Olmsted syndrome, X-linked

Summary

Olmsted syndrome, X-linked (MONDO:0010486) is a disease caused by MBTPS2 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: MBTPS2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Olmsted syndrome, X-linked
Mondo ID	MONDO:0010486
OMIM	300918
DOID	DOID:0112012
UMLS	C3806745
MedGen	813075
GARD	0015273
Is cancer (heuristic)	no

Also known as: Olmsted syndrome, X-linked · Olmsted syndrome, X-linked, X-linked recessive · palmoplantar keratoderma, mutilating, with periorificial keratotic plaques, X-linked

Data availability: 5 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › keratosis › palmoplantar keratosis › hereditary palmoplantar keratoderma › Olmsted syndrome › Olmsted syndrome, X-linked

Related subtypes (2): Olmsted syndrome 2, Olmsted syndrome 1

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 uncertain significance, 1 pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
126905	NM_015884.4(MBTPS2):c.1391T>C (p.Phe464Ser)	MBTPS2	Pathogenic	no assertion criteria provided
2441801	NM_015884.4(MBTPS2):c.527G>A (p.Gly176Glu)	MBTPS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029415	NM_015884.4(MBTPS2):c.124G>A (p.Gly42Arg)	MBTPS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2582521	NM_015884.4(MBTPS2):c.670+2688G>C	MBTPS2	Uncertain significance	criteria provided, single submitter
3598208	NM_015884.4(MBTPS2):c.1418A>T (p.Asn473Ile)	MBTPS2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · Orphanet: 7 · 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
MBTPS2	Strong	X-linked	Olmsted syndrome, X-linked	16

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MBTPS2	Orphanet:216796	Osteogenesis imperfecta type 1
MBTPS2	Orphanet:216812	Osteogenesis imperfecta type 3
MBTPS2	Orphanet:216820	Osteogenesis imperfecta type 4
MBTPS2	Orphanet:2273	Ichthyosis follicularis-alopecia-photophobia syndrome
MBTPS2	Orphanet:2340	Keratosis follicularis spinulosa decalvans
MBTPS2	Orphanet:659	Mutilating palmoplantar keratoderma with periorificial keratotic plaques
MBTPS2	Orphanet:85284	BRESEK syndrome

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
MBTPS2	HGNC:15455	ENSG00000012174	O43462	Membrane-bound transcription factor site-2 protease	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MBTPS2	Membrane-bound transcription factor site-2 protease	Zinc metalloprotease that mediates intramembrane proteolysis of proteins such as ATF6, ATF6B, SREBF1/SREBP1 and SREBF2/SREBP2.

Protein-family classification

Druggable: 1 · 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
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MBTPS2	Protease	yes	3.4.24.85	MBTPS2, Peptidase_M50, PDZ_sf

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
endothelial cell	1
parietal pleura	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MBTPS2	264	ubiquitous	marker	endothelial cell, tibia, parietal pleura

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MBTPS2	2,136

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MBTPS2	O43462	87.78

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. 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
ATF6B (ATF6-beta) activates chaperones	1	2855.0×	0.004	MBTPS2
ATF6 (ATF6-alpha) activates chaperones	1	1903.3×	0.004	MBTPS2
CREB3 factors activate genes	1	1268.9×	0.004	MBTPS2
Assembly of active LPL and LIPC lipase complexes	1	601.0×	0.006	MBTPS2
Plasma lipoprotein remodeling	1	475.8×	0.006	MBTPS2
Unfolded Protein Response (UPR)	1	356.9×	0.006	MBTPS2
Regulation of cholesterol biosynthesis by SREBP (SREBF)	1	317.2×	0.006	MBTPS2
Plasma lipoprotein assembly, remodeling, and clearance	1	228.4×	0.008	MBTPS2
Metabolism of steroids	1	137.6×	0.011	MBTPS2
Cellular responses to stress	1	36.8×	0.037	MBTPS2
Metabolism of lipids	1	31.6×	0.037	MBTPS2
Cellular responses to stimuli	1	31.5×	0.037	MBTPS2
Transport of small molecules	1	25.1×	0.043	MBTPS2
Metabolism	1	11.6×	0.086	MBTPS2

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
bone maturation	1	5617.3×	0.002	MBTPS2
regulation of response to endoplasmic reticulum stress	1	3370.4×	0.002	MBTPS2
ATF6-mediated unfolded protein response	1	2106.5×	0.002	MBTPS2
regulation of cholesterol biosynthetic process	1	1532.0×	0.002	MBTPS2
membrane protein intracellular domain proteolysis	1	1203.7×	0.002	MBTPS2
positive regulation of cholesterol biosynthetic process	1	1123.5×	0.002	MBTPS2
mitotic G2 DNA damage checkpoint signaling	1	443.5×	0.004	MBTPS2
endoplasmic reticulum unfolded protein response	1	295.6×	0.005	MBTPS2
cholesterol metabolic process	1	195.9×	0.007	MBTPS2
response to endoplasmic reticulum stress	1	166.8×	0.007	MBTPS2
protein maturation	1	163.6×	0.007	MBTPS2
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	MBTPS2

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
MBTPS2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MBTPS2	3.4.24.85	S2P endopeptidase

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	1	MBTPS2
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)
MBTPS2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.