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Normal serum ApoB48 and red cells vitamin E concentrations after supplementation in a novel compound heterozygous case of abetalipoproteinemia

  • Mathilde Di Filippo
    Correspondence
    Corresponding author. Hospices Civils de Lyon, Laboratoire de Biologie Médicale Multi Sites, Centre de Biologie et de Pathologie Est, Service de biochimie et biologie moléculaire Grand Est, Bron cedex, F-69677, France.
    Affiliations
    Laboratoire de Biologie Médicale Multi Sites, Centre de Biologie et de Pathologie Est, Service de Biochimie et Biologie Moléculaire Grand Est, Hospices Civils de Lyon, Bron cedex, F-69677, France

    INSERM U1060, Laboratoire Carmen, Université Lyon 1, INRA U1235, INSA de Lyon, CENS, Centre de Recherche en Nutrition Humaine Rhône Alpes, Villeurbanne F-69621, Oullins cedex, F-69921, France
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  • Sophie Collardeau Frachon
    Affiliations
    INSERM U1060, Laboratoire Carmen, Université Lyon 1, INRA U1235, INSA de Lyon, CENS, Centre de Recherche en Nutrition Humaine Rhône Alpes, Villeurbanne F-69621, Oullins cedex, F-69921, France

    Laboratoire de Biologie Médicale Multi Sites, Centre de Biologie et de Pathologie Est, Institut de Pathologie, Hospices Civils de Lyon, Bron cedex, F-69677, France
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  • Alexandre Janin
    Affiliations
    Laboratoire de Biologie Médicale Multi Sites, Centre de Biologie et de Pathologie Est, Service de Biochimie et Biologie Moléculaire Grand Est, Hospices Civils de Lyon, Bron cedex, F-69677, France

    Université de Lyon, Université Claude Bernard Lyon 1, Institut NeuroMyoGène, CNRS UMR5310, INSERM U1217, Lyon, F-69622, France
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  • Sujith Rajan
    Affiliations
    NYU Winthrop Hospital, 101 Mineola Blvd, Mineola, USA
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  • Oriane Marmontel
    Affiliations
    Laboratoire de Biologie Médicale Multi Sites, Centre de Biologie et de Pathologie Est, Service de Biochimie et Biologie Moléculaire Grand Est, Hospices Civils de Lyon, Bron cedex, F-69677, France

    INSERM U1060, Laboratoire Carmen, Université Lyon 1, INRA U1235, INSA de Lyon, CENS, Centre de Recherche en Nutrition Humaine Rhône Alpes, Villeurbanne F-69621, Oullins cedex, F-69921, France
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  • Charlotte Decourt
    Affiliations
    Laboratoire de Biologie Médicale Multi Sites, Centre de Biologie et de Pathologie Est, Service de Biochimie et Biologie Moléculaire Grand Est, Hospices Civils de Lyon, Bron cedex, F-69677, France
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  • Amandine Rubio
    Affiliations
    Gastroentérologie et Nutrition Pédiatrique Hôpital Couple Enfant, CHU de Grenoble Alpes, Grenoble, F-38043, France

    Laboratoire de Bioénergétique Fondamentale et Appliquée, INSERM U1055, Univ. Grenoble Alpes, F-38000, France
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  • Séverine Nony
    Affiliations
    Laboratoire de Biologie Médicale Multi Sites, Centre de Biologie et de Pathologie Est, Service de Biochimie et Biologie Moléculaire Grand Est, Hospices Civils de Lyon, Bron cedex, F-69677, France
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  • Sabrina Dumont
    Affiliations
    Laboratoire de Biologie Médicale Multi Sites, Centre de Biologie et de Pathologie Est, Service de Biochimie et Biologie Moléculaire Grand Est, Hospices Civils de Lyon, Bron cedex, F-69677, France
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  • Charlotte Cuerq
    Affiliations
    INSERM U1060, Laboratoire Carmen, Université Lyon 1, INRA U1235, INSA de Lyon, CENS, Centre de Recherche en Nutrition Humaine Rhône Alpes, Villeurbanne F-69621, Oullins cedex, F-69921, France

    Laboratoire de Biologie Médicale Multi Sites, Centre de Biologie et de Pathologie Sud, Service de Biochimie et Biologie Moléculaire, Hospices Civils de Lyon, Pierre, Benite cedex, F-69495, France
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  • Sybil Charrière
    Affiliations
    INSERM U1060, Laboratoire Carmen, Université Lyon 1, INRA U1235, INSA de Lyon, CENS, Centre de Recherche en Nutrition Humaine Rhône Alpes, Villeurbanne F-69621, Oullins cedex, F-69921, France

    Fédération d'endocrinologie, maladies métaboliques, diabète et nutrition, Hôpital Louis Pradel, Hospices Civils de Lyon, Bron cedex, F-69677, France
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  • Philippe Moulin
    Affiliations
    INSERM U1060, Laboratoire Carmen, Université Lyon 1, INRA U1235, INSA de Lyon, CENS, Centre de Recherche en Nutrition Humaine Rhône Alpes, Villeurbanne F-69621, Oullins cedex, F-69921, France

    Fédération d'endocrinologie, maladies métaboliques, diabète et nutrition, Hôpital Louis Pradel, Hospices Civils de Lyon, Bron cedex, F-69677, France
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  • Alain Lachaux
    Affiliations
    Service de Nutrition Pediatrique, Gastroenterologie and Hepatologie, Hôpital Femme Mère Enfants, Hospices Civils de Lyon, Bron cedex, F-69677, France
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  • M. Mahmood Hussain
    Affiliations
    NYU Winthrop Hospital, 101 Mineola Blvd, Mineola, USA
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  • Dominique Bozon
    Affiliations
    Laboratoire de Biologie Médicale Multi Sites, Centre de Biologie et de Pathologie Est, Service de Biochimie et Biologie Moléculaire Grand Est, Hospices Civils de Lyon, Bron cedex, F-69677, France
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  • Noël Peretti
    Affiliations
    INSERM U1060, Laboratoire Carmen, Université Lyon 1, INRA U1235, INSA de Lyon, CENS, Centre de Recherche en Nutrition Humaine Rhône Alpes, Villeurbanne F-69621, Oullins cedex, F-69921, France

    Service de Nutrition Pediatrique, Gastroenterologie and Hepatologie, Hôpital Femme Mère Enfants, Hospices Civils de Lyon, Bron cedex, F-69677, France
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      Highlights

      • Clinically typical abetalipoproteinemia (ABL) proband with two MTTP mutant alleles.
      • ABL with normal apoB48 concentration but deficient serum fat soluble vitamins.
      • c.1868G>T undergoes abnormal splicing and infrequently p.R623L functional variant.
      • Requirement of methods detecting heterozygous copy number variation on MTTP.
      • Normal vitamin E in red cells in case of normal apoB48 secretion.

      Abstract

      Background and aims

      Abetalipoproteinemia (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.

      Methods

      Histology 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.

      Results

      Intestinal 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.

      Conclusions

      Complex 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.

      Graphical abstract

      Keywords

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