Laura S Kremer1, Caroline L'hermitte-Stead2, Pierre Lesimple2, Mylène Gilleron3, Sandrine Filaut4, Claude Jardel3, Tobias B Haack1, Tim M Strom1, Thomas Meitinger1, Hatem Azzouz5, Neji Tebib5, Hélène Ogier de Baulny6, Guy Touati7, Holger Prokisch8, Anne Lombès9. 1. Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, Munich, Germany. 2. Inserm UMR 1016, Institut Cochin, Paris, France; CNRS UMR 8104, Institut Cochin, Paris, France; Université Paris V René Descartes, Institut Cochin, Paris, France. 3. Inserm UMR 1016, Institut Cochin, Paris, France; CNRS UMR 8104, Institut Cochin, Paris, France; Université Paris V René Descartes, Institut Cochin, Paris, France; AP/HP, GHU Pitié-Salpêtrière, Université Paris VI Pierre et Marie Curie, Service de Biochimie Métabolique et Centre de Génétique moléculaire et chromosomique, Paris, France. 4. AP/HP, GHU Pitié-Salpêtrière, Université Paris VI Pierre et Marie Curie, Service de Biochimie Métabolique et Centre de Génétique moléculaire et chromosomique, Paris, France. 5. Hopital La Rabta, Service de Pédiatrie, Tunis, Tunisia. 6. AP/HP, Hôpital Robert Debré, Reference Center for Inherited Metabolic Diseases, Paris, France. 7. Hôpital Purpan, Reference Center for Inherited Metabolic Diseases, Toulouse, France. 8. Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany. 9. Inserm UMR 1016, Institut Cochin, Paris, France; CNRS UMR 8104, Institut Cochin, Paris, France; Université Paris V René Descartes, Institut Cochin, Paris, France. Electronic address: anne.lombes@inserm.fr.
Abstract
BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. LAY SUMMARY: 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.
BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. LAY SUMMARY: 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.
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