title: The mutation ROR2W749X, linked to human BDB, is a recessive mutation in the mouse, causing brachydactyly, mediating patterning of joints and modeling recessive Robinow syndrome.
abstract: Mutations in ROR2 result in a spectrum of genetic disorders in humans that are classified, depending on the nature of the mutation and the clinical phenotype, as either autosomal dominant brachydactyly type B (BDB, MIM 113000) or recessive Robinow syndrome (RRS, MIM 268310). In an attempt to model BDB in mice, the mutation W749X was engineered into the mouse Ror2 gene. In contrast to the human situation, mice heterozygous for Ror2(W749FLAG) are normal and do not develop brachydactyly, whereas homozygous mice exhibit features resembling RRS. Furthermore, both Ror2(W749FLAG/W749FLAG) and a previously engineered mutant, Ror2(TMlacZ/TMlacZ), lack the P2/P3 joint. Absence of Gdf5 expression at the corresponding interzone suggests that the defect is in specification of the joint. As this phenotype is absent in mice lacking the entire Ror2 gene, it appears that specification of the P2/P3 joint is affected by ROR2 activity. Finally, Ror2(W749FLAG/W749FLAG) mice survive to adulthood and exhibit phenotypes (altered body composition, reduced male fertility) not observed in Ror2 knockout mice, presumably due to the perinatal lethality of the latter. Therefore, Ror2(W749FLAG/W749FLAG) mice represent a postnatal model for RRS, provide insight into the mechanism of joint specification, and uncover novel roles of Ror2 in the mouse.
authors: Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA.
authors: Regina
authors: R
authors: Raz
authors: Sigmar
authors: S
authors: Stricker
authors: Elizabetta
authors: E
authors: Gazzerro
authors: Julie L
authors: JL
authors: Clor
authors: Florian
authors: F
authors: Witte
authors: Harakiran
authors: H
authors: Nistala
authors: Stefanie
authors: S
authors: Zabski
authors: Renata C
authors: RC
authors: Pereira
authors: Lisa
authors: L
authors: Stadmeyer
authors: Xiangmin
authors: X
authors: Wang
authors: Lori
authors: L
authors: Gowen
authors: Mark W
authors: MW
authors: Sleeman
authors: George D
authors: GD
authors: Yancopoulos
authors: Ernesto
authors: E
authors: Canalis
authors: Stefan
authors: S
authors: Mundlos
authors: David M
authors: DM
authors: Valenzuela
authors: Aris N
authors: AN
authors: Economides
mesh_terms: D000015:Abnormalities, Multiple / Q000196:embryology / Q000235:genetics*; D000818:Animals; D015992:Body Mass Index; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D005298:Fertility / Q000235:genetics; D005808:Genes, Recessive; D055428:Growth Differentiation Factor 5; D006801:Humans; D007596:Joints / Q000002:abnormalities / Q000196:embryology; D017880:Limb Deformities, Congenital / Q000196:embryology / Q000235:genetics; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009139:Musculoskeletal Abnormalities / Q000196:embryology / Q000235:genetics*; D009154:Mutation; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000502:physiology; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; D013577:Syndrome
chemical_list: D019485:Bone Morphogenetic Proteins; C525893:GDF5 protein, human; C525894:Gdf5 protein, mouse; D055428:Growth Differentiation Factor 5; D020794:Receptor Protein-Tyrosine Kinases; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; C477010:Ror2 protein, mouse