Severe respiratory complex III defect prevents liver adaptation to prolonged fasting

Autor: Pierre Lesimple, Neji Tebib, Tim M. Strom, Thomas Meitinger, Holger Prokisch, Guy Touati, Anne Lombès, Claude Jardel, Mylène Gilleron, Tobias B. Haack, Caroline L’hermitte-Stead, Hélène Ogier de Baulny, Sandrine Filaut, Laura S. Kremer, Hatem Azzouz
Přispěvatelé: Institute of Human Genetics, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz Zentrum München = German Research Center for Environmental Health, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Biochimie Métabolique et Centre de Génétique moléculaire et chromosomique [CHU Pitié Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital La Rabta [Tunis], Service de neurologie pédiatrique et maladies métaboliques, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service Gastroentérologie, hépatologie nutrition, diabétologie et maladies héréditaires du métabolisme pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), This work was supported by grants from the FRM (Fondation pour la Recherche Médicale) grant DPM20121125550 to AL, from the Association Française contre les Myopathies (AFM) to AL and Association contre les Maladies Mitochondriales (AMMi) to AL, German Bundesministerium für Bildung und Forschung (BMBF) through funding of the E-Rare project GENOMIT (01GM1207) (TM, HP), German Network for mitochondrial disorders (mitoNET, 01GM1113C) (TM, HP)., Lombès, Anne, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-German Research Center for Environmental Health-Helmholtz-Zentrum München (HZM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hépatologie et Maladies Héréditaires du Métabolisme, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Centre de référence commun pour les maladies héréditaires du métabolisme, Technische Universität München [München] ( TUM ) -German Research Center for Environmental Health-Helmholtz-Zentrum München ( HZM ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Hôpital La Rabta [Tunis), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 )
Jazyk: angličtina
Rok vydání: 2016
Předmět:
0301 basic medicine
LYRM7
fasting
hyperammonemia
MTO1
Biology
Bioinformatics
Article
Mitochondrial Proteins
03 medical and health sciences
symbols.namesake
0302 clinical medicine
[ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology
respiratory complex III
medicine
Mitochondrial oxidative phosphorylation pathway
Humans
Exome
Genetics
Sanger sequencing
[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology
Hepatology
Respiration
Homozygote
liver failure
High-Throughput Nucleotide Sequencing
Hyperammonemia
medicine.disease
Adaptation
Physiological
3. Good health
Complementation
030104 developmental biology
hypoglycemia
Liver
Lactic acidosis
Coenzyme Q – cytochrome c reductase
symbols
functional complementation
Liver function
Severe lactic acidosis
030217 neurology & neurosurgery
[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Zdroj: Journal of Hepatology
Journal of Hepatology, 2016, 65 (2), pp.377-85. ⟨10.1016/j.jhep.2016.04.017⟩
Journal of Hepatology, Elsevier, 2016, 65 (2), pp.377-85. ⟨10.1016/j.jhep.2016.04.017⟩
Journal of Hepatology, Elsevier, 2016, 65 (2), pp.377-85. 〈10.1016/j.jhep.2016.04.017〉
ISSN: 0168-8278
1600-0641
DOI: 10.1016/j.jhep.2016.04.017⟩
Popis: Next generation sequencing approaches have tremendously improved the diagnosis of rare genetic diseases. It may however be faced with difficult clinical interpretation of variants. Inherited enzymatic diseases provide an invaluable possibility to evaluate the function of the defective enzyme in human cell biology. This is the case for respiratory complex III, which has 11 structural subunits and requires several assembly factors. An important role of complex III in liver function is suggested by its frequent impairment in human cases of genetic complex III defects.We report the case of a child with complex III defect and acute liver dysfunction with lactic acidosis, hypoglycemia, and hyperammonemia. Mitochondrial activities were assessed in liver and fibroblasts using spectrophotometric assays. Genetic analysis was done by exome followed by Sanger sequencing. Functional complementation of defective fibroblasts was performed using lentiviral transduction followed by enzymatic analyses and expression assays.Homozygous, truncating, mutations in LYRM7 and MTO1, two genes encoding essential mitochondrial proteins were found. Functional complementation of the complex III defect in fibroblasts demonstrated the causal role of LYRM7 mutations. Comparison of the patient's clinical history to previously reported patients with complex III defect due to nuclear DNA mutations, some actually followed by us, showed striking similarities allowing us to propose common pathophysiology.Profound complex III defect in liver does not induce actual liver failure but impedes liver adaptation to prolonged fasting leading to severe lactic acidosis, hypoglycemia, and hyperammonemia, potentially leading to irreversible brain damage.The diagnosis of rare genetic disease has been tremendously accelerated by the development of high throughput sequencing technology. In this paper we report the investigations that have led to identify LYRM7 mutations causing severe hepatic defect of respiratory complex III. Based on the comparison of the patient's phenotype with other cases of complex III defect, we propose that profound complex III defect in liver does not induce actual liver failure but impedes liver adaptation to prolonged fasting.
Databáze: OpenAIRE
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