Missense Mutations in LRP5 Are Not a Common Cause of Idiopathic Osteoporosis in Adult Men

Abstract

We studied whether the LRP5 gene contributes to the clinical phenotype of IO in men. Mutation analysis in 66 IO men revealed a range of sequence variants, of which two missense variants were shown to be of functional relevance.Introduction: Mutations in the LDL receptor-related protein 5 (LRP5) gene have been associated with extreme bone phenotypes, which makes LRP5 a plausible candidate gene for idiopathic osteoporosis (IO). Materials and Methods:In 66 men with IO, all 23 exons and exon-intron boundaries of the LRP5 gene were screened for mutations, and functional analyses were performed for those that were putatively involved in the phenotype. Results: Mutation analysis in the IO probands revealed five missense mutations, of which 1067C>T (S356L), 1364C>T (S455L), and 4609G>A (A1537T) were of potential functional significance because they were located in highly conserved regions of LRP5 and not found in a control panel. Segregation analysis in the respective families could not exclude their possible causality for IO. Furthermore, functional analyses clearly showed an inhibitory effect of mutations 1067C>T and 1364C>T on Wnt signal transduction. These effects are most likely caused by impaired LRP5 synthesis in the case of 1067C>T and failure of protein trafficking to the cell surface for 1364C>T. Conclusions: For 2 of 66 IO probands, a mutation in the LRP5 gene with proven functionality was found. The findings indicate that carrying an LRP5 mutation is a risk factor for IO, but that overall, IO in men is infrequently underlied by such a mutation.

Mutations in LRP5 cause primary osteoporosis without features of OI by reducing Wnt signaling activity

“…These have shown that mutations causing OPPG reduce Wnt and/or Norrin signaling [11,38,42], while some mutants are trafficked unequally to the cell membrane [23]. Crabbe et al [43] concluded that mutations associated with idiopathic osteoporosis in adult men may change the expression of LRP5 protein and/or interfere with the interaction of LRP5 with Mesd or with the Wnt/Fzd complex. Saarinen et al [38] found an association between three homozygous OPPG mutations (R570W, R925C, R1036Q) and glucose tolerance, and suggested a potential association with diabetes.…”

Novel mutations affecting LRP5 splicing in patients with osteoporosis-pseudoglioma syndrome (OPPG)

“…1,7 Numerous loss-of-function mutations have been shown to cause OPPG in individuals with homozygous or compound heterozygous mutations. 1,[7][8][9][10][11] Heterozygous carriers of LRP5 mutations have reduced BMD, suggesting a dominant negative effect on bone mass. 2,12 Mutations in LRP5 have also been linked to the recessive form of familial exudative vitreoretinopathy (FEVR).…”

“…LRP5 functions as a transmembrane coreceptor in the canonical Wnt (wingless) signaling pathway, which regulates growth and differentiation of osteoblasts. [7][8][9][10][11][12][13][14][15][16][17] In addition to direct effects on osteoblast function, LRP5 may function indirectly by inhibiting the expression of Tph1, the rate-limiting biosynthetic enzyme for serotonin in the duodenum. Inhibition of Tph1 results in augmented blood levels of serotonin, leading to inhibition of osteoblast proliferation and reduced bone formation.…”

Low density lipoprotein receptor‐related protein 5 (LRP5) mutations and osteoporosis, impaired glucose metabolism and hypercholesterolaemia

“…[2][3][4] Heterozygous gain-offunction mutations result in a high bone mass phenotype. 8,9 Several population-based and cohort studies have associated LRP5 polymorphisms with bone mineral density (BMD). 1,7 Furthermore, children and adult males heterozygous for LRP5 mutations may have primary osteoporosis.…”