Despite 10 years of work since the discovery of SRY, little is known about its biochemical function. The HMG domain, a DNA-binding and DNA-bending motif, plays a central role, being the only region conserved between species and the site of almost all clinical mutations causing XY gonadal dysgenesis. By contrast, SOX9 harbours a number of highly conserved regions, including two domains required for maximal transactivation. The heat shock protein HSP70 recognizes a specific region of SOX9 hitherto of unknown function which may facilitate the assembly of multi-protein complexes at promoter/enhancer regions. The SRY and SOX9 HMG domains carry two nuclear localization signals (NLSs), one at each end which function independently and by distinct mechanisms. The N-terminal NLS is bound by calmodulin while the C-terminal NLS is bound by importin β. Four XY gonadal dysgenesis patients with mutations in SRY NLS regions showed reduced nuclear import accompanied in some cases by reduced importin β recognition. A campomelic dysplasia patient with SOX9 mutation outside the NLS regions also showed defective SOX9 nuclear import implying that nuclear import defects could be a common explanation for SRY and SOX9 HMG domain mutations.
|Number of pages||11|
|Journal||Novartis Foundation Symposium|
|Publication status||Published - 1 Dec 2002|