Context dependent impact of the Y440X campomelic dysplasia Sox9 mutation

Abstract

Mutations in the human, SOX9 gene are associated with the skeletal malformation syndrome, campomelic dysplasia (CD) and sex reversal. Heterozygous mutations in human SOX9 result in conductive and sensorineural deafness in some CD patients, implying a role for SOX9 in ear development. Complete inactivation of the Sox9 gene in mice results in failure of cartilage formation, presumably because of failure to express SOX9 target genes such as extracellular matrix genes, Col2a1, Col9a1, Col11a2 and aggrecan. Because all the SOX9 mutations are heterozygous, are distributed throughout the gene and appear to cause loss of function, the CD phenotype has been attributed to haploinsufficiency of SOX9. However SOX9 proteins containing an intact HMG box and a truncated activation domain may act dominant negatively by competition with the wild-type for binding to target genes and interfere with interaction with partner factors via the transactivation domain. To assess whether such mutations in SOX9 may act in a dominant interference mechanism we generated transgenic and conditional knock’in mice expressing a mouse equivalent of a CD mutation, a Y440X nonsense mutation causing premature termination within the trans-activation domain of SOX9 (Sox9Y440X). We compared the phenotypic impact of the Sox9Y440X mutation with a Sox9 null mutation. These studies point to an essential role for Sox9 in inner ear and intervertebral disc development and context dependent mechanisms for the Y440X nonsense mutation. This work was supported by grants from the Hong Kong Research Grants Council and University Grants Council HKU7222/97M, HKU2/02C, HKU2/01C, HKU 4/05C, AoE/M-04/04