The LRP5 gene encodes a transmembrane low-density lipoprotein receptor that binds and internalizes ligands in the process of receptor-mediated endocytosis. This protein also acts as a co-receptor with Frizzled protein family members for transducing signals by Wnt proteins. The Wnt signaling pathway is a series of steps that affect the way cells and tissues develop. It is important for cell division (proliferation), attachment of cells to one another (adhesion), cell movement (migration), and many other cellular activities.
The LRP5 protein plays an important role in the development of eye and inner ear, and formation of the bone, and is important for glucose and cholesterol metabolism.
The LRP5 gene is located on the long arm of chromosome 11 at 11q13.4 and consists of 23 exons and spans more than 100 kb of genomic DNA. The LRP5 protein composes of 1615 amino acids and weights around 179 kDa.
More than 15 mutations in the LRP5 gene have been identified in people with the eye disease familial exudative vitreoretinopathy. Mutations in the LRP5 gene cause several additional disorders characterized by altered bone mineral density. For example, more than 40 LRP5 mutations are responsible for a rare condition called osteoporosis-pseudoglioma (OPPG) syndrome. Also, genetic variations in the LRP5 gene may influence the risk of developing osteoporosis, a disease that most often affects older women. LRP5 mutations have also been identified in several people with juvenile primary osteoporosis, a form of the disease that appears in childhood. Other LRP5 mutations cause disorders associated with an increase in bone mineral density. These include autosomal dominant osteopetrosis type 1 and autosomal dominant osteosclerosis.
Lev et al. (2003) reported the case of two male siblings with the osteoporosis-pseudoglioma syndrome. They were born to healthy and consanguineous parents (the father is the mother's uncle) of Tunisian Jewish ancestry. Both patients patients were homozygous for a genetic change in the LRP5 gene. However, the exact mutation was not exactly determined at the time of the study. Yet, linkage analysis demonstrated the carrier status of the parents and, at least, two other siblings.
Marques-Pinheiro et al. (2010) reported a novel frameshift mutation identified in a 22 year-old Tunisian boy of a consanguineous family. This patient was found to have low bone mineral density (BMD). He also experienced multiple fractures during childhood and suffered ocular alterations with blindness. Direct DNA sequencing showed a homozygous 5 base pair insertion in exon 5 of the LRP5 gene. This new mutation is located in the first EGF-like domain and gives rise to a truncated protein of 384 amino acids. The functional significance of this mutation clearly indicates a loss-of-function mutation of the LRP5 gene leading to the observed OPPG phenotype. Marques-Pinheiro et al. (2010) hinted that some of the LRP5 gene polymorphisms might be involved in causing osteoporosis in the general population.