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Volume 271, Number 47, Issue of November 22, 1996 pp. 29945-29952
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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A Novel Abetalipoproteinemia Genotype
IDENTIFICATION OF A MISSENSE MUTATION IN THE 97-kDa SUBUNIT OF THE MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN THAT PREVENTS COMPLEX FORMATION WITH PROTEIN DISULFIDE ISOMERASE

(Received for publication, July 12, 1996, and in revised form, September 3, 1996)

Edward F. Rehberg , Marie-Elisabeth Samson-Bouma ^§ , Bernadette Kienzle , Laura Blinderman , Haris Jamil , John R. Wetterau , Lawrence P. Aggerbeck ^¶ and David A. Gordon

From the  Department of Metabolic Diseases, Bristol-Myers Squibb, Princeton, New Jersey 08543-4000, the ^§ U327 Institut National de la Santé et de la Recherche Médicale, Faculté de Médecine Xavier Bichat, BP 416, 75870 Paris, Cedex 18, France, and the ^¶ Centre de Génétique Moléculaire, Centre National de la Recherche Scientifique, 91198 Gif-sur-Yvette, France

The microsomal triglyceride transfer protein (MTP) is a heterodimer composed of the ubiquitous multifunctional protein, protein disulfide isomerase, and a unique 97-kDa subunit. Mutations that lead to the absence of a functional 97-kDa subunit cause abetalipoproteinemia, an autosomal recessive disease characterized by a defect in the assembly and secretion of apolipoprotein B (apoB) containing lipoproteins. Previous studies of abetalipoproteinemic patient, C.L., showed that the 97-kDa subunit was undetectable. In this report, [³⁵S]methionine labeling showed that this tissue was capable of synthesizing the 97-kDa MTP subunit. Electrophoretic analysis showed two bands, one with a molecular mass of the wild type 97-kDa subunit and the other with a slightly lower molecular weight. Sequence analysis of cDNAs from additional intestinal biopsies showed this patient to be a compound heterozygote. One allele contained a perfect in-frame deletion of exon 10, explaining the lower molecular weight band. cDNAs of the second allele were found to contain 3 missense mutations: His²⁹⁷  Gln, Asp³⁸⁴  Ala, and Arg⁵⁴⁰  His. Transient expression of each mutant showed that only the Arg⁵⁴⁰  His mutant was non-functional based upon its inability to reconstitute apoB secretion in a cell culture system. The other amino acid changes are silent polymorphisms. High level coexpression in a baculovirus system of the wild type 97-kDa subunit or the Arg⁵⁴⁰  His mutant along with human protein disulfide isomerase showed that the wild type was capable of forming an active MTP complex while the mutant was not. Biochemical analysis of lysates from these cells showed that the Arg to His conversion interrupted the interaction between the 97-kDa subunit and protein disulfide isomerase. Replacement of Arg⁵⁴⁰ with a lysine residue maintained the ability of the 97-kDa subunit to complex with protein disulfide isomerase and form the active MTP holoprotein. These 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. Of the 13 mutant MTP 97-kDa subunit alleles described to date, this is the first encoding a missense mutation.

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