATA7-related retinopathy

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

9 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 2 benign, 2 pathogenic, 1 conflicting classifications of pathogenicity, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
41423	NM_006744.4(RBP4):c.111+1G>A	RBP4	Pathogenic	no assertion criteria provided
976725	NM_006744.4(RBP4):c.526G>T (p.Glu176Ter)	RBP4	Pathogenic	criteria provided, single submitter
13068	NM_006744.4(RBP4):c.278G>A (p.Gly93Asp)	RBP4	Likely pathogenic	criteria provided, single submitter
13067	NM_006744.4(RBP4):c.176T>A (p.Ile59Asn)	FFAR4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
499650	NM_006744.4(RBP4):c.24G>T (p.Leu8Phe)	RBP4	Uncertain significance	criteria provided, multiple submitters, no conflicts
931421	NM_006744.4(RBP4):c.109C>G (p.Arg37Gly)	RBP4	Uncertain significance	criteria provided, multiple submitters, no conflicts
966812	NM_006744.4(RBP4):c.302C>A (p.Pro101His)	RBP4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1277035	NM_006744.4(RBP4):c.356-25G>C	RBP4	Benign	criteria provided, multiple submitters, no conflicts
931422	NM_006744.4(RBP4):c.355+123T>G	RBP4	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · 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
RBP4	Definitive	Autosomal recessive	progressive retinal dystrophy due to retinol transport defect	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RBP4	Orphanet:352718	Progressive retinal dystrophy due to retinol transport defect
RBP4	Orphanet:98938	Colobomatous microphthalmia

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
RBP4	HGNC:9922	ENSG00000138207	P02753	Retinol-binding protein 4	gencc,clinvar
FFAR4	HGNC:19061	ENSG00000186188	Q5NUL3	Free fatty acid receptor 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RBP4	Retinol-binding protein 4	Retinol-binding protein that mediates retinol transport in blood plasma.
FFAR4	Free fatty acid receptor 4	G-protein-coupled receptor for long-chain fatty acids (LCFAs) with a major role in adipogenesis, energy metabolism and inflammation.

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
GPCR	1	12.0×	0.164
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RBP4	Other/Unknown	no		Lipocln_cytosolic_FA-bd_dom, Retinol-bd/Purpurin, Calycin
FFAR4	GPCR	yes		GPCR_Rhodpsn, GPCR_Rhodpsn_7TM

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
liver	1
right lobe of liver	1
type B pancreatic cell	1
mucosa of sigmoid colon	1
mucosa of transverse colon	1
rectum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RBP4	244	broad	marker	right lobe of liver, liver, type B pancreatic cell
FFAR4	132	tissue_specific	marker	mucosa of sigmoid colon, mucosa of transverse colon, rectum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RBP4	1,143
FFAR4	1,014

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RBP4	P02753	23
FFAR4	Q5NUL3	12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
Retinoid metabolism disease events	1	5710.0×	0.001	RBP4
Defective visual phototransduction due to STRA6 loss of function	1	1903.3×	0.002	RBP4
Free fatty acid receptors	1	1142.0×	0.002	FFAR4
The canonical retinoid cycle in rods (twilight vision)	1	259.6×	0.005	RBP4
Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1)	1	259.6×	0.005	FFAR4
Retinoid metabolism and transport	1	124.1×	0.009	RBP4
G alpha (q) signalling events	1	28.7×	0.035	FFAR4

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
negative regulation of somatostatin secretion	1	8426.0×	0.002	FFAR4
retinol transport	1	4213.0×	0.002	RBP4
ghrelin secretion	1	4213.0×	0.002	FFAR4
positive regulation of glucagon secretion	1	4213.0×	0.002	FFAR4
vitamin A import into cell	1	4213.0×	0.002	RBP4
female genitalia morphogenesis	1	2808.7×	0.003	RBP4
hormone secretion	1	2106.5×	0.003	FFAR4
embryonic organ morphogenesis	1	2106.5×	0.003	RBP4
urinary bladder development	1	2106.5×	0.003	RBP4
embryonic retina morphogenesis in camera-type eye	1	1203.7×	0.004	RBP4
regulation of D-glucose transmembrane transport	1	1053.2×	0.004	FFAR4
negative regulation of cardiac muscle cell proliferation	1	936.2×	0.005	RBP4
vagina development	1	766.0×	0.005	RBP4
phototransduction, visible light	1	648.1×	0.006	RBP4
heart trabecula formation	1	561.7×	0.006	RBP4
maintenance of gastrointestinal epithelium	1	526.6×	0.006	RBP4
positive regulation of brown fat cell differentiation	1	495.6×	0.006	FFAR4
retinal metabolic process	1	468.1×	0.006	RBP4
cardiac muscle tissue development	1	443.5×	0.006	RBP4
white fat cell differentiation	1	421.3×	0.006	FFAR4
uterus development	1	401.2×	0.006	RBP4
detection of light stimulus involved in visual perception	1	324.1×	0.007	RBP4
response to muscle activity	1	290.6×	0.008	RBP4
negative regulation of cytokine production	1	255.3×	0.008	FFAR4
negative regulation of interleukin-1 beta production	1	255.3×	0.008	FFAR4
retinol metabolic process	1	247.8×	0.008	RBP4
positive regulation of immunoglobulin production	1	240.7×	0.008	RBP4
brown fat cell differentiation	1	216.1×	0.008	FFAR4
embryonic skeletal system development	1	195.9×	0.009	RBP4
response to retinoic acid	1	191.5×	0.009	RBP4

Therapeutics

Drug target analysis

Approved (phase 4): 2 · 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
RBP4	RETINOL
FFAR4	DIHYDROERGOTAMINE MESYLATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FFAR4	8	4
RBP4	3	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
RETINOL	4	RBP4
DIHYDROERGOTAMINE MESYLATE	4	FFAR4
LOPERAMIDE HYDROCHLORIDE	4	FFAR4
TOLTERODINE TARTRATE	4	FFAR4
TOLVAPTAN	4	FFAR4
ELAGOLIX SODIUM	4	FFAR4
TINLAREBANT	3	RBP4
FENRETINIDE	3	RBP4
LINOLEIC ACID	2	FFAR4
RELCOVAPTAN	2	FFAR4
DEVAZEPIDE	2	FFAR4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
FFAR4	121	Functional:71, Binding:50
RBP4	32	Binding:29, Functional:3

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
FFAR4	121

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

11 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)
RETINOL	4	RBP4
DIHYDROERGOTAMINE MESYLATE	4	FFAR4
LOPERAMIDE HYDROCHLORIDE	4	FFAR4
TOLTERODINE TARTRATE	4	FFAR4
TOLVAPTAN	4	FFAR4
ELAGOLIX SODIUM	4	FFAR4
TINLAREBANT	3	RBP4
FENRETINIDE	3	RBP4
LINOLEIC ACID	2	FFAR4
RELCOVAPTAN	2	FFAR4
DEVAZEPIDE	2	FFAR4

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	RBP4, FFAR4
B	Phased (≥1) drug, not yet approved	0
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: 0.