High bone mass osteogenesis imperfecta

Summary

High bone mass osteogenesis imperfecta (MONDO:0017791) is a disease with 3 cohort genes. The dominant Reactome pathway is Anchoring fibril formation (3 cohort genes).

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 3

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	high bone mass osteogenesis imperfecta
Mondo ID	MONDO:0017791
Orphanet	314029
UMLS	C5190607
MedGen	1672817
GARD	0021366
Is cancer (heuristic)	no

Also known as: high bone mass OI

Data availability: 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 › high bone mass osteogenesis imperfecta

Related subtypes (9): brittle bone disorder, osteogenesis imperfecta type 13, osteogenesis imperfecta-retinopathy-seizures-intellectual disability syndrome, osteogenesis imperfecta, IIA 22, osteogenesis imperfecta, type 21, osteogenesis imperfecta, type 20, COL1A2-related osteogenesis imperfecta, osteogenesis imperfecta and a reduction of bone mineral density., osteogenesis imperfecta, type 23

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: 46 · Orphanet: 20 · 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
COL1A1	Definitive	Autosomal dominant	osteogenesis imperfecta type 4	20
COL1A2	Definitive	Autosomal dominant	osteogenesis imperfecta	21
BMP1	Strong	Autosomal recessive	osteogenesis imperfecta type 13	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BMP1	Orphanet:216812	Osteogenesis imperfecta type 3
BMP1	Orphanet:314029	High bone mass osteogenesis imperfecta
COL1A1	Orphanet:1310	Caffey disease
COL1A1	Orphanet:1899	Arthrochalasia Ehlers-Danlos syndrome
COL1A1	Orphanet:216796	Osteogenesis imperfecta type 1
COL1A1	Orphanet:216804	Osteogenesis imperfecta type 2
COL1A1	Orphanet:216812	Osteogenesis imperfecta type 3
COL1A1	Orphanet:216820	Osteogenesis imperfecta type 4
COL1A1	Orphanet:230857	Ehlers-Danlos/osteogenesis imperfecta syndrome
COL1A1	Orphanet:287	Classical Ehlers-Danlos syndrome
COL1A1	Orphanet:31112	Dermatofibrosarcoma protuberans
COL1A1	Orphanet:314029	High bone mass osteogenesis imperfecta
COL1A2	Orphanet:1899	Arthrochalasia Ehlers-Danlos syndrome
COL1A2	Orphanet:216796	Osteogenesis imperfecta type 1
COL1A2	Orphanet:216804	Osteogenesis imperfecta type 2
COL1A2	Orphanet:216812	Osteogenesis imperfecta type 3
COL1A2	Orphanet:216820	Osteogenesis imperfecta type 4
COL1A2	Orphanet:230851	Cardiac-valvular Ehlers-Danlos syndrome
COL1A2	Orphanet:230857	Ehlers-Danlos/osteogenesis imperfecta syndrome
COL1A2	Orphanet:314029	High bone mass osteogenesis imperfecta

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BMP1	HGNC:1067	ENSG00000168487	P13497	Bone morphogenetic protein 1	gencc
COL1A1	HGNC:2197	ENSG00000108821	P02452	Collagen alpha-1(I) chain	gencc
COL1A2	HGNC:2198	ENSG00000164692	P08123	Collagen alpha-2(I) chain	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BMP1	Bone morphogenetic protein 1	Metalloprotease that plays key roles in regulating the formation of the extracellular matrix (ECM) via processing of various precursor proteins into mature functional enzymes or structural proteins.
COL1A1	Collagen alpha-1(I) chain	Type I collagen is a member of group I collagen (fibrillar forming collagen).
COL1A2	Collagen alpha-2(I) chain	Type I collagen is a member of group I collagen (fibrillar forming collagen).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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	12.2×	0.159
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BMP1	Protease	yes	2.7.11.4	EGF-type_Asp/Asn_hydroxyl_site, EGF, CUB_dom
COL1A1	Other/Unknown	no		Fib_collagen_C, VWF_dom, Collagen
COL1A2	Other/Unknown	no		Fib_collagen_C, Collagen, Collagen_superfamily

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
stromal cell of endometrium	3
periodontal ligament	2
skin of hip	2
left uterine tube	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BMP1	236	ubiquitous	marker	stromal cell of endometrium, left uterine tube, right adrenal gland cortex
COL1A1	298	ubiquitous	marker	stromal cell of endometrium, skin of hip, periodontal ligament
COL1A2	295	ubiquitous	marker	periodontal ligament, stromal cell of endometrium, skin of hip

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COL1A1	5,341
BMP1	2,003
COL1A2	179

Intra-cohort edges

A	B	Sources
COL1A1	COL1A2	intact

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COL1A1	P02452	14
BMP1	P13497	8
COL1A2	P08123	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 32. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Anchoring fibril formation	3	761.3×	6e-08	BMP1, COL1A1, COL1A2
Crosslinking of collagen fibrils	3	571.0×	7e-08	BMP1, COL1A1, COL1A2
Defective VWF binding to collagen type I	2	2537.8×	1e-06	COL1A1, COL1A2
Assembly of collagen fibrils and other multimeric structures	3	200.3×	1e-06	BMP1, COL1A1, COL1A2
Collagen biosynthesis and modifying enzymes	3	170.4×	1e-06	BMP1, COL1A1, COL1A2
Enhanced cleavage of VWF variant by ADAMTS13	2	1903.3×	1e-06	COL1A1, COL1A2
Defective VWF cleavage by ADAMTS13 variant	2	1903.3×	1e-06	COL1A1, COL1A2
Enhanced binding of GP1BA variant to VWF multimer:collagen	2	1087.6×	3e-06	COL1A1, COL1A2
Defective binding of VWF variant to GPIb:IX:V	2	1087.6×	3e-06	COL1A1, COL1A2
GP1b-IX-V activation signalling	2	634.4×	1e-05	COL1A1, COL1A2
Platelet Adhesion to exposed collagen	2	447.8×	2e-05	COL1A1, COL1A2
Scavenging by Class A Receptors	2	400.7×	2e-05	COL1A1, COL1A2
Fibronectin matrix formation	2	380.7×	2e-05	COL1A1, COL1A2
Platelet Aggregation (Plug Formation)	2	292.8×	3e-05	COL1A1, COL1A2
Syndecan interactions	2	282.0×	3e-05	COL1A1, COL1A2
MET activates PTK2 signaling	2	253.8×	4e-05	COL1A1, COL1A2
GPVI-mediated activation cascade	2	205.8×	6e-05	COL1A1, COL1A2
Collagen chain trimerization	2	173.0×	8e-05	COL1A1, COL1A2
Developmental Lineage of Pancreatic Ductal Cells	2	152.3×	9e-05	COL1A1, COL1A2
Collagen degradation	2	117.1×	2e-04	COL1A1, COL1A2
Non-integrin membrane-ECM interactions	2	102.9×	2e-04	COL1A1, COL1A2
ECM proteoglycans	2	100.2×	2e-04	COL1A1, COL1A2
Integrin cell surface interactions	2	89.6×	2e-04	COL1A1, COL1A2
Cell surface interactions at the vascular wall	2	63.4×	4e-04	COL1A1, COL1A2
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	2	58.1×	5e-04	COL1A1, COL1A2
HDL assembly	1	475.8×	0.003	BMP1
Collagen formation	1	152.3×	0.007	BMP1
RUNX2 regulates osteoblast differentiation	1	152.3×	0.007	COL1A1
SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription	1	102.9×	0.011	COL1A2
Degradation of the extracellular matrix	1	39.2×	0.027	BMP1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
collagen fibril organization	3	224.7×	5e-06	BMP1, COL1A1, COL1A2
skeletal system development	3	125.8×	1e-05	BMP1, COL1A1, COL1A2
skin morphogenesis	2	936.2×	3e-05	COL1A1, COL1A2
blood vessel development	2	249.7×	3e-04	COL1A1, COL1A2
cellular response to amino acid stimulus	2	204.3×	4e-04	COL1A1, COL1A2
protein heterotrimerization	1	5617.3×	0.001	COL1A2
cellular response to vitamin E	1	5617.3×	0.001	COL1A1
cellular response to fluoride	1	2808.7×	0.002	COL1A1
tooth mineralization	1	1872.4×	0.003	COL1A1
cellular response to acetaldehyde	1	1123.5×	0.005	COL1A1
intramembranous ossification	1	936.2×	0.005	COL1A1
cartilage development involved in endochondral bone morphogenesis	1	802.5×	0.006	COL1A1
bone trabecula formation	1	702.2×	0.006	COL1A1
collagen-activated tyrosine kinase receptor signaling pathway	1	432.1×	0.009	COL1A1
response to hyperoxia	1	374.5×	0.009	COL1A1
negative regulation of cell-substrate adhesion	1	351.1×	0.009	COL1A1
collagen metabolic process	1	351.1×	0.009	COL1A2
collagen biosynthetic process	1	351.1×	0.009	COL1A1
positive regulation of cartilage development	1	312.1×	0.009	BMP1
extracellular matrix assembly	1	312.1×	0.009	COL1A2
response to steroid hormone	1	280.9×	0.009	COL1A1
cartilage condensation	1	255.3×	0.010	BMP1
endochondral ossification	1	181.2×	0.013	COL1A1
cellular response to fibroblast growth factor stimulus	1	181.2×	0.013	COL1A1
odontogenesis	1	175.5×	0.013	COL1A2
response to cAMP	1	170.2×	0.013	COL1A1
face morphogenesis	1	165.2×	0.013	COL1A1
response to hydrogen peroxide	1	156.0×	0.013	COL1A1
dorsal/ventral pattern formation	1	140.4×	0.014	BMP1
embryonic skeletal system development	1	130.6×	0.014	COL1A1

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 3 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BMP1	0	0
COL1A1	0	0
COL1A2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
BMP1	30	Binding:29, ADMET:1
COL1A1	8	Binding:8
COL1A2	4	Functional:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BMP1	2.7.11.4, 3.4.24.19, 3.4.24.21	[3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)] kinase, procollagen C-endopeptidase, astacin

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	1	BMP1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	COL1A1, COL1A2

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
BMP1	30	—
COL1A1	8	—
COL1A2	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.