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

Regina Raz, Sigmar Stricker, Elizabetta Gazzerro, Julie L. Clor, Florian Witte, Harakiran Nistala, Stefanie Zabski, Renata C. Pereira, Lisa Stadmeyer, Xiangmin Wang, Lori Gowen, Mark W. Sleeman, George D. Yancopoulos, Ernesto Canalis, Stefan Mundlos, David M. Valenzuela, Aris N. Economides

Research output: Contribution to journalArticle

23 Citations (Scopus)

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 Ror2W749FLAG are normal and do not develop brachydactyly, whereas homozygous mice exhibit features resembling RRS. Furthermore, both Ror2W749FLAG/W749FLAG and a previously engineered mutant, Ror2™/acZ/tm/acZ, 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, Ror2W749FLAG/ 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, Ror2W749FLAG/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.

Original languageEnglish
Pages (from-to)1713-1723
Number of pages11
JournalDevelopment
Volume135
Issue number9
DOIs
Publication statusPublished - May 2008

Fingerprint

Brachydactyly
Joints
Mutation
Phenotype
Inborn Genetic Diseases
Autosomal Dominant Robinow Syndrome
bis(diazo)benzidine
Body Composition
Knockout Mice
Genes
Fertility

Keywords

  • Brachydactyly B
  • Knock-in mouse
  • Phalanx formation
  • ROR2 receptor

ASJC Scopus subject areas

  • Anatomy
  • Cell Biology

Cite this

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. / Raz, Regina; Stricker, Sigmar; Gazzerro, Elizabetta; Clor, Julie L.; Witte, Florian; Nistala, Harakiran; Zabski, Stefanie; Pereira, Renata C.; Stadmeyer, Lisa; Wang, Xiangmin; Gowen, Lori; Sleeman, Mark W.; Yancopoulos, George D.; Canalis, Ernesto; Mundlos, Stefan; Valenzuela, David M.; Economides, Aris N.

In: Development, Vol. 135, No. 9, 05.2008, p. 1713-1723.

Research output: Contribution to journalArticle

Raz, R, Stricker, S, Gazzerro, E, Clor, JL, Witte, F, Nistala, H, Zabski, S, Pereira, RC, Stadmeyer, L, Wang, X, Gowen, L, Sleeman, MW, Yancopoulos, GD, Canalis, E, Mundlos, S, Valenzuela, DM & Economides, AN 2008, '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', Development, vol. 135, no. 9, pp. 1713-1723. https://doi.org/10.1242/dev.015149
Raz, Regina ; Stricker, Sigmar ; Gazzerro, Elizabetta ; Clor, Julie L. ; Witte, Florian ; Nistala, Harakiran ; Zabski, Stefanie ; Pereira, Renata C. ; Stadmeyer, Lisa ; Wang, Xiangmin ; Gowen, Lori ; Sleeman, Mark W. ; Yancopoulos, George D. ; Canalis, Ernesto ; Mundlos, Stefan ; Valenzuela, David M. ; Economides, Aris N. / 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. In: Development. 2008 ; Vol. 135, No. 9. pp. 1713-1723.
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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 Ror2W749FLAG are normal and do not develop brachydactyly, whereas homozygous mice exhibit features resembling RRS. Furthermore, both Ror2W749FLAG/W749FLAG and a previously engineered mutant, Ror2™/acZ/tm/acZ, 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, Ror2W749FLAG/ 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, Ror2W749FLAG/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.",
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AU - Raz, Regina

AU - Stricker, Sigmar

AU - Gazzerro, Elizabetta

AU - Clor, Julie L.

AU - Witte, Florian

AU - Nistala, Harakiran

AU - Zabski, Stefanie

AU - Pereira, Renata C.

AU - Stadmeyer, Lisa

AU - Wang, Xiangmin

AU - Gowen, Lori

AU - Sleeman, Mark W.

AU - Yancopoulos, George D.

AU - Canalis, Ernesto

AU - Mundlos, Stefan

AU - Valenzuela, David M.

AU - Economides, Aris N.

PY - 2008/5

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N2 - 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 Ror2W749FLAG are normal and do not develop brachydactyly, whereas homozygous mice exhibit features resembling RRS. Furthermore, both Ror2W749FLAG/W749FLAG and a previously engineered mutant, Ror2™/acZ/tm/acZ, 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, Ror2W749FLAG/ 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, Ror2W749FLAG/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.

AB - 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 Ror2W749FLAG are normal and do not develop brachydactyly, whereas homozygous mice exhibit features resembling RRS. Furthermore, both Ror2W749FLAG/W749FLAG and a previously engineered mutant, Ror2™/acZ/tm/acZ, 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, Ror2W749FLAG/ 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, Ror2W749FLAG/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.

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