LRP4 – Sclerosteosis 2

LRP4 encodes a Wnt signaling coreceptor that binds sclerostin to inhibit canonical Wnt/β-catenin signaling in bone. Biallelic pathogenic variants in LRP4 cause sclerosteosis type 2, an autosomal recessive high bone mass disorder characterized by cranial and tubular bone hyperostosis.

Clinical Validity (Strong)

Three unrelated probands with biallelic LRP4 variants have been reported with sclerosteosis, supported by functional studies and a knock-in mouse model ([PMID:26751728]; [PMID:35052419]; [PMID:32286743]).

Genetic Evidence (Moderate)

Inheritance is autosomal recessive with recessive segregation of variants in three independent families. No additional affected relatives beyond the proband generation have been described. Disease-causing variants include missense changes within the third β-propeller domain and splice-site variants outside this region. A recurrent variant, c.3509G>A (p.Arg1170Gln), impairs sclerostin binding and recurs in multiple probands ([PMID:26751728]).

Functional Evidence (Moderate)

Luciferase reporter assays demonstrate that p.Arg1170Gln and p.Arg632His reduce sclerostin-mediated inhibition of Wnt signaling in vitro ([PMID:26751728]; [PMID:35052419]). Circulating sclerostin levels are markedly elevated in patients, indicating loss of bone retention. An Lrp4R1170Q/R1170Q knock-in mouse recapitulates the human high bone mass phenotype and increased serum sclerostin ([PMID:28477420]).

Mechanism of Pathogenicity

Recessive loss-of-function variants disrupt the sclerostin–LRP4 interaction, leading to unchecked Wnt activation and high bone mass. Impaired membrane trafficking is not implicated in sclerosteosis alleles.

Conflicting Evidence

No studies have refuted the association of biallelic LRP4 variants with sclerosteosis 2.

Conclusion

Biallelic LRP4 variants causing loss of sclerostin retention underlie autosomal recessive sclerosteosis 2; genetic testing of LRP4 informs diagnosis and management of this high bone mass disorder.

References

• Journal of bone and mineral research • 2016 • A Novel Domain-Specific Mutation in a Sclerosteosis Patient Suggests a Role of LRP4 as an Anchor for Sclerostin in Human Bone PMID:26751728
• Genes • 2021 • Identification of Compound Heterozygous Variants in LRP4 Demonstrates That a Pathogenic Variant outside the Third β-Propeller Domain Can Cause Sclerosteosis PMID:35052419
• Birth defects research • 2020 • A novel biallelic splice-site variant in the LRP4 gene causes sclerosteosis 2. PMID:32286743
• Journal of bone and mineral research • 2017 • The Lrp4R1170Q Homozygous Knock-In Mouse Recapitulates the Bone Phenotype of Sclerosteosis in Humans. PMID:28477420

Evidence Based Scoring (AI generated)