LRP6

Chr 12AD

LDL receptor related protein 6

Also known as: ADCAD2, EVR8, OPTA4, STHAG7

NCBI Gene: 4040 ENSG00000070018 UniProt: O75581

The LRP6 protein functions as a cell-surface coreceptor in the Wnt/beta-catenin signaling pathway, which is critical for retinal angiogenesis and bone formation. Mutations cause autosomal dominant disorders including exudative vitreoretinopathy, osteopetrosis, selective tooth agenesis, and coronary artery disease. This gene is highly constrained against loss-of-function variants (LOEUF 0.318), reflecting its essential role in development.

Summary from RefSeq, OMIM, UniProt

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Primary Disease Associations & Inheritance

{Coronary artery disease, autosomal dominant, 2}MIM #610947

Exudative vitreoretinopathy 8MIM #621268

Osteopetrosis, autosomal dominant 4MIM #621449

Tooth agenesis, selective, 7MIM #616724

UniProtVitreoretinopathy, exudative 8

Active trials

120

Pubs (1 yr)

P/LP submissions

P/LP missense

0.32

LOEUF· LoF intol.

LOF

Mechanism· G2P

Clinical Summary— LRP6

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.70) — some intolerance to loss-of-function variants.

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ClinVar Variants

67 unique Pathogenic / Likely Pathogenic· 321 VUS of 600 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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GeneReview available — LRP6

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

0.32LOEUF

pLI 0.697

Z-score 6.79

OE 0.22 (0.15–0.32)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint

2.75Z-score

OE missense 0.74 (0.69–0.79)

657 obs / 887.9 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios

LoF OE0.22 (0.15–0.32)

0≤0.351.4

Missense OE0.74 (0.69–0.79)

0≤0.61.4

Synonymous OE1.07

0≤1.21.6

LoF obs/exp: 19 / 87.6Missense obs/exp: 657 / 887.9Syn Z: -0.92

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedLRP6-related tooth agenesisLOFAD

0.5379th %ile

GOF

0.6833th %ile

LOF

0.58top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 34% of P/LP variants are LoF · LOEUF 0.32

GOFprediction above median · 1 literature citation

DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNDownregulation of LRP6 or coexpression of a truncated LRP6 dominant-negative peptide inhibited cellular uptake of complexes containing the protective antigen (PA) carrier of anthrax toxin moieties and protected targeted cells from death, as did antibodies against epitopes in the LRP6 extracellular dPMID:16564009

GOFOf interest, when overexpressed, D995G did not induce any defects, but Y505C and P1427Q caused more severe CE defects in zebrafish.CONCLUSION: Our results suggested that over-active canonical WNT signaling induced by gain-of-function mutation in LRP6 could also contribute to human NTDs, and a balancPMID:28960852

LOFRather, LRP6 haploinsufficiency increased the activating phosphorylation and decreased the inhibitory phosphorylation of GSK-3ÃÅ½ÃÂ², a kinase involved in proinflammatory signaling and mitochondrial dysfunction.PMID:23743975

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.