title: A Novel Domain-Specific Mutation in a Sclerosteosis Patient Suggests a Role of LRP4 as an Anchor for Sclerostin in Human Bone.
abstract: Mutations in the LRP4 gene, coding for a Wnt signaling coreceptor, have been found to cause several allelic conditions. Among these, two are characterized by a strong skeletal involvement, namely sclerosteosis and Cenani-Lenz syndrome. In this work, we evaluated the role of LRP4 in the pathophysiology of these diseases. First, we report a novel LRP4 mutation, leading to the substitution of arginine at position 1170 in glutamine, identified in a patient with sclerosteosis. This mutation is located in the central cavity of the third β-propeller domain, which is in line with two other sclerosteosis mutations we previously described. Reporter assays demonstrate that this mutation leads to impaired sclerostin inhibition of Wnt signaling. Moreover, we compared the effect of this novel variant to mutations causing Cenani-Lenz syndrome and show that impaired membrane trafficking of the LRP4 protein is the likely mechanism underlying Cenani-Lenz syndrome. This is in contrast to sclerosteosis mutations, previously shown to impair the binding between LRP4 and sclerostin. In addition, to better understand the biology of LRP4, we investigated the circulating sclerostin levels in the serum of a patient suffering from sclerosteosis owing to a LRP4 mutation. We demonstrate that impaired sclerostin binding to the mutated LRP4 protein leads to dramatic increase in circulating sclerostin in this patient. With this study, we provide the first evidence suggesting that LRP4 is responsible for the retention of sclerostin in the bone environment in humans. These findings raise potential concerns about the utility of determining circulating sclerostin levels as a marker for other bone-related parameters. Although more studies are needed to fully understand the mechanism whereby LRP4 facilitates sclerostin action, it is clear that this protein represents a potent target for future osteoporosis therapies and an interesting alternative for the antisclerostin treatment currently under study.
authors.affiliation: Department of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Igor
authors.initials: I
authors.lastname: Fijalkowski
authors.affiliation: Department of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Ellen
authors.initials: E
authors.lastname: Geets
authors.affiliation: Department of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Ellen
authors.initials: E
authors.lastname: Steenackers
authors.affiliation: Department of Clinical Chemistry, Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Viviane
authors.initials: V
authors.lastname: Van Hoof
authors.affiliation: Unidad de Genética, Servicio de Pediatria, Hospital Clinico Universitario "Lozano Blesa", GCV-CIBERER, Facultad de Medicina, Universidad de Zaragoza, Zaragoza, Spain.
authors.forename: Feliciano J
authors.initials: FJ
authors.lastname: Ramos
authors.affiliation: Department of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: Mortier
authors.affiliation: Centro de Genética Médica, Centro Hospitalar do Porto, and Unit for Multidisciplinary Research in Biomedicine, UMIB, ICBAS-UP,, Porto, Portugal.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Fortuna
authors.affiliation: Department of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Van Hul
authors.affiliation: Department of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Eveline
authors.initials: E
authors.lastname: Boudin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D019943:Amino Acid Substitution; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D005819:Genetic Markers / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D015576:Hyperostosis / Q000235:genetics / Q000378:metabolism; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D011485:Protein Binding; D000072417:Protein Domains; D013576:Syndactyly / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; D026502:LDL-Receptor Related Proteins; C551781:LRP4 protein, human; C422903:SOST protein, human
keywords: ANABOLICS; LRPs; SCLEROSTEOSIS; WNT; β-CATENIN