Skeletal phenotype in patients with LRP5 mutations – Evidence for a significant carrier phenotype
Mutations in LRP5, coding for the low density lipoprotein receptor-related protein 5, have been shown to cause a variety of skeletal disorders including autosomal recessive Osteoporosis-pseudoglioma syndrome (OPPG) and autosomal dominant High Bone Mass (HBM) disorder. While homozygous LRP5 mutations result in OPPG, characterized by severe osteoporosis and blindness, heterozygous LRP5 mutations may result in milder osteoporosis. In this study we have assessed skeletal phenotypes and LRP5 mutations in a large Finnish OPPG-family.
DNA samples were collected from 37 individuals, two of whom had OPPG. The exons and exon-intron boundaries of LRP5 were sequenced. Skeletal phenotype was assessed by fracture history, bone mineral density (BMD) and spinal radiographs. Two different missense mutations were identified. R570W was found in seven individuals and R1036Q in four individuals. The two patients with OPPG were homozygous for R570W, one individual was a compound heterozygote for both mutations, four were heterozygous for R570W and three heterozygous for R1036Q.
The two patients homozygous for R570W were blind and had severe osteoporosis and multiple compression fractures. The compound heterozygote individual had severe osteoporosis but normal vision. All heterozygous carriers had normal vision but their BMD was notably decreased and several had spinal compression fractures.
In conclusion, the skeletal and ocular phenotypes vary depending on the type and combination of LRP5 mutations. Even heterozygous mutation carriers may develop severe skeletal complications and should be assessed for osteoporosis.