LRP5 – Worth-type Autosomal Dominant Osteosclerosis

The low-density lipoprotein receptor-related protein 5 (LRP5) is a Wnt co-receptor essential for skeletal homeostasis. Heterozygous gain-of-function variants cause a high bone mass phenotype historically termed autosomal dominant osteosclerosis or Worth syndrome (autosomal dominant osteosclerosis, Worth type). Clinically, this manifests as endosteal hyperostosis with increased bone mineral density and characteristic facial torus palatinus.

LRP5-related Worth syndrome follows an autosomal dominant inheritance mode. To date, 155 affected individuals across at least 10 unrelated families have been reported with heterozygous LRP5 missense variants (155 probands [PMID:37659026], 10 families [PMID:12579474]). Segregation analyses, including mother–daughter transmission, confirm co-segregation of these variants. Neurological involvement, such as chronic headache and hypo-/anosmia, occurs in 19.4% of cases [PMID:37659026].

The variant spectrum is restricted to missense changes clustering in the extracellular aminoterminal region before the first epidermal growth factor–like domain. Notable pathogenic alleles include c.724G>A (p.Ala242Thr) among six distinct missense variants (e.g., p.Gly171Arg, p.Thr253Ile) [PMID:12579474]. No loss-of-function or splice mutations have been linked to the HBM phenotype, underscoring a specific gain-of-function mechanism.

Functional studies demonstrate that HBM-associated LRP5 mutants reduce binding to and inhibition by Dickkopf-1 and sclerostin, leading to enhanced Wnt/β-catenin signaling. Transgenic mice expressing the human G171V mutant recapitulate high bone mass with dramatic increases in trabecular and cortical bone parameters [PMID:12817748]. In vitro assays of T253I and M282V variants confirm impaired DKK1-mediated inhibition and altered osteoblast differentiation.

No conflicting reports have refuted the pathogenic role of LRP5 gain-of-function variants in Worth syndrome. The robust co-segregation data, absence of these alleles in controls, and concordant functional concordance support a definitive gene–disease relationship.

Genetic testing for LRP5 missense variants is essential for accurate diagnosis and counseling in autosomal dominant osteosclerosis (Worth type). Understanding this gain-of-function mechanism informs clinical decision-making and highlights Wnt pathway modulation as a therapeutic strategy.

References

• Archives of osteoporosis • 2023 • LRP5 high bone mass (Worth-type autosomal dominant endosteal hyperostosis): case report and historical review of the literature. PMID:37659026
• American journal of human genetics • 2003 • Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density. PMID:12579474
• Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research • 2003 • High bone mass in mice expressing a mutant LRP5 gene. PMID:12817748

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