LRP4 – Sclerosteosis Type 2

Sclerosteosis Type 2 is a rare autosomal recessive bone dysplasia characterized by progressive hyperostosis of the skull and tubular bones, often accompanied by syndactyly. It results from loss of function of LRP4, a co-receptor for sclerostin that negatively regulates WNT/β-catenin signaling. This entity is classified as Sclerosteosis 2 and is clinically and genetically distinct from SOST‐related sclerosteosis. Biallelic pathogenic variants in LRP4 abrogate sclerostin‐mediated inhibition of WNT signaling, leading to excessive bone formation and high bone mass.

Genetic evidence includes three unrelated probands with molecularly confirmed sclerosteosis Type 2 (PMID:32286743; PMID:26751728; PMID:35052419). One patient harbored a homozygous splice–site variant c.1048+6T>C that disrupts the native donor site and impairs an SC35 enhancer element (PMID:32286743). A second individual carried a homozygous missense variant c.3509G>A (p.Arg1170Gln) in the third β-propeller domain (PMID:26751728). A third case exhibited compound heterozygosity for c.1895G>A (p.Arg632His) and the recurrent c.3509G>A (p.Arg1170Gln) allele, broadening the mutational spectrum to the first propeller domain (PMID:35052419). No extended segregation data have been reported.

Functional assays provide strong support for pathogenicity. In silico and minigene analyses confirm that c.1048+6T>C abolishes canonical splicing of LRP4 transcripts (PMID:32286743). Luciferase reporter assays demonstrate that both p.Arg1170Gln and p.Arg632His weaken LRP4’s facilitation of sclerostin inhibition on WNT/β‐catenin signaling, resulting in pathway overactivation (PMID:26751728; PMID:35052419). Biochemical studies confirm reduced affinity of mutant LRP4 extracellular domains for sclerostin.

An Lrp4R1170Q/R1170Q knock-in mouse model recapitulates key aspects of the human phenotype, exhibiting increased trabecular and cortical bone mass, enhanced bone strength, elevated serum sclerostin, and decreased bone sclerostin deposition (PMID:28477420). This in vivo evidence confirms that impaired anchoring of sclerostin by mutant LRP4 is central to the disease mechanism.

Collectively, three independent probands with biallelic LRP4 variants, concordant in vitro functional deficits, and a corroborating animal model establish a Moderate level of clinical validity for LRP4 in Sclerosteosis Type 2. Genetic testing panels for hyperostosis syndromes should include LRP4 splice–site and missense variants across all β-propeller domains. Early radiological assessment, including skull imaging in patients presenting with syndactyly, is essential to distinguish Sclerosteosis Type 2 from isolated limb malformations.

References

• 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 • 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
• Journal of bone and mineral research • 2017 • The Lrp4R1170Q Homozygous Knock-In Mouse Recapitulates the Bone Phenotype of Sclerosteosis in Humans. PMID:28477420
• 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

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