Lipoid proteinosis

Summary

Lipoid proteinosis (MONDO:0009530) is a disease caused by ECM1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ECM1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 46
• Phenotypes (HPO): 23

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		500	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

23 HPO clinical features (Orphanet curated; top 23 by frequency):

HPO ID	Term	Frequency
HP:0000168	Abnormality of the gingiva	Very frequent (80-99%)
HP:0000179	Thick lower lip vermilion	Very frequent (80-99%)
HP:0000199	Tongue nodules	Very frequent (80-99%)
HP:0001061	Acne	Very frequent (80-99%)
HP:0001072	Thickened skin	Very frequent (80-99%)
HP:0001482	Subcutaneous nodule	Very frequent (80-99%)
HP:0001609	Hoarse voice	Very frequent (80-99%)
HP:0008066	Abnormal blistering of the skin	Very frequent (80-99%)
HP:0011830	Abnormal oral mucosa morphology	Very frequent (80-99%)
HP:0100699	Scarring	Very frequent (80-99%)
HP:0200034	Papule	Very frequent (80-99%)
HP:0200039	Pustule	Very frequent (80-99%)
HP:0000171	Microglossia	Frequent (30-79%)
HP:0000218	High palate	Frequent (30-79%)
HP:0000962	Hyperkeratosis	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002205	Recurrent respiratory infections	Frequent (30-79%)
HP:0002293	Alopecia of scalp	Frequent (30-79%)
HP:0200043	Verrucae	Frequent (30-79%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0002514	Cerebral calcification	Occasional (5-29%)
HP:0100582	Nasal polyposis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	lipoid proteinosis
Mondo ID	MONDO:0009530
MeSH	D008065
OMIM	247100
Orphanet	530
DOID	DOID:14498
ICD-11	326368380
NCIT	C84829
SNOMED CT	38692000
UMLS	C0023795
MedGen	6112
GARD	0003268
Is cancer (heuristic)	no

Also known as: hyalinosis cutis et mucosae · lipid proteinosis · lipoid proteinosis · lipoproteinosis · Urbach Wiethe disease · Urbach-Wiethe disease

Data availability: 46 ClinVar variants · 5 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inherited lipid metabolism disorder › lipoid proteinosis

Related subtypes (28): cortisone reductase deficiency, familial hyperlipidemia, hypolipoproteinemia, steroid inherited metabolic disorder, corticosterone methyloxidase type 1 deficiency, 46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency, vitamin D hydroxylation-deficient rickets, type 1B, mitochondrial trifunctional protein deficiency, pancreatic triacylglycerol lipase deficiency, glucocorticoid resistance, syndromic dyslipidemia, inborn disorder of glycosphingolipid and glycosylphosphatidylinositol anchor glycosylation, disorder of plasmalogens biosynthesis, disorder of phospholipids, sphingolipids and fatty acids biosynthesis, inborn disorder of ketolysis, lysosomal lipid storage disorder, sterol metabolism disorder, disorder of sphingolipid biosynthesis, glycosylphosphatidylinositol biosynthesis defect 18, neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures, developmental and epileptic encephalopathy, 77, developmental and epileptic encephalopathy, 80, developmental and epileptic encephalopathy, 55, inherited fatty acid metabolism disorder, glycosylphosphatidylinositol biosynthesis defect 16, glycosylphosphatidylinositol biosynthesis defect 15, glycosylphosphatidylinositol biosynthesis defect 17, CYP7B1-related disorder of oxysterol accumulation

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

46 retrieved; paginated sample, class counts are floors:

21 pathogenic, 6 uncertain significance, 6 likely pathogenic, 4 not provided, 3 pathogenic/likely pathogenic, 3 benign, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1034085	NM_004425.4(ECM1):c.233del (p.Pro78fs)	ECM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1192520	NM_004425.4(ECM1):c.806G>A (p.Cys269Tyr)	ECM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1526253	NM_004425.4(ECM1):c.1287_1288del (p.Arg430fs)	ECM1	Pathogenic	criteria provided, single submitter
1687218	NM_004425.4(ECM1):c.1209_1210insTAGGAAGCCAATTGATATCATAGCTCAGACCATACCTATGTATCCAAATGGTTCTTTTTTTCC (p.Asn404Ter)	ECM1	Pathogenic	criteria provided, single submitter
1802155	NM_004425.4(ECM1):c.1450_1454del (p.Ala484fs)	ECM1	Pathogenic	criteria provided, single submitter
1803965	NM_004425.4(ECM1):c.542_543insAACCAAATCTGAA (p.Cys181Ter)	ECM1	Pathogenic	criteria provided, single submitter
222945	NM_004425.4(ECM1):c.506dup (p.Gly170fs)	ECM1	Pathogenic	criteria provided, single submitter
222947	NM_004425.4(ECM1):c.507del (p.Arg171fs)	ECM1	Pathogenic	criteria provided, single submitter
2585237	NM_004425.4(ECM1):c.1246C>T (p.Arg416Ter)	ECM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3064070	NM_004425.4(ECM1):c.1304+33_*300del	ECM1	Pathogenic	criteria provided, single submitter
3242455	NM_004425.4(ECM1):c.1441C>T (p.Arg481Ter)	ECM1	Pathogenic	criteria provided, single submitter
3242456	NM_004425.4(ECM1):c.1305-2A>G	ECM1	Pathogenic	no assertion criteria provided
3242457	NM_004425.4(ECM1):c.735_736del (p.Cys245_Glu246delinsTer)	ECM1	Pathogenic	no assertion criteria provided
3242458	NM_004425.4(ECM1):c.709-2A>G	ECM1	Pathogenic	no assertion criteria provided
3242459	NM_004425.4(ECM1):c.1412_1413dup (p.Leu472fs)	ECM1	Pathogenic	no assertion criteria provided
3242460	NM_004425.4(ECM1):c.826del (p.Gln276fs)	ECM1	Pathogenic	no assertion criteria provided
4078669	NM_004425.4(ECM1):c.1077G>A (p.Trp359Ter)	ECM1	Pathogenic	criteria provided, single submitter
4688540	NM_004425.4(ECM1):c.18_22dup (p.Ala8fs)	ECM1	Pathogenic	criteria provided, single submitter
587581	NM_004425.4(ECM1):c.1393-1G>T	ECM1	Pathogenic	criteria provided, single submitter
7472	NM_004425.4(ECM1):c.1036C>T (p.Gln346Ter)	ECM1	Pathogenic	no assertion criteria provided
7473	NM_004425.4(ECM1):c.1304+35_*302del	ECM1	Pathogenic	no assertion criteria provided
7475	NM_004425.4(ECM1):c.157C>T (p.Arg53Ter)	ECM1	Pathogenic	criteria provided, multiple submitters, no conflicts
7477	NM_004425.4(ECM1):c.480G>A (p.Trp160Ter)	ECM1	Pathogenic	no assertion criteria provided
987237	NM_004425.4(ECM1):c.760C>T (p.Arg254Ter)	ECM1	Pathogenic	criteria provided, multiple submitters, no conflicts
3064079	NM_004425.4(ECM1):c.1051C>T (p.Gln351Ter)	ECM1	Likely pathogenic	criteria provided, single submitter
3362542	NM_004425.4(ECM1):c.49_52del (p.Ala17fs)	ECM1	Likely pathogenic	criteria provided, single submitter
4845807	NM_004425.4(ECM1):c.1392+1G>A	ECM1	Likely pathogenic	criteria provided, single submitter
7471	NM_004425.4(ECM1):c.1019del (p.Gln340fs)	ECM1	Likely pathogenic	criteria provided, single submitter
7476	NM_004425.4(ECM1):c.499T>A (p.Phe167Ile)	ECM1	Likely pathogenic	criteria provided, single submitter
930258	NM_004425.4(ECM1):c.142del (p.Ser48fs)	ECM1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
ECM1	Definitive	Autosomal recessive	lipoid proteinosis	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ECM1	Orphanet:530	Lipoid proteinosis

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ECM1	HGNC:3153	ENSG00000143369	Q16610	Extracellular matrix protein 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ECM1	Extracellular matrix protein 1	Involved in endochondral bone formation as negative regulator of bone mineralization.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ECM1	Other/Unknown	no		ECM1, Serum_albumin-like

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
lower esophagus mucosa	1
pharyngeal mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ECM1	253	ubiquitous	marker	lower esophagus mucosa, buccal mucosa cell, pharyngeal mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ECM1	1,835

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ECM1	Q16610	69.05

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Platelet degranulation	1	87.8×	0.011	ECM1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of type 2 immune response	1	16852.0×	0.001	ECM1
negative regulation of peptidase activity	1	8426.0×	0.001	ECM1
regulation of T cell migration	1	2407.4×	0.002	ECM1
negative regulation of cytokine-mediated signaling pathway	1	1872.4×	0.002	ECM1
endochondral bone growth	1	1685.2×	0.002	ECM1
chondrocyte development	1	936.2×	0.003	ECM1
negative regulation of bone mineralization	1	936.2×	0.003	ECM1
regulation of bone mineralization	1	732.7×	0.003	ECM1
biomineral tissue development	1	648.1×	0.003	ECM1
positive regulation of endothelial cell proliferation	1	230.8×	0.007	ECM1
ossification	1	227.7×	0.007	ECM1
positive regulation of angiogenesis	1	115.4×	0.012	ECM1
positive regulation of canonical NF-kappaB signal transduction	1	72.6×	0.018	ECM1
angiogenesis	1	62.4×	0.019	ECM1
inflammatory response	1	37.7×	0.030	ECM1
signal transduction	1	16.1×	0.066	ECM1
regulation of transcription by RNA polymerase II	1	11.7×	0.086	ECM1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
ECM1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ECM1

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)
ECM1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.