Review articleLRP5 mutations in osteoporosis-pseudoglioma syndrome and high-bone-mass disorders
Introduction
Investigating rare genetic disorders holds considerable appeal as a means of unraveling the physiological mechanisms that regulate tissues and organs. Thus, identification of the LDL receptor-related protein 5 (LRP5) has proved a breakthrough in elucidating the genetic and molecular mechanisms involved in bone mass regulation.
Several studies pointed to 11q12-13 as a key chromosomal region for clinical disorders characterized by severe bone mass abnormalities: osteoporosis-pseudoglioma syndrome (OPPG) [1], familial high-bone-mass syndromes [2], and an autosomal recessive form of osteopetrosis [4]. Moreover, 11q12-13 may explain the normal distribution of bone mass in the general population [3]. The LRP5 has recently been identified as the gene responsible for osteoporosis-pseudoglioma syndrome [5] and for a dominant pattern of high-bone-mass syndrome [6].
Section snippets
Osteoporosis-pseudoglioma syndrome [MIM (Mendelian Inheritance in Man) 259770]
Congenital blindness with osteoporosis was first described in 1931 [7]. Since then, over 50 cases have been reported, mainly in patients from the Mediterranean rim [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32]. McKusick [33], [34] coined the term OPPG to designate this combination. Transmission is autosomal and recessive; some cases have occurred in the children of consanguineous parents.
From the gene to the protein
The LRP5 (LDL receptor-related protein 5) is a membrane co-receptor expressed in many cells, including osteoblasts [37]. It belongs to the LDL-receptor family, which also comprises the VLDL receptor (VLDL-R) and the apolipoprotein E receptor 2 [38]. The LRP5 is located at the hub of a complex signaling pathway (www.stanford.edu/~rnusse/wntwindow.html). The LRP5 (formerly called LR3 or LRP7) was cloned in 1998 by several groups [39], [40], [41]. At the time, this locus at 11q13 was under intense
Role for LPR5 in bone diseases
4.1. Role in bone accrual and normal bone mass distribution in the general population
The LRP5 is among the major factors regulating bone mass accrual, together with estrogens, growth hormone, IGF-1, and their receptors. The LPR5 seems not only to regulate the level of bone formation in a given individual, but also to affect osteoclast–osteoblast coupling by regulating the RANK–RANKL (receptor activator of NF-kappaB ligand) and osteoprotegerin (OPG) pathway. Thus, studies in high-bone-mass
Conclusion
Identification of the membrane receptor LRP5 and of the Wnt/beta-catenin signaling pathway is a breakthrough in the understanding of bone tissue physiology. Mutations affecting LRP5 can result in a severe pediatric disease called osteoporosis-pseudoglioma syndrome (OPPG), high-bone-mass syndromes often detected in adulthood, or other disorders characterized by sclerotic bone dysplasia. In clinical practice, OPPG should be considered in patients with congenital blindness and fractures or
Acknowledgments
We thank Professor Gérard Karsenty and Professor Lawrence Chan (Baylor College of Medicine, Houston, TX) for allowing us to communicate data on microarchitectural parameters in LRP5-deficient mice.
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