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.
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.
Raz
Regina
R
Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA.
Stricker
Sigmar
S
Gazzerro
Elizabetta
E
Clor
Julie L
JL
Witte
Florian
F
Nistala
Harakiran
H
Zabski
Stefanie
S
Pereira
Renata C
RC
Stadmeyer
Lisa
L
Wang
Xiangmin
X
Gowen
Lori
L
Sleeman
Mark W
MW
Yancopoulos
George D
GD
Canalis
Ernesto
E
Mundlos
Stefan
S
Valenzuela
David M
DM
Economides
Aris N
AN
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
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