Hypomorphic and dominant-negative impact of truncated SOX9 dysregulates Hedgehog-Wnt signaling, causing campomelia.

ABSTRACT: Haploinsufficiency for SOX9, the master chondrogenesis transcription factor, can underlie campomelic dysplasia (CD), an autosomal dominant skeletal malformation syndrome, because heterozygous Sox9 null mice recapitulate the bent limb (campomelia) and some other phenotypes associated with CD. However, in vitro cell assays suggest haploinsufficiency may not apply for certain mutations, notably those that truncate the protein, but in these cases in vivo evidence is lacking and underlying mechanisms are unknown. Here, using conditional mouse mutants, we compared the impact of a heterozygous Sox9 null mutation (Sox9^+/-) with the Sox9^+/Y440X CD mutation that truncates the C-terminal transactivation domain but spares the DNA-binding domain. While

SUBMITTER: Au TYK 

PROVIDER: S-EPMC9910594 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature