WNT1 – Osteogenesis Imperfecta Type XV

Autosomal recessive osteogenesis imperfecta type XV (OI-XV) is caused by biallelic loss-of-function variants in WNT1, a key ligand in the canonical WNT/β-catenin signaling pathway essential for osteoblast differentiation and bone homeostasis. Since the initial report of a homozygous nonsense WNT1 mutation in two siblings with severe OI in 2013 (PMID:23656646), subsequent studies have identified over 25 unrelated patients with OI-XV harboring compound heterozygous or homozygous WNT1 variants (PMID:39126373). Segregation in multiple consanguineous families and in sibling pairs confirms autosomal recessive inheritance (PMID:23499310, PMID:23656646).

Genetic evidence includes a spectrum of variant classes: 8 predicted loss-of-function alleles (nonsense, splice-site, frameshift) and 7 missense changes affecting conserved residues. A representative recurrent variant, c.703C>T (p.Arg235Trp), abolishes WNT1 activity and segregates with OI-XV in affected individuals. Functional tier: Strong. Rationale: 25 probands with biallelic WNT1 variants; segregation in 2 siblings and 4 consanguineous families (PMID:39126373, PMID:23656646, PMID:23499310).

In vitro assays uniformly demonstrate that WNT1 missense and truncating alleles fail to activate LRP5-mediated β-catenin signaling, leading to impaired osteoblast differentiation and matrix mineralization. Animal models strengthen the functional evidence: Wnt1^sw/sw^ (swaying) mice recapitulate human OI-XV bone fragility and osteopenia, with defective osteoblast activity and matrix composition (PMID:24634143). Parathyroid hormone treatment rescues bone formation defects in Wnt1^+/R235W^ mice, underscoring therapeutic potential.

Mechanism of pathogenicity is loss-of-function resulting in haploinsufficiency for heterozygotes and complete loss in homozygotes. Multi-omics analyses of human OI-XV bone samples reveal reduced WNT1 secretion, downregulation of mature osteocyte markers (e.g., SOST), aberrant progenitor differentiation trajectories, and enhanced osteoclast activity (PMID:39126373). These data converge to demonstrate that WNT1 is indispensable for osteoblast maturation and bone matrix quality.

No studies have refuted the WNT1–OI-XV association. The breadth of genetic and experimental concordance establishes a Definitive gene–disease relationship. Clinically, identifying biallelic WNT1 mutations informs prognosis, guides genetic counseling, and supports early initiation of osteoanabolic therapies such as teriparatide or PTH analogs.

Key Take-home: WNT1 loss-of-function causes autosomal recessive OI type XV through deficient canonical WNT signaling, and patients benefit from targeted osteoanabolic treatment.

References

• Bone research • 2021 • The WNT1G177C mutation specifically affects skeletal integrity in a mouse model of osteogenesis imperfecta type XV. PMID:34759273
• Journal of bone and mineral research • 2020 • Mice Carrying a Ubiquitous R235W Mutation of Wnt1 Display a Bone-Specific Phenotype. PMID:32369212
• Bone • 2024 • Multi-omics analyses reveal aberrant differentiation trajectory with WNT1 loss-of-function in type XV osteogenesis imperfecta. PMID:39126373
• American journal of human genetics • 2013 • WNT1 mutations in families affected by moderately severe and progressive recessive osteogenesis imperfecta. PMID:23499310
• The New England journal of medicine • 2013 • WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta. PMID:23656646
• Human molecular genetics • 2014 • The swaying mouse as a model of osteogenesis imperfecta caused by WNT1 mutations. PMID:24634143

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