Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinaemia

Abstract

The microsomal triglyceride transfer protein (MTP), which catalyses the transport of triglyceride, cholesteryl ester and phospholipid between phospholipid surfaces, is a heterodimer composed of the multifunctional protein, protein disulphide isomerase, and a unique large subunit with an apparent M(r) of 88K (refs 1-3). It is isolated as a soluble protein from the lumen of the microsomal fraction of liver and intestine. The large subunit of MTP was not detectable in four unrelated subjects with abetalipoproteinaemia, a rare autosomal recessive disease characterized by a defect in the assembly or secretion of plasma lipoproteins that contain apolipoprotein B (ref. 6). We report here the isolation and sequencing of complementary DNA encoding the large subunit of MTP. A comparison of this sequence to corresponding genomic sequences from two abetalipoproteinaemic subjects revealed a homozygous frameshift mutation in one subject and a homozygous nonsense mutation in the other. The results indicate that a defect in the gene for the large subunit of MTP is the proximal cause of abetalipoproteinaemia in these two subjects, and that MTP is required for the secretion of plasma lipoproteins that contain apolipoprotein B.

Clinical utility gene card for: Abetalipoproteinaemia – Update 2014

“…[1][2][3][4][5][6] The majority of variants associated with abetalipoproteinaemia are 'private' to specific families or ethnic communities.…”

Cholesterol absorption status and fasting plasma cholesterol are modulated by the microsomal triacylglycerol transfer protein −493 G/T polymorphism and the usual diet in women

“…The microsomal triglyceride transfer protein (MTP) is a heterodimeric lipid transfer protein mainly present in hepatocytes and enterocytes. MTP has an essential role in the assembly process and secretion of very low-density lipoproteins (VLDL) and chylomicrons into the plasma [40]. Indeed, it is able to transfer cholesterol esters [13] and triglycerides from the endoplasmic reticulum membranes to nascent apo-B lipoproteins [46].…”

“…Indeed, it is able to transfer cholesterol esters [13] and triglycerides from the endoplasmic reticulum membranes to nascent apo-B lipoproteins [46]. For instance, the loss of activity resulting from mutations in the coding regions of the MTP gene expresses the rare genetic disorder abetalipoproteinemia, with a suppressed chylomicron secretion and hypocholesterolemia [40,45]. The MTP gene is polymorphic, with several genetic variants especially in the promoter region [14,17].…”

Enhanced expression of hepatic acyl-coenzyme A synthetase and microsomal triglyceride transfer protein messenger RNAs in the obese and hypertriglyceridemic rat with visceral fat accumulation

“…The consensus sequence was obtained by direct PCR sequencing (Applied Biosystems 373 Automated DNA Sequencer) of 4 independent PCR products using dye-labeled dideoxynucleotides as described previously. 17 A 355-bp fragment of the product (784-1138) was used. The sequence is as follows:…”

“…Genetic disruption of the MTP gene causes abetalipoproteinemia in which secretion of very-low density lipoprotein (VLDL) particles or chylomicron from the liver and intestines is virtually absent. [14][15][16][17][18] In other words, an increase in these key proteins in relation to VLDL production and secretion is thought to cause hyperlipoproteinemia. However, it has been difficult to study the direct role of visceral fat accumulation in lipoprotein metabolism separately from insulin resistance in humans because insulin influences the functions of many proteins and enzymes involved in lipoprotein metabolism.…”