Osteogenesis imperfecta, type 19

Summary

Osteogenesis imperfecta, type 19 (MONDO:0049223) 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: 6

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	osteogenesis imperfecta, type 19
Mondo ID	MONDO:0049223
OMIM	301014
DOID	DOID:0111847
UMLS	C4746956
MedGen	1648353
GARD	0025944
Is cancer (heuristic)	no

Also known as: OI19 · osteogenesis imperfecta, type XIX, X-linked recessive

Data availability: 6 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › osteochondrodysplasia › osteogenesis imperfecta › osteogenesis imperfecta and a reduction of bone mineral density. › osteogenesis imperfecta, type 19

Related subtypes (32): Cole-Carpenter syndrome 1, calvarial doughnut lesions-bone fragility syndrome, osteogenesis imperfecta type 1, osteogenesis imperfecta type 2, osteogenesis imperfecta type 4, gnathodiaphyseal dysplasia, geroderma osteodysplastica, osteogenesis imperfecta type 3, osteogenesis imperfecta type 9, osteoporosis-pseudoglioma syndrome, Wiedemann-Rautenstrauch syndrome, spondylo-ocular syndrome, Bruck syndrome 2, osteogenesis imperfecta type 7, osteogenesis imperfecta type 8, osteogenesis imperfecta type 5, osteogenesis imperfecta type 11, autosomal recessive cutis laxa type 2B, osteogenesis imperfecta type 10, osteogenesis imperfecta type 12, osteogenesis imperfecta type 6, short stature-optic atrophy-Pelger-Huët anomaly syndrome, osteogenesis imperfecta type 14, osteogenesis imperfecta type 15, osteogenesis imperfecta type 16, Cole-Carpenter syndrome 2, Singleton-Merten syndrome 2, osteogenesis imperfecta type 17, autosomal recessive cutis laxa type 2A, Ehlers-Danlos syndrome, spondylodysplastic type, 1, Singleton-Merten syndrome 1, osteogenesis imperfecta, type 18

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

6 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
558767	NM_015884.4(MBTPS2):c.1376A>G (p.Asn459Ser)	MBTPS2	Pathogenic	no assertion criteria provided
558768	NM_015884.4(MBTPS2):c.1515G>C (p.Leu505Phe)	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
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
992371	NM_015884.4(MBTPS2):c.175C>T (p.Arg59Cys)	MBTPS2	Uncertain significance	no assertion criteria provided

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	osteogenesis imperfecta, type 19	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.