1. From a dominant to an oligogenic model of inheritance with environmental modifiers in acute intermittent porphyria
- Author
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Jérôme Lamoril, Caroline Schmitt, Zoubida Karim, Gaël Nicolas, Sylvie Simonin, Enrique Casalino, Hugo Lenglet, A. M. Robreau, Jean-Charles Deybach, Thomas Grange, Hana Manceau, Florian Bouchet-Crivat, Hervé Puy, Narjesse Karboul, Laurent Gouya, Katell Peoc'h, Arienne Mirmiran, Laboratoire Pierre Aigrain (LPA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL), Centre Français des Porphyries, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Louis Mourier - AP-HP [Colombes], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Français des Porphyries Hôpital Louis Mourier, Université Paris Diderot - Paris 7 (UPD7), Centre Français des Porphyrines, Service urgences, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Louis Mourier - AP-HP [Colombes], Service de Biochimie et de Biologie moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Faculté de Pharmacie-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Département de Génétique et Centre de Référence Maladies Rares Syndrome de Marfan et pathologies apparentées (AP HP, hôpital Bichat), Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), PSL Research University (PSL), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hopital Louis Mourier - AP-HP [Colombes], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Hopital Louis Mourier - AP-HP [Colombes], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Faculté de Pharmacie
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0301 basic medicine ,Male ,Penetrance ,[SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology ,MESH: Hydroxymethylbilane Synthase ,MESH: Penetrance ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Prevalence ,Exome ,Genetics (clinical) ,Acute intermittent porphyria ,Genetics ,education.field_of_study ,MESH: Gene-Environment Interaction ,Oligogenic Inheritance ,[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology ,General Medicine ,[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,3. Good health ,Hydroxymethylbilane Synthase ,Female ,France ,Databases, Nucleic Acid ,Population ,Mutation, Missense ,Biology ,MESH: Databases, Nucleic Acid ,03 medical and health sciences ,medicine ,[SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] ,Humans ,Allele ,education ,Molecular Biology ,MESH: Prevalence ,MESH: Mutation, Missense ,MESH: Humans ,[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,Heritability ,medicine.disease ,MESH: Porphyria, Acute Intermittent ,MESH: Male ,MESH: France ,030104 developmental biology ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,Porphyria, Acute Intermittent ,Gene-Environment Interaction ,MESH: Female - Abstract
International audience; Acute intermittent porphyria (AIP) is a disease affecting the heme biosynthesis pathway caused by mutations of the hydroxymethylbilane synthase (HMBS) gene. AIP is thought to display autosomal dominant inheritance with incomplete penetrance. We evaluated the prevalence, penetrance and heritability of AIP, in families with the disease from the French reference center for porphyria (CFP) (602 overt patients; 1968 relatives) and the general population, using Exome Variant Server (EVS; 12 990 alleles) data. The pathogenicity of the 42 missense variants identified was assessed in silico, and in vitro, by measuring residual HMBS activity of the recombinant protein. The minimal estimated prevalence of AIP in the general population was 1/1299. Thus, 50 000 subjects would be expected to carry the AIP genetic trait in France. Penetrance was estimated at 22.9% in families with AIP, but at only 0.5-1% in the general population. Intrafamily correlation studies showed correlations to be strong overall and modulated by kinship and the area in which the person was living, demonstrating strong influences of genetic and environmental modifiers on inheritance. Null alleles were associated with a more severe phenotype and a higher penetrance than for other mutant alleles. In conclusion, the striking difference in the penetrance of HMBS mutations between the general population and the French AIP families suggests that AIP inheritance does not follow the classical autosomal dominant model, instead of being modulated by strong environmental and genetic factors independent from HMBS. An oligogenic inheritance model with environmental modifiers might better explain AIP penetrance and heritability.
- Published
- 2017
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