WNT1 – Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a heritable bone‐fragility disorder characterized by low bone mass, frequent fractures, and skeletal deformities. While most cases are due to dominant COL1A1/COL1A2 variants, biallelic loss-of-function mutations in WNT1 underlie a recessive form of OI (type XV) with variable extra-skeletal involvement. WNT1 encodes a secreted ligand activating canonical WNT/β-catenin signaling in osteoblasts, critical for bone formation.

1 Clinical Validity

A total of ≥30 unrelated probands from AR-OI cohorts carry biallelic WNT1 variants with consistent phenotypes, including severe vertebral compression fractures and multiple long-bone fractures (PMID:33093841). Segregation in consanguineous families, including 9 affected relatives in a large Pakistani pedigree, further supports pathogenicity (PMID:30447692). Experimental concordance across in vitro and in vivo models establishes WNT1 as a definitive OI gene.

2 Genetic Evidence

WNT1-related OI is inherited in an autosomal recessive manner. Case series document ≥30 probands with biallelic WNT1 variants (PMID:33093841), including missense (e.g., c.369A>T (p.Glu123Asp)), nonsense, splice, and frameshift alleles. Segregation analysis in a large Pakistani family showed 9 affected individuals homozygous for p.Gly324Cys (PMID:30447692). The variant spectrum encompasses at least 20 distinct alleles, with recurrent founder and hotspot mutations reported in multiple populations.

3 Functional Evidence

Functional studies demonstrate that pathogenic WNT1 variants fail to activate canonical WNT/β-catenin signaling in TopFlash assays (e.g., p.Cys143Phe, p.Val355Phe) and reduce osteoblast differentiation and mineralization (PMID:23499309). The Wnt1(sw/sw) mouse model recapitulates OI features, including osteopenia and bone fragility, confirming loss-of-function in vivo (PMID:24634143). Mesenchymal-specific Wnt1 deletion in mice leads to spontaneous fractures due to impaired osteoblast activity and increased osteoclastogenesis (PMID:30690791).

4 Integration and Conclusion

Both genetic and experimental data provide definitive evidence that biallelic WNT1 mutations cause a recessive form of OI (type XV). The genotype–phenotype correlation indicates that truncating alleles confer more severe skeletal phenotypes and earlier fracture onset. Functional assays and animal models confirm a haploinsufficient mechanism via impaired canonical WNT signaling. WNT1 testing should be included in diagnostic panels for OI, and variant interpretation benefits from combined segregation and functional data.

Key Take-home: Biallelic loss-of-function WNT1 variants definitively cause autosomal recessive osteogenesis imperfecta (type XV), with consistent clinical and functional evidence supporting molecular diagnosis and potential therapeutic targeting of WNT signaling.

References

• Journal of medical genetics • 2013 • Mutations in WNT1 are a cause of osteogenesis imperfecta. PMID:23434763
• Frontiers in genetics • 2020 • Genotypic and Phenotypic Analysis in Chinese Cohort With Autosomal Recessive Osteogenesis Imperfecta. PMID:33093841
• Journal of biomedical science • 2018 • Novel mutation G324C in WNT1 mapped in a large Pakistani family with severe recessively inherited Osteogenesis Imperfecta. PMID:30447692
• Human molecular genetics • 2014 • The swaying mouse as a model of osteogenesis imperfecta caused by WNT1 mutations. PMID:24634143
• American journal of human genetics • 2013 • Mutations in WNT1 cause different forms of bone fragility. PMID:23499309
• Journal of bone and mineral research • 2019 • Mesenchymal Cell-Derived Juxtacrine Wnt1 Signaling Regulates Osteoblast Activity and Osteoclast Differentiation. PMID:30690791

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