Genotypic and Phenotypic Spectrum and Pathogenesis of WNT1 Variants in a Large Cohort of Patients With OI/Osteoporosis

Context: Mutations in WNT1 can cause rare inherited disorders such as osteogenesis imperfecta (OI) and early-onset osteoporosis (EOOP). Owing to its rarity, the clinical characteristics and pathogenic mechanism of WNT1 mutations remain unclear.

Objective: We aimed to explore the phenotypic and genotypic spectrum and treatment responses of a large cohort of patients with WNT1-related OI/OP and the molecular mechanisms of WNT1 variants.

Methods: The phenotypes and genotypes of patients and their responses to bisphosphonates or denosumab were evaluated. Western blot analysis, quantitative polymerase chain reaction, and immunofluorescence staining were used to evaluate the expression levels of WNT1, total β-catenin, and type I collagen in the tibial bone or skin from one patient.

Results: We included 16 patients with 16 mutations identified in WNT1, including a novel mutation. The types of WNT1 mutations were related to skeletal phenotypes, and biallelic nonsense mutations or frameshift mutations could lead to an earlier occurrence of fragility fractures and more severe skeletal phenotypes. Some rare comorbidities were identified in this cohort, including cerebral abnormalities, hematologic diseases, and pituitary adenoma. Bisphosphonates and denosumab significantly increased the spine and proximal hip BMD of patients with WNT1 mutations and reshaped the compressed vertebrae. We report for the first time a decreased β-catenin level in the bone of patient 10 with c.677C > T and c.502G > A compared to the healthy control, which revealed the potential mechanisms of WNT1-induced skeletal phenotypes.

Conclusion: Biallelic nonsense mutations or frameshift mutations of WNT1 could lead to an earlier occurrence of fragility fractures and a more severe skeletal phenotype in OI and EOOP induced by WNT1 mutations. The reduced osteogenic activity caused by WNT pathway downregulation could be a potential pathogenic mechanism of WNT1-related OI and EOOP.