Keratosis follicularis spinulosa decalvans

Summary

Keratosis follicularis spinulosa decalvans (MONDO:0000136) is a disease caused by MBTPS2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Europe)
• Causal gene: MBTPS2 (GenCC Definitive)
• Cohort genes: 2
• Phenotypes (HPO): 17

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	<1 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

17 HPO clinical features (Orphanet curated; top 17 by frequency):

HPO ID	Term	Frequency
HP:0000653	Sparse eyelashes	Frequent (30-79%)
HP:0000989	Pruritus	Frequent (30-79%)
HP:0001041	Facial erythema	Frequent (30-79%)
HP:0002287	Progressive alopecia	Frequent (30-79%)
HP:0004552	Scarring alopecia of scalp	Frequent (30-79%)
HP:0007502	Follicular hyperkeratosis	Frequent (30-79%)
HP:0025084	Folliculitis	Frequent (30-79%)
HP:0032152	Keratosis pilaris	Frequent (30-79%)
HP:0045059	Hyperkeratotic papule	Frequent (30-79%)
HP:0045075	Sparse eyebrow	Frequent (30-79%)
HP:0000498	Blepharitis	Occasional (5-29%)
HP:0000509	Conjunctivitis	Occasional (5-29%)
HP:0000613	Photophobia	Occasional (5-29%)
HP:0000982	Palmoplantar keratoderma	Occasional (5-29%)
HP:0001047	Atopic dermatitis	Occasional (5-29%)
HP:0001131	Corneal dystrophy	Occasional (5-29%)
HP:0008404	Nail dystrophy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	keratosis follicularis spinulosa decalvans
Mondo ID	MONDO:0000136
Orphanet	2340
DOID	DOID:0080753
ICD-11	303213910
SNOMED CT	238626006
UMLS	C0343057
MedGen	83355
GARD	0006829
NORD	1288
Is cancer (heuristic)	no

Also known as: keratosis pilaris decalvans

Data availability: 3 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › keratosis › keratosis follicularis spinulosa decalvans

Related subtypes (8): acquired keratosis, cholesteatoma, palmoplantar keratosis, porokeratosis, hereditary papulotranslucent acrokeratoderma, acrokeratosis verruciformis, seborrheic keratosis, trichostasis spinulosa

Subtypes (2): keratosis follicularis spinulosa decalvans, X-linked, keratosis follicularis spinulosa decalvans, autosomal dominant

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 23 · Orphanet: 9 · 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	Definitive	X-linked	keratosis follicularis spinulosa decalvans	16
LRP1	Moderate	Autosomal recessive	keratosis pilaris atrophicans	7

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
LRP1	Orphanet:2340	Keratosis follicularis spinulosa decalvans
LRP1	Orphanet:79100	Atrophoderma vermiculata

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
MBTPS2	HGNC:15455	ENSG00000012174	O43462	Membrane-bound transcription factor site-2 protease	gencc
LRP1	HGNC:6692	ENSG00000123384	Q07954	Prolow-density lipoprotein receptor-related protein 1	gencc

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.
LRP1	Prolow-density lipoprotein receptor-related protein 1	Endocytic receptor involved in endocytosis and in phagocytosis of apoptotic cells.

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
Protease	1	18.3×	0.108
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MBTPS2	Protease	yes	3.4.24.85	MBTPS2, Peptidase_M50, PDZ_sf
LRP1	Other/Unknown	no		LDLR_classB_rpt, EGF-type_Asp/Asn_hydroxyl_site, EGF

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
endothelial cell	1
parietal pleura	1
tibia	1
ascending aorta	1
descending thoracic aorta	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MBTPS2	264	ubiquitous	marker	endothelial cell, tibia, parietal pleura
LRP1	293	ubiquitous	marker	stromal cell of endometrium, descending thoracic aorta, ascending aorta

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LRP1	2,662
MBTPS2	2,136

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LRP1	Q07954	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MBTPS2	O43462	87.78

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 22. 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
ATF6B (ATF6-beta) activates chaperones	1	1427.5×	0.012	MBTPS2
ATF6 (ATF6-alpha) activates chaperones	1	951.7×	0.012	MBTPS2
CREB3 factors activate genes	1	634.4×	0.012	MBTPS2
Scavenging of heme from plasma	1	439.2×	0.013	LRP1
Assembly of active LPL and LIPC lipase complexes	1	300.5×	0.013	MBTPS2
Binding and Uptake of Ligands by Scavenger Receptors	1	271.9×	0.013	LRP1
Plasma lipoprotein remodeling	1	237.9×	0.013	MBTPS2
Metabolism of fat-soluble vitamins	1	190.3×	0.014	LRP1
Unfolded Protein Response (UPR)	1	178.4×	0.014	MBTPS2
Regulation of cholesterol biosynthesis by SREBP (SREBF)	1	158.6×	0.014	MBTPS2
Visual phototransduction	1	129.8×	0.014	LRP1
Retinoid metabolism and transport	1	124.1×	0.014	LRP1
Metabolism	2	11.6×	0.014	MBTPS2, LRP1
Plasma lipoprotein assembly, remodeling, and clearance	1	114.2×	0.014	MBTPS2
Metabolism of steroids	1	68.8×	0.021	MBTPS2
Metabolism of vitamins and cofactors	1	58.3×	0.023	LRP1
Sensory Perception	1	47.6×	0.027	LRP1
Cellular responses to stress	1	18.4×	0.065	MBTPS2
Vesicle-mediated transport	1	17.4×	0.066	LRP1
Metabolism of lipids	1	15.8×	0.066	MBTPS2
Cellular responses to stimuli	1	15.7×	0.066	MBTPS2
Transport of small molecules	1	12.6×	0.078	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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of transcytosis	1	8426.0×	0.003	LRP1
positive regulation of lipid transport	1	4213.0×	0.003	LRP1
positive regulation of reverse cholesterol transport	1	4213.0×	0.003	LRP1
bone maturation	1	2808.7×	0.003	MBTPS2
astrocyte activation involved in immune response	1	2106.5×	0.003	LRP1
negative regulation of platelet-derived growth factor receptor-beta signaling pathway	1	2106.5×	0.003	LRP1
regulation of extracellular matrix disassembly	1	1685.2×	0.003	LRP1
positive regulation of lysosomal protein catabolic process	1	1685.2×	0.003	LRP1
regulation of response to endoplasmic reticulum stress	1	1685.2×	0.003	MBTPS2
amyloid-beta clearance by transcytosis	1	1203.7×	0.003	LRP1
ATF6-mediated unfolded protein response	1	1053.2×	0.003	MBTPS2
amyloid-beta clearance by cellular catabolic process	1	1053.2×	0.003	LRP1
positive regulation of amyloid-beta clearance	1	1053.2×	0.003	LRP1
regulation of extracellular matrix organization	1	936.2×	0.003	LRP1
transcytosis	1	842.6×	0.003	LRP1
negative regulation of smooth muscle cell migration	1	766.0×	0.003	LRP1
regulation of cholesterol biosynthetic process	1	766.0×	0.003	MBTPS2
enzyme-linked receptor protein signaling pathway	1	648.1×	0.004	LRP1
membrane protein intracellular domain proteolysis	1	601.9×	0.004	MBTPS2
positive regulation of cholesterol biosynthetic process	1	561.7×	0.004	MBTPS2
lipoprotein transport	1	495.6×	0.004	LRP1
amyloid-beta clearance	1	468.1×	0.004	LRP1
aorta morphogenesis	1	443.5×	0.004	LRP1
apoptotic cell clearance	1	443.5×	0.004	LRP1
positive regulation of endocytosis	1	401.2×	0.004	LRP1
lysosomal transport	1	351.1×	0.005	LRP1
positive regulation of cholesterol efflux	1	312.1×	0.005	LRP1
negative regulation of SMAD protein signal transduction	1	300.9×	0.005	LRP1
retinoid metabolic process	1	247.8×	0.006	LRP1
mitotic G2 DNA damage checkpoint signaling	1	221.7×	0.007	MBTPS2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
LRP1	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: 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	0
D	Druggable family + AlphaFold only, no drug	1	MBTPS2
E	Difficult family or no structure, no drug	1	LRP1

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)
MBTPS2	0	—
LRP1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.