Mutant Phenotypes in Sox9 in model organisms
Human mutations on the Sox9 protein
From McDowall et al 1999. The types of protein-coding mutations found at the time from clinical samples from Campomelic Dysplasia patients. These mutations all affected Sox9's function, which resulted in CM and evential lethality (except the H65Y mutant).
Knockout mice: Sox9+/+ vs. Sox9+/-
These figures were taken from Bi et al 2001, which is also the highlighted paper on the "Paper Summary" page. The Sox9 +/- mice exhibited incredible similarity compared to human Campomelic Dysplasia. Sox9 +/- mice are thought to result in defective chondrocyte differentiation, and premature skeletal mineralization. Sox9 mutant skeletal elements were only endochondral bone, not membrane bone (doesn't go thru cartilage intermediate).
Mouse cKO
When Sox9 is knocked out in just chondrocytes using a cre-loxP strategy where exon 1 is floxed (and thus will be excised upon cre-mediated recombination) and the Cre is under the Col2a1 promoter, there is abnormal limb morphologies, that are similar to but not exactly like the classic knockout mice (Yap et al 2011). For example, the deltoid tuberosity (black arrow) is present in all three floxed mice, but the classical +/- knockout (above) lacks the deltoid tuberosity.
Zebrafish morphants
Morpholino-mediated knockdown of Sox9a (zebrafish Sox9 homolog) in zebrafish results in a gross decrease of chondrogenesis (Yan et al 2002). These do not necessarily mimic the complete CM phenotype, and would probably not be a good model for the disease.
References
McDowall S, Argentaro A, Ranganathan S, Weller P, Mertin S, Mansour S, Tolmie J, Harley V. (1999)
Functional and structural studies of wild type SOX9 and mutations causing campomelic dysplasia. J Biol Chem. 274(34):24023-30.
Bi, W., Huang, W., Whitworth, D. J., Deng, J. M., Zhang, Z., Behringer, R. R., de Crombrugghe, B. Haploinsufficiency of Sox9 results in defective cartilage primordia and premature skeletal mineralization. Proc. Nat. Acad. Sci. 98: 6698-6703, 2001.
Sook Peng Yap, Xing Xing, Petra Kraus, V. Sivakamasundari, Hsiao Yun Chan, Thomas Lufkin. Generation of mice with a novel conditional null allele of the Sox9 gene. Biotechnol Lett. 2011 Apr 12. [Epub ahead of print]
Yan, Y.-L., Miller, C.T., Nissen, R.M., Singer, A., Liu, D., Kirn, A., Draper, B., Willoughby, J., Morcos, P.A., Amsterdam, A., Chung, B.-C., Westerfield, M., Haffter, P., Hopkins, N., Kimmel, C., and Postlethwait, J.H. (2002). A zebrafish Sox9 gene required for cartilage morphogenesis. Development 129(21):5065-5079
Functional and structural studies of wild type SOX9 and mutations causing campomelic dysplasia. J Biol Chem. 274(34):24023-30.
Bi, W., Huang, W., Whitworth, D. J., Deng, J. M., Zhang, Z., Behringer, R. R., de Crombrugghe, B. Haploinsufficiency of Sox9 results in defective cartilage primordia and premature skeletal mineralization. Proc. Nat. Acad. Sci. 98: 6698-6703, 2001.
Sook Peng Yap, Xing Xing, Petra Kraus, V. Sivakamasundari, Hsiao Yun Chan, Thomas Lufkin. Generation of mice with a novel conditional null allele of the Sox9 gene. Biotechnol Lett. 2011 Apr 12. [Epub ahead of print]
Yan, Y.-L., Miller, C.T., Nissen, R.M., Singer, A., Liu, D., Kirn, A., Draper, B., Willoughby, J., Morcos, P.A., Amsterdam, A., Chung, B.-C., Westerfield, M., Haffter, P., Hopkins, N., Kimmel, C., and Postlethwait, J.H. (2002). A zebrafish Sox9 gene required for cartilage morphogenesis. Development 129(21):5065-5079
