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.
Highlights
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)
MTP forms a heterodimer with protein disulfide isomerase (PDI), named prolyl 4-hydroxylase  polypeptide (P4HB), which is responsible of the assembly of apolipoprotein B (ApoB)–containing lipoproteins in the liver and the intestine
The identification of mutations in the MTTP gene in DNA from patients is important for establishing the diagnosis of ABL in the context of two other hereditary hypocholesterolemias, homozygous familial hypobetalipoproteinemia (HHBL; OMIM#107730) and Anderson’s disease, known as Chylomicron retention disease (OMIM#246700), which are due to mutations in the APOB and SAR1B genes, respectively
Summary
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. Molecular and functional analysis of two new MTTP gene mutations in an atypical case of abetalipoproteinemia. ABL patients are usually diagnosed during infancy, and they exhibit marked lipid malabsorption, very low levels of cholesterol and triglycerides, the absence of ApoB in the plasma, the absence of chylomicrons after fat loading, and essential fatty acid and fat-soluble vitamin deficiencies ( vitamin E); parental lipoprotein profiles are normal. ABL was suspected because of the presence, at the ultrastructural level, of large amounts of free lipid droplets accumulated in the cytoplasm of enterocytes and hepatocytes in intestinal and liver biopsies
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