Mutations in <it>LRP5 </it>cause primary osteoporosis without features of OI by reducing Wnt signaling activity

• Main Authors: Korvala Johanna, Jüppner Harald, Mäkitie Outi, Sochett Etienne, Schnabel Dirk, Mora Stefano, Bartels Cynthia F, Warman Matthew L, Deraska Donald, Cole William G, Hartikka Heini, Ala-Kokko Leena, Männikkö Minna
• Format: Article
• Language: English
• Published: BMC 2012-04-01
• Series: BMC Medical Genetics
• Online Access: http://www.biomedcentral.com/1471-2350/13/26

<p>Abstract</p> <p>Background</p> <p>Primary osteoporosis is a rare childhood-onset skeletal condition whose pathogenesis has been largely unknown. We have previously shown that primary osteoporosis can be caused by heterozygous missense mutations in the Low-density lipoprotein receptor-related protein 5 (<it>LRP5</it>) gene, and the role of <it>LRP5 </it>is further investigated here.</p> <p>Methods</p> <p><it>LRP5 </it>was analyzed in 18 otherwise healthy children and adolescents who had evidence of osteoporosis (manifested as reduced bone mineral density i.e. BMD, recurrent peripheral fractures and/or vertebral compression fractures) but who lacked the clinical features of osteogenesis imperfecta (OI) or other known syndromes linked to low BMD. Also 51 controls were analyzed. Methods used in the genetic analyses included direct sequencing and multiplex ligation-dependent probe amplification (MLPA). <it>In vitro </it>studies were performed using luciferase assay and quantitative real-time polymerase chain reaction (qPCR) to examine the effect of two novel and three previously identified mutations on the activity of canonical Wnt signaling and on expression of tryptophan hydroxylase 1 (<it>Tph1</it>) and 5-hydroxytryptamine (<it>5-Htr1b</it>).</p> <p>Results</p> <p>Two novel <it>LRP5 </it>mutations (c.3446 T > A; p.L1149Q and c.3553 G > A; p.G1185R) were identified in two patients and their affected family members. <it>In vitro </it>analyses showed that one of these novel mutations together with two previously reported mutations (p.C913fs, p.R1036Q) significantly reduced the activity of the canonical Wnt signaling pathway. Such reductions may lead to decreased bone formation, and could explain the bone phenotype. Gut-derived Lrp5 has been shown to regulate serotonin synthesis by controlling the production of serotonin rate-limiting enzyme, Tph1. <it>LRP5 </it>mutations did not affect <it>Tph1 </it>expression, and only one mutant (p.L1149Q) reduced expression of serotonin receptor <it>5-Htr1b </it>(<it>p </it>< 0.002).</p> <p>Conclusions</p> <p>Our results provide additional information on the role of <it>LRP5 </it>mutations and their effects on the development of juvenile-onset primary osteoporosis, and hence the pathogenesis of the disorder. The mutations causing primary osteoporosis reduce the signaling activity of the canonical Wnt signaling pathway and may therefore result in decreased bone formation. The specific mechanism affecting signaling activity remains to be resolved in future studies.</p>