Structure-function studies on 24-dehydrocholesterol reductase, the affected enzyme in desmosterolosis, a severe inherited disorder of sterol metabolism

Seladin1/DHCR24, the putative 24-dehydrocholestorol reductase.



DHCR24 mutations have been shown to be associated with desmosterolosis, a rare but severe inherited disorder. How these mutations result in the pathology requires the understanding of the actual catalytic activities of DHCR24, which has been proposed to participate in cholesterol biosynthesis by catalyzing the NADPH-dependent reduction of desmosterol (and other unsaturated cholesterol precursors) into cholesterol (and all other 24-25 saturated precursors) Towards this goal, we are aiming to obtain catalytically active forms of human DHCR24, which is associated to the ER membrena presumably through an N.terminal domain, preceding the catalytic region. Attempts to produce protein forms in E. coli or s. cerevisiae were not successful, but promising results have been recently obtained by expressing it in Pichia pastori cells (in collaboration with Dr. Camattari and Pichler, TU Graz, Austria). The effect of DHCR24 localization and mutations recapitulating desmosterolosis is also being studied (in collaboration with Prof. Maggi, Galbiati and Caruso, UniMI) in mammalian cell lines derived from neural tissue, which have been chosen as a model of immature neurons.