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

  title={Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinaemia},
  author={Daru Young Sharp and Laura Blinderman and Kelly A. Combs and Bernadette K. Kienzle and Beverly Ricci and Karen Wager-Smith and C M Gil and Christoph W. Turck and Marie-Elizabeth Boumas and Daniel J. Rader and Lawrence Aggerbeck and Richard E. Gregg and David A. Gordon and John R. Wetterau},
THE microsomal triglyceride transfer protein (MTP), which catalyses the transport of triglyceride, cholesteryl ester and phospho-lipid between phospholipid surfaces, is a heterodimer composed of the multifunctional protein, protein disulphide isomerase, and a unique large subunit with an apparent Mr of 88K (refs 1–3). It is isolated as a soluble protein from the lumen of the microsomal fraction of liver and intestine4. The large subunit of MTP was not detectable in four unrelated subjects with… 
A Novel Abetalipoproteinemia Genotype
Results indicate that a positively charged amino acid at position 540 in the 97-kDa subunit is critical for the productive association with protein disulfide isomerase.
Mutations of the microsomal triglyceride-transfer-protein gene in abetalipoproteinemia.
It is established that defects of the MTP gene are the predominant, if not sole, cause of hereditary ABL and that an intact carboxyl terminus is necessary for activity.
Novel mutations in the microsomal triglyceride transfer protein gene causing abetalipoproteinemia.
Results indicated that defects of the MTP gene are the proximal cause of ABL, with a patient having the Asn780Tyr mutation having none of the manifestations characteristic of classic ABL even though his plasma apoB and vitamin E were virtually undetectable.
Human microsomal triglyceride transfer protein large subunit gene structure.
Microsomal triglyceride transfer protein (MTP) is a heterodimer consisting of the multifunctional enzyme protein disulfide isomerase and a unique, large 97-kDa subunit. MTP is required for the
Microsomal triglyceride transfer protein (MTP) gene mutations in Canadian subjects with abetalipoproteinemia
It is suggested that genetic and non‐genetic factors can modulate the clinical impact of mutant MTP in ABL patients.
The role of the microsomal triglygeride transfer protein in abetalipoproteinemia.
It was recently demonstrated that abetalipoproteinemia, a hereditary disease characterized as an inability to produce chylomicrons and very low-density lipoproteins in the intestine and liver, results from mutations in the gene encoding the 97-kDa subunit of the microsomal triglyceride transfer protein.
A 30-Amino Acid Truncation of the Microsomal Triglyceride Transfer Protein Large Subunit Disrupts Its Interaction with Protein Disulfide-isomerase and Causes Abetalipoproteinemia (*)
Results indicate that the carboxyl-terminal 30 amino acids of the MTP 97-kDa subunit plays an important role in its interaction with protein disulfide-isomerase.
Loss of both phospholipid and triglyceride transfer activities of microsomal triglyceride transfer protein in abetalipoproteinemia
It is pointed out that ABL is associated with the absence of both triglyceride and phospholipid transfer activities in MTP, with severe consequences for expression, subcellular location, and interaction with protein disulfide isomerase (PDI).
Identification of two classes of lipid molecule binding sites on the microsomal triglyceride transfer protein.
It is proposed that MTP contains at least two distinct classes of lipid molecule binding sites that differ in function, one of which is responsible for lipid transport and the other for phosphatidylcholine transport.
The crystal structure of human microsomal triglyceride transfer protein
A structure for microsomal triglyceride transfer protein, a key protein in lipid metabolism and transport, is provided and suggests that the previous structures of human PDI represent the “substrate-bound” and “free” states rather than differences arising from redox state.


Structural properties of the microsomal triglyceride-transfer protein complex.
More clearly defined structural elements of MTP that may play important functional roles are defined and analysis of far-ultraviolet circular dichroism spectra revealed MTP has about 28% alpha-helical and 28% beta-structural content.
Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia.
This work has shown that MTP activity and the 88-kilodalton component of MTP were present in intestinal biopsy samples from eight control individuals but were absent in four abetalipoproteinemic subjects, suggesting that a defect in MTP is the basis for abetAlipoproteinemia and that M TP is indeed required for lipoprotein assembly.
Protein disulfide isomerase appears necessary to maintain the catalytically active structure of the microsomal triglyceride transfer protein.
The results suggest that the association of PDI with 88K is necessary to maintain the catalytically active form of the triglyceride transfer protein and prevent the aggregation of 88K.
Intrahepatic assembly of very low density lipoproteins: immunologic characterization of apolipoprotein B in lipoproteins and hepatic membrane fractions and its intracellular distribution.
Data suggest that, in cultured rat hepatocytes, the majority of both molecular weight forms of apoB are localized in the endoplasmic reticulum, the initial site of VLDL assembly.