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A Severe Form of Abetalipoproteinemia Caused by New Splicing Mutations

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A Severe Form of Abetalipoproteinemia Caused by New Splicing Mutations A severe form of abetalipoproteinemia caused by new splicing mutations of microsomal triglyceride transfer protein Véronique Pons, Corinne Rolland, Michel Nauze, Marie Danjoux, Gérald Gaibelet, Anne H. Durandy, Agnes Sassolas, Emile Lévy, François Tercé, Xavier Collet, et al. To cite this version: Véronique Pons, Corinne Rolland, Michel Nauze, Marie Danjoux, Gérald Gaibelet, et al.. A severe form of abetalipoproteinemia caused by new splicing mutations of microsomal triglyceride transfer protein. Human Mutation, Wiley, 2011, 32 (7), pp.751. 10.1002/humu.21494. hal-00651635 HAL Id: hal-00651635 https://hal.archives-ouvertes.fr/hal-00651635 Submitted on 14 Dec 2011 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Human Mutation A severe form of abetalipoproteinemia caused by new splicing mutations of microsomal triglyceride transfer protein For Peer Review Journal: Human Mutation Manuscript ID: humu-2010-0522.R1 Wiley - Manuscript type: Research Article Date Submitted by the 07-Feb-2011 Author: Complete List of Authors: Pons, Véronique; INSERM, U1048; Université Toulouse III, Institut de Maladies Métaboliques et Cardiovasculaires Rolland, Corinne; INSERM, U1043; Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP) Nauze, Michel; INSERM, U1048; Université Toulouse III, Institut de Maladies Métaboliques et Cardiovasculaires Danjoux, Marie; CHU Toulouse, Hôpital Purpan, Département d’Anatomopathologie Gaibelet, Gérald; INSERM, U1048; Université Toulouse III, Institut de Maladies Métaboliques et Cardiovasculaires Durandy, Anne; INSERM U768, Université Paris V-René Descartes, Hôpital Necker-Enfants Malades Sassolas, Agnes; UF Dyslipidémies, CBPE, Hospices Civils de Lyon and Lyon University, INSERM U1060, CarMeN Laboratory, Univ Lyon-1 Lévy, Emile; Départements de Nutrition et de Biochimie, Hôpital Sainte-Justine et Université de Montréal Tercé, François; INSERM, U1048; Université Toulouse III, Institut de Maladies Métaboliques et Cardiovasculaires Collet, Xavier; INSERM, U1048; Université Toulouse III, Institut de Maladies Métaboliques et Cardiovasculaires MAS, Emmanuel; INSERM, U1043; Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP); CHU Toulouse, Hôpital des Enfants, Unité de Gastroentérologie, Hépatologie et Nutrition, Département de Pédiatrie abetalipoproteinemia, MTTP, triglyceride transfer, endoplasmic Key Words: reticulum, intestinal HDL John Wiley & Sons, Inc. Page 2 of 78 Human Mutation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 John Wiley & Sons, Inc. Human Mutation Page 3 of 78 New splicing mutations of MT TP 1 Formatted: Font: Italic 1 2 A severe form of abetalipoproteinemia caused by new splicing mutations of microsomal 3 4 triglyceride transfer protein 5 1, 6 1,2 3,4 1,2 5 Deleted : Véronique Pons , Corinne Rolland , Michel Nauze , Marie Danjoux , Gérald Gaibelet 2…3 Deleted : ... [1] 7 1,2 6 7 8 1,2 1,2 8 , Anne Durandy , Agnès Sassolas , Emile Lévy , François Tercé , Xavier Collet * Deleted : 4 9 and Emmanuel Mas 3,4,9* Deleted : 4 5 10 Deleted : 11 Deleted : 5 1 12 INSERM, U1048 , Toulouse, F-31 000 , France; Deleted : 6 13 6 2Université Toulouse III, Institut de Maladies Métaboliques et Cardiovasculaires, Toulouse, Deleted : 14 7…1, Deleted : ... [2] 15 F-31300 France; 2…7 Deleted : ... [3] 16 3 INSERM, U1043, Toulouse, F-31300 France; Deleted : 8 17 8 18 4Université de Toulouse , UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP) , Deleted : 19 Formatted: Font: (Default) Times Toulouse, F-31300 , France; New Roman, Complex Script Font: 20 For Peer Review Times New Roman, French France 5CHU Toulouse, Hôpital Purpan, Département d’Anatomopathologie, Toulouse, F-31300 21 Deleted : U563… ... [4] 22 France; Deleted : 3 23 Formatted 6INSERM U768, Université Paris V-René Descartes, Hôpital Necker-Enfants Malades, 75015 ... [5] 24 Deleted : 25 Paris (France); Formatted 26 ... [6] 7 27 UF Dyslipidémies, CBPE, Hospices Civils de Lyon and Lyon University, INSERM U1060, Deleted : France 28 Formatted ... [7] CarMeN Laboratory, Univ Lyon-1 F-69621, Villeurbanne (France); 3 29 Deleted : 8 30 Départements de Nutrition et de Biochimie, Hôpital Sainte-Justine et Université de Montréal, Formatted: Superscript 31 Montréal, Québec (Canada); Deleted : III Paul-Sabatier, Deleted : 4 32 9 33 CHU Toulouse, Hôpital des Enfants, Unité de Gastroentérologie, Hépatologie et Nutrition, Deleted : 3 34 Département de Pédiatrie, Toulouse, F-31300 , France. Deleted : Hôpital Purpan, 35 4 * These authors equally contributed to the work Deleted : 36 5… Deleted : , ... [8] 37 Deleted : Université Paris Descartes, 38 Faculté de Médecine Paris V-René 39 Corresponding author: Descartes, 40 Emmanuel Mas, MD Deleted : 5 41 Deleted : 6 Hôpital des Enfants - Unité de Gastroentérologie, Hépatologie et Nutrition – 330 avenue de 42 Formatted ... [9] 43 Grande-Bretagne – TSA 70034 – 31059 Toulouse cedex 9 (France) Deleted : Laboratoire des 44 Dyslipidémies, Centre de Biologie Est, Tel. (33) 5 34 55 84 45 Lyon 45 Deleted : 6 46 Fax. (33) 5 34 55 85 67 Deleted : 7 47 E-mail: [email protected] 7 48 Deleted : 8… 49 Deleted : Hôpital des Enfants, ... [10] 50 Deleted : 9¶ 51 52 53 54 55 56 57 58 59 60 John Wiley & Sons, Inc. Page 4 of 78 Human Mutation New splicing mutations of MT TP 2 Formatted: Font: Italic 1 2 ABSTRACT 3 4 Abetalipoproteinemia is a rare autosomal recessive disease characterized by low lipid levels 5 and by the absence of apoB-containing lipoproteins. It is the consequence of microsomal 6 7 triglyceride transfer protein (MT TP) deficiency. Deleted : ed 8 We report 2 patients with new MTTP mutations. We studied their functional consequences on 9 Deleted : MTP MTTP 10 the triglyceride transfer function using duodenal biopsies. We transfected mutants in Formatted: Font: Italic 11 HepG2 and HeLa cells to investigate their association with protein disulfide isomerase ( PDI ) Deleted : MTP 12 Formatted: Font: Italic and their localization at the endoplasmic reticulum. 13 Formatted: Font: Italic 14 These children have a severe abetalipoproteinemia. Both of them had also a mild 15 hypogammaglobulinemia. They are compound heterozygotes with c.619G>T and c.1237- 16 Deleted : mttp 17 28A>G mutations within MTTP gene. mRNA analysis revealed abnormal splicing with 18 Formatted: Font: Italic deletion of exon 6 and 10, respectively. Deletion of exon 6 (∆6-MTTP ) introduced a frame 19 Formatted: Font: Italic 20 shift in the reading frame andFor a premature Peerstop codon at position Review 234. Despite ∆6-MTTP and Deleted : MTP 21 Formatted: Font: Italic ∆ 22 10-MTTP mutants were not capable of binding PDI, both MTTP mutant proteins normally Deleted : MTP 23 localize at the endoplasmic reticulum. However, these two mutations induce a loss of MTTP Formatted: Font: Italic 24 Deleted : MTP triglyceride transfer activity. 25 Deleted : MTP 26 These two mutations lead to abnormal truncated MTTP proteins, incapable of binding PDI Deleted : MTP 27 and responsible for the loss of function of MTTP , thereby explaining the severe Deleted : MTP 28 Deleted : MTP 29 abetalipoproteinemia phenotype of these children. 30 31 Deleted : MTP 32 Keywords: abetalipoproteinemia, MTTP , triglyceride transfer, intestinal HDL, endoplasmic 33 Formatted: Font: Italic 34 reticulum 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 John Wiley & Sons, Inc. Human Mutation Page 5 of 78 New splicing mutations of MT TP 3 Formatted: Font: Italic 1 2 INTRODUCTION 3 4 Abetalipoproteinemia (ABL, OMIM 200100) is a rare autosomal recessive disease 5 Deleted : MTP 6 caused by the deficiency of the microsomal triglyceride transfer protein (MTTP, OMIM 7 8 157147 ). ABL is characterized by the absence of apolipoprotein B (apoB)-containing 9 Deleted : MTP 10 lipoproteins from plasma. MTTP is a 97 kDa protein, containing 894 amino acids, that forms 11 Deleted : MTP 12 a heterodimer with the 55 kDa protein disulfide isomerase (PDI). MTTP is mainly found in 13 14 the endoplasmic reticulum (ER) of hepatocytes and enterocytes (Wetterau, et al., 1992). 15 Deleted : MTP 16 MTTP is required for the transfer of neutral lipids to nascent apoB-lipoproteins, resulting in 17 18 the secretion of very low-density lipoproteins (VLDL) in the liver or chylomicrons (CM) in 19 Deleted : MTP 20 the intestine. When MTTP is Fordeficient, nascent Peer apoB is degraded Review by the proteasome (Benoist Formatted: Font: Italic 21 Deleted : (Zhou, et al., 1998) 22 and Grand-Perret, 1997) . It differs from familial hypobetalipoproteinemia, displaying 23 24 dysfunctional apoB and leading to the absence of apoB-lipoproteins in the plasma. Familial 25 26 hypobetalipoproteinemia is a co-dominant disorder and even if heterozygotes can be 27 28 asymptomatic, they had low levels of total cholesterol (TC), low density lipoprotein (LDL)- 29 30 cholesterol and apoB (OMIM 107730). 31 Deleted : MTP 32 ABL was characterized as the consequence of MTTP absence or dysfunction in 1992 33 Deleted : mttp 34 by Wettereau et al. (Wetterau, et al., 1992). The genetic defects in MTTP gene, located on Formatted: Font: Italic 35 36 chromosome 4q22-24, were confirmed one year later (Sharp, et al., 1993; Shoulders, et al., 37 38 1993). ABL is a very uncommon disease, which highlights the crucial role of this protein. 39 Deleted : MTP Indeed, the mttp -deficient mice died at embryonic day 10.5 with abnormal neurological 40 41 development (exencephalia) (Raabe, et al., 1998).
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