Oropharyngeal Skeletal Disease Accompanying High Bone Mass and Novel LRP5 Mutation

Abstract

Gain-of-function mutation in the gene encoding LRP5 causes high bone mass. A 59-year-old woman carrying a novel LRP5 missense mutation, Arg154Met, manifested skeletal disease affecting her oropharynx as well as dense bones, showing that exuberant LRP5 effects are not always benign.Introduction: Gain-of-function mutation (Gly171Val) of LDL receptor-related protein 5 (LRP5) was discovered in 2002 in two American kindreds with high bone mass and benign phenotypes. In 2003, however, skeletal disease was reported for individuals from the Americas and Europe carrying any of six novel LRP5 missense mutations affecting the same LRP5 protein domain. Furthermore, in 2004, we described a patient with neurologic complications from dense bones and extensive oropharyngeal exostoses caused by the Gly171Val defect. Materials and Methods:A 59-year-old woman was referred for dense bones. Three years before, mandibular buccal and lingual exostoses (osseous "tori") were removed because of infections from food trapping between the teeth and exostoses. Maxillary buccal and palatal exostoses were asymptomatic. Radiographic skeletal survey showed marked thickening of the skull base and diaphyses of long bones (endosteal hyperostosis). BMD Z scores assessed by DXA were +8.5 and +8.7 in the total hip and L 1 -L 4 spine (both ∼195% average control), respectively. LRP5 mutation analysis was carried out for the LRP5 domain known to cause high bone mass. Results: Biochemical evaluation excluded most secondary causes of dense bones, and male-to-male transmission in her family indicated autosomal dominant inheritance. PCR amplification and sequencing of LRP5 exons 2-4 and adjacent splice sites revealed heterozygosity for a new LRP5 missense mutation, Arg154Met. Conclusions: LRP5 Arg154Met is a novel defect that changes the same first "␤-propeller" module as the eight previously reported LRP5 gain-of-function missense mutations. Arg154Met alters a region important for LRP5 antagonism by dickkopf (Dkk). Therefore, our patient's extensive oropharyngeal exostoses and endosteal hyperostosis likely reflect increased Wnt signaling and show that exuberant LRP5 effects are not always benign.

LRP5 Mutations Linked to High Bone Mass Diseases Cause Reduced LRP5 Binding and Inhibition by SOST

“…We introduced six HBM mutations, D111Y, R154M, G171V, N198S, A214T, and T253I, identified in four independent studies (11)(12)(13)33) into the first YWTD ␤-propeller domain of LRP5 (Fig. 1A).…”

“…Loss-of-function mutations of LRP5 are associated with familial osteoporosis (10), whereas LRP5 HBM mutations are associated with high bone mass diseases (11)(12)(13)33). LRP5 HBM mutations, which have been identified in several independent studies, are all missense mutations clustered in the first YWTD ␤-propeller domain of the LRP5 ectodomain (Fig.…”

Diseases of Wnt signaling

“…Next came the initial description of mutations in the human LRP5 gene that give rise to conditions of extremely low bone mass [58] or extremely high bone mass [57,66]. These reports were quickly followed by a succession of papers describing other mutations in LRP5 that resulted in altered bone mass [67][68][69][70][71][72][73]. In addition, mutations in LRP5 have been described that give rise to Familial Exudative Vitreoretinopathy (FEVR) [74,75], however bone density measurements are not reported for these families.…”

Association of Low-Density Lipoprotein Receptor-Related Protein 5 (LRP5) Promoter SNP with Peak Bone Mineral Density in Chinese Women

“…Mutations in the YWTD/ EGF domains of the gene have been associated with osteoporosis pseudoglioma syndrome (OPPG) [10,11] . In contrast, gain-of-function mutations such as Gly171Val [12,13] and Arg154Met [14] are reported to cause the autosomal dominant high bone mass phenotype, increased trabecular volumetric BMD and cortical size. Other mutations cause autosomal dominant osteopetrosis and autosomal dominant osteosclerosis [15] .…”