title: Skeletal characteristics associated with homozygous and heterozygous WNT1 mutations.
abstract: Recent reports have shown that homozygous or compound heterozygous mutations in WNT1 can give rise to severe bone fragility resembling osteogenesis imperfecta, whereas heterozygous WNT1 mutations have been found in adults with dominant early-onset osteoporosis. Here we assessed the effects of WNT1 mutations in four children with recessive severe bone fragility and in heterozygous family members. In vitro studies using the Topflash luciferase reporter system showed that two WNT1 missense mutations that were observed in these families, p.Cys143Phe and p.Val355Phe, decreased the ability of WNT1 to stimulate WNT signaling by >90%. Analyses of iliac bone samples revealed no major abnormalities in bone mineralization density distribution, an indicator of material bone properties, whereas a shift towards higher bone mineralization density is characteristic of classical osteogenesis imperfecta caused by mutations in COL1A1/COL1A2. Intravenous bisphosphonate treatment of four children with homozygous or compound heterozygous WNT1 mutations was associated with increasing lumbar spine areal bone mineral density z-scores, as measured by dual energy X-ray absorptiometry, but the effect was smaller than what had previously been reported for children with classical osteogenesis imperfecta. Family members with heterozygous WNT1 mutation tended to have low bone mass. Three of these heterozygous individuals had radiographic signs of vertebral fractures. These observations suggest that more effective treatment approaches are needed for children with recessive WNT1-related bone fragility and that a systematic work-up for osteoporosis is warranted for WNT1 mutation carriers in these families.
authors.affiliation: Shriners Hospital for Children and McGill University, Montreal, Quebec, Canada.
authors.forename: Telma
authors.initials: T
authors.lastname: Palomo
authors.affiliation: Shriners Hospital for Children and McGill University, Montreal, Quebec, Canada.
authors.forename: Hadil
authors.initials: H
authors.lastname: Al-Jallad
authors.affiliation: Shriners Hospital for Children and McGill University, Montreal, Quebec, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Moffatt
authors.affiliation: Shriners Hospital for Children and McGill University, Montreal, Quebec, Canada.
authors.forename: Francis H
authors.initials: FH
authors.lastname: Glorieux
authors.affiliation: University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: Lentle
authors.affiliation: Ludwig Boltzmann Institute of Osteology, Hanusch Hospital of WGKK, AUVA Trauma Center Meidling, 1st Med. Dept., Hanusch Hospital, Vienna, Austria.
authors.forename: Paul
authors.initials: P
authors.lastname: Roschger
authors.affiliation: Ludwig Boltzmann Institute of Osteology, Hanusch Hospital of WGKK, AUVA Trauma Center Meidling, 1st Med. Dept., Hanusch Hospital, Vienna, Austria.
authors.forename: Klaus
authors.initials: K
authors.lastname: Klaushofer
authors.affiliation: Shriners Hospital for Children and McGill University, Montreal, Quebec, Canada. Electronic address: frauch@shriners.mcgill.ca.
authors.forename: Frank
authors.initials: F
authors.lastname: Rauch
mesh_terms: D015519:Bone Density / Q000235:genetics; D024042:Collagen Type I / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D004164:Diphosphonates / Q000627:therapeutic use; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation / Q000235:genetics; D010013:Osteogenesis Imperfecta / Q000188:drug therapy / Q000235:genetics*; D010024:Osteoporosis / Q000235:genetics / Q000517:prevention & control; D016103:Spinal Fractures / Q000235:genetics / Q000517:prevention & control; D051155:Wnt1 Protein / Q000235:genetics*
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D004164:Diphosphonates; C495247:WNT1 protein, human; D051155:Wnt1 Protein
keywords: Backscattered electron imaging; Bone fragility; Osteogenesis imperfecta; Osteoporosis; Vertebral fractures; WNT1