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

Inherited diseases are often caused by a mutation in a single-gene that leads to production of a specific protein with an altered function with respect to that of the "healthy" counterpart. The possibility exists to administer drugs that correct the malfunctioning, thus relieve the disease, provided sufficient information is available on the protein (the precise role, the structure, the reaction it catalyzes if an enzyme, etc.) and on the effects of the mutations on its properties. In order to open the way to the search of suitable drugs or therapeutic approaches, we here propose to carry out, for the first time, the detailed characterization of 24-dehydrocholesterol reductase (DHCR24), an enzyme proposed to be involved in the biosynthesis of cholesterol or compounds of the same type, the molecular defects of which are believed to cause desmosterolosis, a rare disease leading to severe physical and mental developmental defects. The studies we here propose will deal with: i. establishing the link between the, as yet poorly characterised, enzymatic activity and the function of DHCR24 in the cell; ii. the in vitro characterization of the enzymatic activities of DHCR24; iii. the modulation of its function in the cell depending on pre-and post-translational processing, interaction with subcellular structures and other proteins and how (iv) the genetic mutations affect DHCR24 functions. These studies will open the way to the determination of the effect of the genetic mutations on the properties of the protein present in cells of people affected by desmosterolosis. As a result we will contribute to the understanding of the link between the malfunctioning of DHCR24 and the disease and we will set a firm basis for the design and development of drugs capable to correct the defects.