Human Molecular Genetics

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© 1993 Oxford University Press

RESEARCH-ARTICLE

Abetalipoproteinemia is caused by defects of the gene encoding the 97 kDa subunit of a microsomal triglyceride transfer protein

Carol C. Shoulders, David J. Brett, Jayne D. Bayllss, Teresa M.E. Narcisi, Adam Jarmuz, Tamsin T. Grantham, Patricia R.D. Leoni, Shoumo Bhattacharya, Richard J. Pease, Paul M. Cullen⁺, Sassoon Levi¹, Peter G.H. Byfield², Paul Purkiss² and James Scott^*

MRC Molecular Medicine Group London W12 ONN ¹Gastroenterology Unit, Department of Medicine, Royal Postgraduate Medical School, Hammersmith Hospital London W12 ONN ²Haemostass Research Group, MRC Clinical Research Centre Harrow, Middlesexx HA1 3UJ, UK

^*To whom correspondence should be addressed

Received September 7, 1993; Revised October 21, 1993; Accepted October 21, 1993

Abetallpoproteinemia is an inherited disorder of llpoprotein metabolism. Affected Individuals produce virtually no circulating apollpoprotein B-containing llpoproteins (chylomicrons, very low density llpoprotein, low intensity llpoprotein and llpoprotein (a)). Malabsorption of the antioxidant vitamin E occurs, leading to spinocerebellar and retinal degeneration. Biochemical and genetic studies show that abetallpoproteinemia is not a defect of lipid biosynthesis or of the apollpoprotein B gene. Instead a microsomal triglycerlde transfer protein, which exists as a complex with protein disulphide Isomerase in the endoplasmic reticulum, has been Implicated. We have cloned and sequenced the human cDNA encoding microsomal triglyceride transfer protein. The predicted amino acid sequence shows extensive homology to vitellogenin, the precursor of the llpovitellin complex, which has been shown by X-ray crystallography to contain a large lipid storage cavity. Microsomal triglyceride transfer protein is expressed in ovary, testls and kidney, in addition to liver and small Intestine. A homozygous mutation that disrupts splicing has been identified in affected siblings with classical abetallpoproteinemia. These results elucidate a key process in the packaging of apollpoprotein B with lipid, and should increase our understanding of the processses regulating the production of atherogenic llpoproteins.

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