title: A mutation in FRIZZLED2 impairs Wnt signaling and causes autosomal dominant omodysplasia.
abstract: Autosomal dominant omodysplasia is a rare skeletal dysplasia characterized by short humeri, radial head dislocation, short first metacarpals, facial dysmorphism and genitourinary anomalies. We performed next-generation whole-exome sequencing and comparative analysis of a proband with omodysplasia, her unaffected parents and her affected daughter. We identified a de novo mutation in FRIZZLED2 (FZD2) in the proband and her daughter that was not found in unaffected family members. The FZD2 mutation (c.1644G>A) changes a tryptophan residue at amino acid 548 to a premature stop (p.Trp548*). This altered protein is still produced in vitro, but we show reduced ability of this mutant form of FZD2 to interact with its downstream target DISHEVELLED. Furthermore, expressing the mutant form of FZD2 in vitro is not able to facilitate the cellular response to canonical Wnt signaling like wild-type FZD2. We therefore conclude that the FRIZZLED2 mutation is a de novo, novel cause for autosomal dominant omodysplasia.
authors.affiliation: Division of Human Genetics.
authors.forename: Howard M
authors.initials: HM
authors.lastname: Saal
authors.affiliation: Division of Human Genetics, Division of Patient Services.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Prows
authors.affiliation: Division of Human Genetics.
authors.forename: Iris
authors.initials: I
authors.lastname: Guerreiro
authors.affiliation: Division of Human Genetics.
authors.forename: Milene
authors.initials: M
authors.lastname: Donlin
authors.affiliation: Division of Human Genetics.
authors.forename: Luke
authors.initials: L
authors.lastname: Knudson
authors.affiliation: Division of Human Genetics.
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Sund
authors.affiliation: Division of Developmental Biology and Division of Plastic Surgery, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 7016, Cincinnati, OH 45229, USA.
authors.forename: Ching-Fang
authors.initials: CF
authors.lastname: Chang
authors.affiliation: Division of Developmental Biology and Division of Plastic Surgery, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 7016, Cincinnati, OH 45229, USA.
authors.forename: Samantha A
authors.initials: SA
authors.lastname: Brugmann
authors.affiliation: Division of Human Genetics, Division of Developmental Biology and rolf.stottmann@cchmc.org.
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Stottmann
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000473:pathology; D004252:DNA Mutational Analysis; D059472:Exome; D019066:Facies; D005260:Female; D051157:Frizzled Receptors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015870:Gene Expression; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D006811:Humerus / Q000002:abnormalities* / Q000378:metabolism; D007223:Infant; D050279:Metacarpal Bones / Q000002:abnormalities* / Q000378:metabolism; D009154:Mutation; D010009:Osteochondrodysplasias / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D010375:Pedigree; D010641:Phenotype; D011485:Protein Binding; D021381:Protein Transport; D011859:Radiography; D060449:Wnt Signaling Pathway
chemical_list: C489742:FZD2 protein, human; D051157:Frizzled Receptors