Autosomal dominant osteopetrosis 1

Summary

Autosomal dominant osteopetrosis 1 (MONDO:0011877) is a disease caused by LRP5 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: LRP5 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 486

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		33	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant osteopetrosis 1
Mondo ID	MONDO:0011877
MeSH	C536056
OMIM	607634
Orphanet	2783
DOID	DOID:0110937
UMLS	C1843330
MedGen	335932
GARD	0004151
Is cancer (heuristic)	no

Also known as: autosomal dominant osteopetrosis type 1 · LRP5 osteopetrosis (disease) · OPTA1 · osteopetrosis (disease) caused by mutation in LRP5 · osteopetrosis autosomal dominant type 1 · osteopetrosis, autosomal dominant 1 · osteopetrosis, autosomal dominant type 1

Data availability: 486 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › autosomal dominant osteopetrosis › autosomal dominant osteopetrosis 1

Related subtypes (3): autosomal dominant osteopetrosis 2, osteopetrosis, autosomal dominant 3, osteopetrosis, autosomal dominant 4

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

486 retrieved; paginated sample, class counts are floors:

307 uncertain significance, 69 likely benign, 61 conflicting classifications of pathogenicity, 21 benign/likely benign, 11 pathogenic/likely pathogenic, 8 likely pathogenic, 5 pathogenic, 3 benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
801448	NM_000085.5(CLCNKB):c.910C>T (p.Arg304Ter)	CLCNKB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1179140	NM_002335.4(LRP5):c.2555C>T (p.Thr852Met)	LRP5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1450334	NM_002335.4(LRP5):c.3122C>T (p.Thr1041Met)	LRP5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1512510	NM_002335.4(LRP5):c.3236+2T>G	LRP5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
191023	NM_002335.4(LRP5):c.685C>T (p.Arg229Trp)	LRP5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1943870	NM_002335.4(LRP5):c.4263del (p.Phe1422fs)	LRP5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
225406	NM_002335.4(LRP5):c.593A>G (p.Asn198Ser)	LRP5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
287187	NM_002335.4(LRP5):c.2737dup (p.Cys913fs)	LRP5	Pathogenic	criteria provided, multiple submitters, no conflicts
4796870	NM_002335.4(LRP5):c.2717_2718del (p.Cys906fs)	LRP5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6269	NM_002335.4(LRP5):c.1282C>T (p.Arg428Ter)	LRP5	Pathogenic	criteria provided, multiple submitters, no conflicts
6274	NM_002335.4(LRP5):c.1481G>A (p.Arg494Gln)	LRP5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6281	NM_002335.4(LRP5):c.511G>C (p.Gly171Arg)	LRP5	Pathogenic	no assertion criteria provided
6282	NM_002335.4(LRP5):c.724G>A (p.Ala242Thr)	LRP5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6283	NM_002335.4(LRP5):c.640G>A (p.Ala214Thr)	LRP5	Pathogenic	criteria provided, multiple submitters, no conflicts
6285	NM_002335.4(LRP5):c.758C>T (p.Thr253Ile)	LRP5	Pathogenic	no assertion criteria provided
865885	NM_002335.4(LRP5):c.209_210delinsAA (p.Phe70Ter)	LRP5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1520877	NM_002335.4(LRP5):c.1210G>A (p.Gly404Arg)	LRP5	Likely pathogenic	criteria provided, multiple submitters, no conflicts
162391	NM_002335.4(LRP5):c.3562C>T (p.Arg1188Trp)	LRP5	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2085657	NM_002335.4(LRP5):c.1378G>A (p.Glu460Lys)	LRP5	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2152119	NM_002335.4(LRP5):c.3863A>G (p.Asp1288Gly)	LRP5	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3573936	NM_002335.4(LRP5):c.4191_4192dup (p.Phe1398fs)	LRP5	Likely pathogenic	criteria provided, single submitter
3600191	NM_002335.4(LRP5):c.1264G>A (p.Ala422Thr)	LRP5	Likely pathogenic	criteria provided, single submitter
3600192	NM_002335.4(LRP5):c.1293C>G (p.Tyr431Ter)	LRP5	Likely pathogenic	criteria provided, single submitter
3600212	NM_002335.4(LRP5):c.2626G>A (p.Gly876Ser)	LRP5	Likely pathogenic	criteria provided, single submitter
1008864	NM_002335.4(LRP5):c.1096G>A (p.Val366Met)	LRP5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1009413	NM_002335.4(LRP5):c.1331G>A (p.Arg444His)	LRP5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1025837	NM_002335.4(LRP5):c.1183C>T (p.Arg395Trp)	LRP5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1042717	NM_002335.4(LRP5):c.4566G>A (p.Pro1522=)	LRP5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1043257	NM_002335.4(LRP5):c.533G>A (p.Arg178Gln)	LRP5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1060132	NM_002335.4(LRP5):c.4466C>T (p.Thr1489Met)	LRP5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 26 · Orphanet: 12 · 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
LRP5	Strong	Autosomal dominant	autosomal dominant osteopetrosis 1	26

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LRP5	Orphanet:178377	Osteosclerosis-developmental delay-craniosynostosis syndrome
LRP5	Orphanet:2783	Autosomal dominant osteopetrosis type 1
LRP5	Orphanet:2788	Osteoporosis-pseudoglioma syndrome
LRP5	Orphanet:2790	Endosteal hyperostosis, Worth type
LRP5	Orphanet:2924	Isolated polycystic liver disease
LRP5	Orphanet:3416	Hyperostosis corticalis generalisata
LRP5	Orphanet:498481	LRP5-related primary osteoporosis
LRP5	Orphanet:891	Familial exudative vitreoretinopathy
LRP5	Orphanet:90050	Retinopathy of prematurity
CLCNKB	Orphanet:358	Gitelman syndrome
CLCNKB	Orphanet:89938	Bartter syndrome type 4
CLCNKB	Orphanet:93605	Bartter syndrome type 3

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
LRP5	HGNC:6697	ENSG00000162337	O75197	Low-density lipoprotein receptor-related protein 5	gencc,clinvar
CLCNKB	HGNC:2027	ENSG00000184908	P51801	Chloride channel protein ClC-Kb	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LRP5	Low-density lipoprotein receptor-related protein 5	Acts as a coreceptor with members of the frizzled family of seven-transmembrane spanning receptors to transduce signal by Wnt proteins.
CLCNKB	Chloride channel protein ClC-Kb	Anion-selective channel permeable to small monovalent anions with ion selectivity for chloride > bromide > nitrate > iodide.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LRP5	Other/Unknown	no		LDLR_classB_rpt, EGF, LDrepeatLR_classA_rpt
CLCNKB	Other/Unknown	no		CBS_dom, ClC, Cl_channel-K

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
ascending aorta	1
mucosa of transverse colon	1
right lobe of liver	1
adult mammalian kidney	1
metanephros cortex	1
renal medulla	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LRP5	224	ubiquitous	marker	right lobe of liver, mucosa of transverse colon, ascending aorta
CLCNKB	165	broad	marker	renal medulla, adult mammalian kidney, metanephros cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LRP5	2,619
CLCNKB	767

Structural data

PDB: 0 · AlphaFold-only: 2 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CLCNKB	P51801	87.16
LRP5	O75197	78.65

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. 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
Signaling by LRP5 mutants	1	815.7×	0.009	LRP5
Signaling by RNF43 mutants	1	634.4×	0.009	LRP5
Negative regulation of TCF-dependent signaling by WNT ligand antagonists	1	356.9×	0.009	LRP5
Signaling by WNT in cancer	1	300.5×	0.009	LRP5
Regulation of FZD by ubiquitination	1	259.6×	0.009	LRP5
Disassembly of the destruction complex and recruitment of AXIN to the membrane	1	178.4×	0.011	LRP5
Stimuli-sensing channels	1	68.0×	0.024	CLCNKB
TCF dependent signaling in response to WNT	1	58.9×	0.024	LRP5
Signaling by WNT	1	56.0×	0.024	LRP5
Diseases of signal transduction by growth factor receptors and second messengers	1	28.4×	0.042	LRP5
Disease	1	6.5×	0.160	LRP5
Signal Transduction	1	5.1×	0.187	LRP5

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
cell-cell signaling involved in mammary gland development	1	2808.7×	0.004	LRP5
mesodermal cell migration	1	1685.2×	0.004	LRP5
extracellular matrix-cell signaling	1	1685.2×	0.004	LRP5
anatomical structure regression	1	1685.2×	0.004	LRP5
Norrin signaling pathway	1	1685.2×	0.004	LRP5
apoptotic process involved in blood vessel morphogenesis	1	1404.3×	0.004	LRP5
establishment of blood-retinal barrier	1	1404.3×	0.004	LRP5
glucose catabolic process	1	1203.7×	0.004	LRP5
retinal blood vessel morphogenesis	1	1203.7×	0.004	LRP5
transepithelial chloride transport	1	936.2×	0.004	CLCNKB
retina morphogenesis in camera-type eye	1	936.2×	0.004	LRP5
renal absorption	1	842.6×	0.004	CLCNKB
cell migration involved in gastrulation	1	766.0×	0.004	LRP5
bone marrow development	1	766.0×	0.004	LRP5
osteoblast proliferation	1	702.2×	0.004	LRP5
branching involved in mammary gland duct morphogenesis	1	702.2×	0.004	LRP5
establishment of blood-brain barrier	1	702.2×	0.004	LRP5
positive regulation of osteoblast proliferation	1	601.9×	0.004	LRP5
osteoblast development	1	495.6×	0.004	LRP5
renal sodium ion absorption	1	495.6×	0.004	CLCNKB
gastrulation with mouth forming second	1	468.1×	0.004	LRP5
bone remodeling	1	468.1×	0.004	LRP5
regulation of insulin secretion involved in cellular response to glucose stimulus	1	468.1×	0.004	LRP5
positive regulation of mesenchymal cell proliferation	1	300.9×	0.006	LRP5
bone morphogenesis	1	300.9×	0.006	LRP5
positive regulation of mitotic nuclear division	1	271.8×	0.007	LRP5
chloride transport	1	227.7×	0.008	CLCNKB
adipose tissue development	1	200.6×	0.008	LRP5
response to peptide hormone	1	195.9×	0.008	LRP5
amino acid transport	1	156.0×	0.010	LRP5

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
LRP5	0	0
CLCNKB	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
LRP5	1	Binding:1

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	0
E	Difficult family or no structure, no drug	2	LRP5, CLCNKB

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)
LRP5	1	—
CLCNKB	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.