Abstract
Background and aimsAbetalipoproteinemia (ABL) is a rare recessive monogenic disease due to MTTP (microsomal triglyceride transfer protein) mutations leading to the absence of plasma apoB-containing lipoproteins. Here we characterize a new ABL case with usual clinical phenotype, hypocholesterolemia, hypotriglyceridemia but normal serum apolipoprotein B48 (apoB48) and red blood cell vitamin E concentrations. MethodsHistology and MTP activity measurements were performed on intestinal biopsies. Mutations in MTTP were identified by Sanger sequencing, quantitative digital droplet and long-range PCR. Functional consequences of the variants were studied in vitro using a minigene splicing assay, measurement of MTP activity and apoB48 secretion. ResultsIntestinal steatosis and the absence of measurable lipid transfer activity in intestinal protein extract supported the diagnosis of ABL. A novel MTTP c.1868G>T variant inherited from the patient's father was identified. This variant gives rise to three mRNA transcripts: one normally spliced, found at a low frequency in intestinal biopsy, carrying the p.(Arg623Leu) missense variant, producing in vitro 65% of normal MTP activity and apoB48 secretion, and two abnormally spliced transcripts resulting in a non-functional MTP protein. Digital droplet PCR and long-range sequencing revealed a previously described c.1067+1217_1141del allele inherited from the mother, removing exon 10. Thus, the patient is compound heterozygous for two dysfunctional MTTP alleles. The p.(Arg623Leu) variant may maintain residual secretion of apoB48. ConclusionsComplex cases of primary dyslipidemia require the use of a cascade of different methodologies to establish the diagnosis in patients with non-classical biological phenotypes and provide better knowledge on the regulation of lipid metabolism.
Highlights
Abetalipoproteinemia (ABL; OMIM 200100) is a rare autosomal recessive disorder characterized by extremely low levels of plasma total cholesterol (TC) and triglycerides (TG) due to an almost complete absence of apolipoprotein B-containing lipoprotein secretion [1]
The underlying mechanism involves the absence of microsomal triglyceride transfer protein (MTP)-protein disulfide isomerase (PDI) heterodimer that acts as a chaperone for the production of apolipoprotein B (apoB)-LP
ApoB48 concentration in fasting plasma at 3 different ages (2, 3.5, and 4 years) was found to range from 8.40 to 11.06 mg/L in the normal IR. These values were higher than the limit of quantification (0.25 mg/L), and higher than apolipoprotein B48 (apoB48) levels found in other ABL, in chylomicron retention disease (CMRD), and in Ho-FHBL patients (Fig. 2C)
Summary
Abetalipoproteinemia (ABL; OMIM 200100) is a rare autosomal recessive disorder characterized by extremely low levels of plasma total cholesterol (TC) and triglycerides (TG) due to an almost complete absence of apolipoprotein B (apoB)-containing lipoprotein (apoB-LP) secretion [1]. This defect affects both apoB48-containing chylomicrons (CM) and apoB100-containing very-low density lipoproteins (VLDL) leading to an absence of low density lipoproteins (LDL) [2,3]. The diagnosis was delayed by her normal plasma apoB48 concentration, mild hypolipoproteinemia in both parents, and the requirement of additional methods to Sanger sequencing allowing the subsequent identification of heterozygous copy number variations (CNV)
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