LDL Receptor-related Protein Mutations in Primary Osteoporosis

The LDL receptor-related protein 5 gene (LRP5 – OMIM 603506, chromosome 11q13.4) is a 1,615 aa transmembrane protein that interacts with the secreted glycoprotein WNT (wingless – OMIM 604663, chromosome 2q35) and its Frizzled receptor to enhance autocrine WNT signaling of osteoblast-induced bone formation. The interaction of LRP5-WNT-Frizzled receptor is inhibited by another protein termed dickkopf (DKK – OMIM 605189, chromosome 10q11.2) that binds to LRP5 near its amino terminal and interrupts Wnt signaling, thereby modulating the extent of osteogenesis. When a mutation in this region of LRP5 prevents its binding to DKK, there is further increase in WNT signaling and bone formation leading to high bone mass. Homozygous loss-of-function (LOF) mutations throughout other regions of LRP5 have been identified in subjects with the osteoporosis-pseudoglioma syndrome (OMIM 259770), an illness characterized by developmental delay, seizures, impaired vision due to a pseudoglioma of the retina, and lax ligaments, as well as decreased bone mineralization.

Schematic representation of the LRP5 protein and its domain structure. Mutations of individuals with OPPG are indicated above the protein structure; heterozygous mutations are marked in bold. Mutations of individuals with high bone mass phenotype, situated in the first YWTD/EDF domain, are indicated below the protein. Mutations of individuals with primary osteoporosis (this study) are marked on red.

Hartikka et al found heterozygous LOF mutations in LRP5 in 3 out of 20 children and adolescents with primary osteoporosis, defined as isolated osteoporosis without stigmata of other illnesses and manifested by fractures with low impact trauma beginning in early childhood. Two missense mutations (Ala29Thr, Arg1036Gln) and one frame shift mutation (Cys913fs) were detected. Examination of family members revealed osteoporosis and similar mutations in a parent and/or a sibling, indicating autosomal dominant transmission of this trait attributable to haploinsufficiency of LRP5.

Editor’s Comment: Osteopenia and osteoporosis in children and adolescents are most commonly secondary to chronic illnesses, nutritional deprivation, limited mobility, excessive exposure to glucocorticoids, or deficiencies in growth, sex, and/or thyroid hormones. Osteogenesis imperfecta (OI) is due to heterozygous LOF mutations in the genes encoding components of type I collagen (COL1A1, COL1A2). In addition to osseous fragility, patients with OI often have blue sclerae, joint laxity, and dental abnormalities. None of the patients studied by Hartikka et al had a mutation in either of these genes. Juvenile idiopathic osteoporosis develops 2 to 3 years before puberty and is manifested by the acute onset of bone pain due to long bone fracture(s) or vertebral collapse. Heterozygous gain-of-function (GOF) mutations in LRP5 impair binding to DKK and lead to increased bone mass, a trait transmitted in an autosomal dominant manner.¹ Although initially considered a benign variant, later reports associated this trait with intracranial hypertension, cranial nerve palsies, and extensive maxillary and mandibular exotoses.² The phenotype of the subject with homozygous GOF mutations in LRP5 has not been described, but might be anticipated to be a lethal form of osteopetrosis.


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Current GGH - Vol. 24 No. 1 View table of contents Download PDF
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