Osteoporosis pseudoglioma syndrome (OPPGS) is a rare autosomal recessive disorder characterised by congenital or juvenile-onset blindness, severe juvenile-onset osteoporosis, and skeletal fragility. OPPGS is caused by loss-of-function mutations in the LRP5 gene, a member of the LDL receptor family. It activates the canonical Wnt/β-catenin pathway, regulating osteoblastic bone formation. We investigated a 40-year-old Caucasian male presenting with congenital blindness and osteoporosis, with multiple fractures before the age of ten; and his 57-year-old mother, showing a milder bone-specific phenotype, with low bone mineral density (BMD) (spine T-score −2.7; femoral neck T-score −1.7) and no adult fractures, within a non-consanguineous family. We sequenced all 23 exons of LRP5 in the index case and his mother and found a heterozygous missense mutation, g.C2254T, p.R752W, in both. The index case carried another heterozygous missense mutation, g.T235C, p.W79R, not found in his mother. Both these missense mutations are novel. To assess pathogenicity, we created and validated three-dimensional homology models for the four extracellular YWTD β-propeller/EGF-like domains (E1E4) of LRP5. Mutation W79R is located in the second β-strand of blade 2 (E1 domain), within the highly conserved YWTD signature motif and deeply buried in the protein core; energy stability calculations using FoldX predict this mutation to severely destabilise structure (mean ΔΔG=~5 kcal/mol; >1.6 kcal/mol is considered destabilising). The R752W mutation is located in blade 3 of E3 domain, near the interface with E4, but is also predicted to destabilise structure, albeit to a lesser extent (mean ΔΔG=~2 kcal/mol). In conclusion, the novel mutation R752W is associated with low BMD, as seen in the mother, but the combination of this mutation with the novel W79R, causes a severe case of OPPGS due to destabilisation of the β-propeller motifs of the LRP5 protein which are required for protein and ligand binding.
17 May 2014 - 20 May 2014