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Case Reports
. 2012 Mar;53(3):548-555.
doi: 10.1194/jlr.M020024. Epub 2012 Jan 11.

Molecular and functional analysis of two new MTTP gene mutations in an atypical case of abetalipoproteinemia

Mathilde Di Filippo  1 , Hervé Créhalet  2 , Marie Elisabeth Samson-Bouma  3 , Véronique Bonnet  2 , Lawrence P Aggerbeck  4 , Jean-Pierre Rabès  5 , Frederic Gottrand  6 , Gérald Luc  7 , Dominique Bozon  2 , Agnès Sassolas  8
Affiliations
Case Reports

Molecular and functional analysis of two new MTTP gene mutations in an atypical case of abetalipoproteinemia

Mathilde Di Filippo et al. J Lipid Res. 2012 Mar.

Abstract

Abetalipoproteinemia (ABL) is an inherited disease characterized by the defective assembly and secretion of apolipoprotein B-containing lipoproteins caused by mutations in the microsomal triglyceride transfer protein large subunit (MTP) gene (MTTP). We report here a female patient with an unusual clinical and biochemical ABL phenotype. She presented with severe liver injury, low levels of LDL-cholesterol, and subnormal levels of vitamin E, but only mild fat malabsorption and no retinitis pigmentosa or acanthocytosis. Our objective was to search for MTTP mutations and to determine the relationship between the genotype and this particular phenotype. The subject exhibited compound heterozygosity for two novel MTTP mutations: one missense mutation (p.Leu435His) and an intronic deletion (c.619-5_619-2del). COS-1 cells expressing the missense mutant protein exhibited negligible levels of MTP activity. In contrast, the minigene splicing reporter assay showed an incomplete splicing defect of the intronic deletion, with 26% of the normal splicing being maintained in the transfected HeLa cells. The small amount of MTP activity resulting from the residual normal splicing in the patient explains the atypical phenotype observed. Our investigation provides an example of a functional analysis of unclassified variations, which is an absolute necessity for the molecular diagnosis of atypical ABL cases.

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Figures

Fig. 1.
Fig. 1.
Ultrastructure of intestinal and liver biopsies after a 12 h fast. The enterocytes (a, b) and hepatocytes (c) were engorged with numerous small or very large lipid droplets (L) free in the cytoplasm. The Golgi apparatus (G) is empty (b). Hepatic intercellular spaces were sometimes enlarged with fibrosis (c). The cell nucleus is labeled N.
Fig. 2.
Fig. 2.
Triglyceride transfer activity of normal and mutant MTTP in COS-1 cells over a period of 48 h. Cell homogenates were used to measure triglyceride transfer from donor to acceptor vesicles using fluorescent-labeled method membranes. Columns and bars represents means ± SD (n = 2).
Fig. 3.
Fig. 3.
Size separation of RT-PCR products as determined by 2% agarose gel electrophoresis. M: molecular weight marker. Lanes 1, 2, and 3: normal minigene. Lanes 4, 5, and 6: mutant (c.619-5_619-2del) minigene.
Fig. 4.
Fig. 4.
Intestinal biosynthesis of ApoB48 and MTP in organ culture. ApoB48 was synthesized by the duodenal biopsy (B) and secreted in the medium (M) with the same molecular weight as normal control (N). MTP from the patient had the same molecular weight as normal control (N). PDI was coimmunoprecipitated: the binding of MTP with PDI was intact in the intestinal biopsy.
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