Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density

Abstract

Bone is a dynamic tissue that is subject to the balanced processes of bone formation and bone resorption. Imbalance can give rise to skeletal pathologies with increased bone density. In recent years, several genes underlying such sclerosing bone disorders have been identified. The LDL receptor-related protein 5 (LRP5) gene has been shown to be involved in both osteoporosis-pseudoglioma syndrome and the high-bone-mass phenotype and turned out to be an important regulator of peak bone mass in vertebrates. We performed mutation analysis of the LRP5 gene in 10 families or isolated patients with different conditions with an increased bone density, including endosteal hyperostosis, Van Buchem disease, autosomal dominant osteosclerosis, and osteopetrosis type I. Direct sequencing of the LRP5 gene revealed 19 sequence variants. Thirteen of these were confirmed as polymorphisms, but six novel missense mutations (D111Y, G171R, A214T, A214V, A242T, and T253I) are most likely disease causing. Like the previously reported mutation (G171V) that causes the high-bone-mass phenotype, all mutations are located in the aminoterminal part of the gene, before the first epidermal growth factor-like domain. These results indicate that, despite the different diagnoses that can be made, conditions with an increased bone density affecting mainly the cortices of the long bones and the skull are often caused by mutations in the LRP5 gene. Functional analysis of the effects of the various mutations will be of interest, to evaluate whether all the mutations give rise to the same pathogenic mechanism.

Figure 1

Photo of hard palate of a patient from family C, demonstrating the bony prominence (torus palatinus) and associated dental alterations.

Figure 2

X-ray of forearm of patient from family F, demonstrating thickened cortical bone with no alterations in external shape.

Figure 3

Radiograph of the skull of an affect member of family F, showing the very dense aspect of bone.

Figure 4

Radiograph of the skull of an affected member of family G, demonstrating a diffuse osteosclerosis.

Figure 5

Radiograph of lumbar spine and pelvis of an affected member of family G, demonstrating a diffuse osteosclerosis.

Figure 6

X-ray of a femur of an affected member of family H, demonstrating an increased thickness of the long bones and narrowing of the medullary canals.

Figure 7

X-ray of the cervical spine of an affected member of family H, showing an increased bone density.

Figure 8

Alignment of the aminoterminal part of the LRP5 protein with its most closely related homologue, LRP6, in human, mouse, and Xenopus. The signal peptide, one LDLR repeat with its six YWTD repeats (indicated with a line), and the following EGF repeat are shown. The numbering of the amino acid sequence is based on the human LRP5. The positions of the six novel missense mutations are indicated with an asterisk (*). These residues are highly conserved in human, mouse, and Xenopus LRP5 as well as in human, mouse, and Xenopus LRP6.