A homozygous mutation disrupting splicing in the gene encoding the 97 kDa subunit of microsomal triglyceride transfer protein was identified as the cause of abetalipoproteinemia in affected siblings.
The study identifies a mutation in the microsomal triglyceride transfer protein gene as the cause of abetalipoproteinemia, elucidating a key process in apolipoprotein B packaging.
Abetalipoproteinemia is an inherited disorder of lipoprotein metabolism. Affected individuals produce virtually no circulating apolipoprotein B-containing lipoproteins (chylomicrons, very low density lipoprotein, low density lipoprotein and lipoprotein (a)). Malabsorption of the antioxidant vitamin E occurs, leading to spinocerebellar and retinal degeneration. Biochemical and genetic studies show that abetalipoproteinemia is not a defect of lipid biosynthesis or of the apolipoprotein B gene. Instead a microsomal triglyceride 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 lipovitellin complex, which has been shown by X-ray crystallography to contain a large lipid storage cavity. Microsomal triglyceride transfer protein is expressed in ovary, testis and kidney, in addition to liver and small intestine. A homozygous mutation that disrupts splicing has been identified in affected siblings with classical abetalipoproteinemia. These results elucidate a key process in the packaging of apolipoprotein B with lipid, and should increase our understanding of the processes regulating the production of atherogenic lipoproteins.
Shoulders et al. (1993) studied Abetalipoproteinemia. Microsomal triglyceride transfer protein (MTP) gene mutation was evaluated on Identification of genetic defect causing abetalipoproteinemia. A homozygous mutation disrupting splicing in the gene encoding the 97 kDa subunit of microsomal triglyceride transfer protein was identified as the cause of abetalipoproteinemia in affected siblings.