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LRP5 is a single‐pass transmembrane co‐receptor in the canonical Wnt/β‐catenin signaling pathway, critical for osteoblast differentiation and cortical bone accrual. Hyperostosis corticalis generalisata is a rare autosomal dominant sclerosing bone dysplasia characterized by diffuse endosteal hyperostosis of long bones and skull, with markedly increased bone mineral density ([HP:0011001]). Heterozygous gain‐of‐function variants in LRP5 have been implicated in familial high bone mass phenotypes overlapping with hyperostosis corticalis generalisata. The inheritance is autosomal dominant with high penetrance and variable expressivity.
Mutation screening in 10 families or isolated patients with increased cortical bone density identified six novel missense variants clustered in the aminoterminal β‐propeller domain of LRP5, among which c.331G>T (p.Asp111Tyr) was observed in a proband with hyperostosis corticalis generalisata ([PMID:12579474]). These six unrelated probands support a strong gene–disease association, with variants segregating in affected family members in at least two pedigrees and absent from population controls. No loss‐of‐function alleles were reported in this disease context, consistent with a gain‐of‐function mechanism.
The variant spectrum in hyperostosis corticalis generalisata comprises missense substitutions affecting highly conserved residues (Asp111, Gly171, Ala214, Ala242, Thr253), all mapping to the first YWTD β‐propeller repeat. Recurrent hotspots include Gly171Arg/Val and Thr253Ile, suggesting critical contact points for regulatory antagonists. No structural or splice variants were described in this cohort.
Functional assays demonstrate that these high bone mass LRP5 mutations reach the cell surface but exhibit reduced binding to the Wnt antagonists DKK1 and SOST, leading to persistent Wnt signaling in osteoblasts. Reduced inhibition by DKK1/SOST was shown using ex vivo reporter assays, correlating with gain‐of‐function effects on canonical Wnt activation ([PMID:12579474]). These data are concordant with the hyperostotic phenotype.
The pathogenic mechanism involves impaired antagonist‐mediated downregulation of LRP5, resulting in osteoblast overactivity and excessive cortical bone deposition. Mouse models expressing the orthologous G171V substitution recapitulate high bone mass and cortical expansion, reinforcing translational relevance. No studies have refuted this association in hyperostosis corticalis generalisata.
In conclusion, heterozygous missense variants in the aminoterminal β‐propeller domain of LRP5 cause autosomal dominant hyperostosis corticalis generalisata by a gain‐of‐function mechanism that diminishes DKK1/SOST inhibition. Genetic testing for LRP5 missense variants enables accurate diagnosis and informs therapeutic strategies targeting Wnt antagonists.
Gene–Disease AssociationStrongSix unrelated probands with heterozygous LRP5 missense variants in hyperostosis corticalis generalisata across multiple families and consistent variant clustering in a critical functional domain ([PMID:12579474]) with supportive experimental data Genetic EvidenceStrongIdentification of six missense variants in six unrelated probands with autosomal dominant hyperostosis corticalis generalisata; segregation in multiple pedigrees and absence in controls Functional EvidenceModerateEx vivo assays demonstrate reduced DKK1/SOST inhibition and enhanced Wnt signaling by HBM-LRP5 variants, consistent with gain-of-function mechanism ([PMID:12579474]) |