ABETALIPOPROTEINEMIA IS CAUSED BY DEFECTS OF THE GENE ENCODING THE 97KDA SUBUNIT OF A MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN

Abetalipoproteinemia is an inherited disorder of lipoprotein metabolis m. Affected individuals produce virtually no circulating apolipoprotei n B-containing lipoproteins (chylomicrons, very low density lipoprotei n, low density lipoprotein and lipoprotein (a)). Malabsorption of the antioxidant vitamin E occurs, leading to spinocerebellar and retinal d egeneration. Biochemical and genetic studies show that abetalipoprotei nemia is not a defect of lipid biosynthesis or of the apolipoprotein B gene. Instead a microsomal triglyceride transfer protein, which exist s as a complex with protein disulphide isomerase in the endoplasmic re ticulum, has been implicated. We have cloned and sequenced the human c DNA encoding microsomal triglyceride transfer protein. The predicted a mino acid sequence shows extensive homology to vitellogenin, the precu rsor of the lipovitellin complex, which has been shown by X-ray crysta llography to contain a large lipid storage cavity. Microsomal triglyce ride transfer protein is expressed in ovary, testis and kidney, in add ition to liver and small intestine. A homozygous mutation that disrupt s splicing has been identified in affected siblings with classical abe talipoproteinemia. These results elucidate a key process in the packag ing of apolipoprotein B with lipid, and should increase our understand ing of the processes regulating the production of atherogenic lipoprot eins.