| Citation | Distinguished for his contribution to the regulation and genetics of lipid transport and metabolism and their relationships to coronary heart disease and obesity, especially through mechanisms involving the two principal cholesterol and triglyceride transport proteins in the blood (apo) B100 and B48. By sequencing and other studies he established that these two proteins are closely related and indeed the product of a single gene, the smaller protein (B48) corresponding to the amino-terminal half of the larger (apo B 100). Gene sequences compared with cDNAs revealed the totally novel origin of this relationship, in that the carboxy-terminal of apo B48 is defined by a unique post-transcriptional mRNA editing reaction to convert C to U, hence to generate a translation stop codon. This new tier in the control of higher eukaryotic gene expression has been shown by Scott to operate through an editing enzyme - a site-specific cytidine deaminase - thus distinguishing this from other mechanisms of RNA editing. He has shown that the single gene is constitutively transcribed, that mRNA for the larger protein has an extended life time, and that the control of production of both proteins is post-translational. To relate these mechanisms to problems of human disease, he has shown that (i) genetic polymorphism at the relevant locus is associated with altered circulating lipid levels, increased coronary heart disease and obesity (ii) the Mendelian recessive disorder familial abetalipoproteinaemia is not a disorder of the apo B gene itself, but rather of a gene required for secretion of apo B (iii) familial combined hyperlipidaemia, a genetically complex disorder in which there is over-production on the larger apo B protein, is linked to another defined locus in some families. In earlier work, the candidate cloned cDNAS for nerve and epidermal growth factors, insulin-like growth factor II and PDGF A-chain, and made salient observations on the role of these growth factors in biology and disease. |