title: Molecular and functional analysis of two new MTTP gene mutations in an atypical case of abetalipoproteinemia.
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.
authors.affiliation: Hospices Civils de Lyon, Centre de Biologie et de Pathologie Est, Département de biochimie et biologie moléculaire, Bron F-69677, France; Université de Lyon, INSERM U1060, INSA de Lyon, INRA U1235, Université Lyon-1, Villeurbanne F-69621, Oullins F-69600, France. Electronic address: mathilde.di-filippo@chu-lyon.fr.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Di Filippo
authors.affiliation: Hospices Civils de Lyon, Centre de Biologie et de Pathologie Est, Département de biochimie et biologie moléculaire, Bron F-69677, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Créhalet
authors.affiliation: INSERM U698, Université Diderot, CHU X. Bichat Secteur C. Bernard, Paris 75877, France.
authors.forename: Marie Elisabeth
authors.initials: ME
authors.lastname: Samson-Bouma
authors.affiliation: Hospices Civils de Lyon, Centre de Biologie et de Pathologie Est, Département de biochimie et biologie moléculaire, Bron F-69677, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Bonnet
authors.affiliation: INSERM UMR S-747, Université Paris Descartes, Paris 75006, France.
authors.forename: Lawrence P
authors.initials: LP
authors.lastname: Aggerbeck
authors.affiliation: INSERM U698, Université Diderot, CHU X. Bichat Secteur C. Bernard, Paris 75877, France; Université Versailles Saint-Quentin-en-Yvelines, UFR de Médecine Paris Ile-de-France Ouest, Guyancourt 78280, France; AP-HP, GH Hôpitaux Universitaires Paris Ile-de-France Ouest, Hôpital Ambroise Paré, Service de Biochimie et Génétique Moléculaire, Boulogne 92104, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Rabès
authors.affiliation: CHRU Lille, Hôpital Jeanne de Flandre, Département de Pédiatrie, Université Lille Nord de France, Faculté de médecine, INSERM U995, IFR114, Lille 59000, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Gottrand
authors.affiliation: Hôpital Universitaire de Lille, Service de Médecine Interne, Université Lille Nord de France, Lille 59000, France.
authors.forename: Gérald
authors.initials: G
authors.lastname: Luc
authors.affiliation: Hospices Civils de Lyon, Centre de Biologie et de Pathologie Est, Département de biochimie et biologie moléculaire, Bron F-69677, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Bozon
authors.affiliation: Hospices Civils de Lyon, Centre de Biologie et de Pathologie Est, Département de biochimie et biologie moléculaire, Bron F-69677, France; Université de Lyon, INSERM U1060, INSA de Lyon, INRA U1235, Université Lyon-1, Villeurbanne F-69621, Oullins F-69600, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Sassolas
mesh_terms: D000012:Abetalipoproteinemia / Q000201:enzymology*; D002352:Carrier Proteins / Q000235:genetics*; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation
chemical_list: D002352:Carrier Proteins; C106092:microsomal triglyceride transfer protein