Rahma Felhi1, Lamia Sfaihi2, Majida Charif3, Valerie Desquiret-Dumas4, Céline Bris4, David Goudenège4, Leila Ammar-Keskes5, Mongia Hachicha2, Dominique Bonneau4, Vincent Procaccio4, Pascal Reynier4, Patrizia Amati-Bonneau4, Guy Lenaers3, Faiza Fakhfakh6. 1. Molecular and Functional Genetics Laboratory, Faculty of Science of Sfax, University of Sfax, Tunisia. Electronic address: Rahma.90felhi@gmail.com. 2. Department of Pediatry, University Hospital Hedi Chaker, Sfax, Tunisia. 3. MitoLab Team, Institut MitoVasc, UMR CNRS 6015, INSERM U1083, Angers University, Angers, France. 4. MitoLab Team, Institut MitoVasc, UMR CNRS 6015, INSERM U1083, Angers University, Angers, France; Department of Biochemistry and Genetics, University Hospital Angers, Angers, France. 5. Human Molecular Genetics Laboratory, Faculty of Medecine of Sfax, University of Sfax, Tunisia. 6. Molecular and Functional Genetics Laboratory, Faculty of Science of Sfax, University of Sfax, Tunisia. Electronic address: Faiza.fakhfakh02@gmail.com.
Abstract
INTRODUCTION: Mitochondrial diseases are a group of disorders caused mainly by the impairment of the mitochondrial oxidative phosphorylation process, due to mutations either in the mitochondrial or nuclear genome. Among them, the mitochondrial neuro-gastrointestinal encephalo-myopathy (MNGIE) syndrome affects adolescents or young adults, and is mostly caused by TYMP mutations encoding a cytosolic thymidine phosphorylase (TP). PATIENTS AND METHODS: The present study reports the molecular investigation by next-generation re-sequencing of 281 nuclear genes, encoding mitochondrial proteins, of consanguineous family including two individuals with MNGIE syndrome associated to optic atrophy. Bioinformatic analysis was also performed in addition to mtDNA deletion screening and mtDNA copy number quantification in blood of the two patients which were carried out by solf clipping program and qPCR respectively. RESULTS: Next-generation re-sequencing revealed a novel homozygous c.2391G > T POLG mutation (p.M797I) co-occurring with the hypomorphic c.1311A > G OPA1 variant (p.I437M). Analysis of the mitochondrial genome in the two patients disclosed mtDNA depletion in blood, but no deletion. Bio-informatics investigations supported the pathogenicity of the novel POLG mutation that is located in the C-terminal subdomain and might change POLG 3D structure, stability and function. CONCLUSION: The novel homozygous p.M797I POLG mutation is responsible for MNGIE combined to optic atrophy and mtDNA depletion in the two patients.
INTRODUCTION:Mitochondrial diseases are a group of disorders caused mainly by the impairment of the mitochondrial oxidative phosphorylation process, due to mutations either in the mitochondrial or nuclear genome. Among them, the mitochondrial neuro-gastrointestinal encephalo-myopathy (MNGIE) syndrome affects adolescents or young adults, and is mostly caused by TYMP mutations encoding a cytosolic thymidine phosphorylase (TP). PATIENTS AND METHODS: The present study reports the molecular investigation by next-generation re-sequencing of 281 nuclear genes, encoding mitochondrial proteins, of consanguineous family including two individuals with MNGIE syndrome associated to optic atrophy. Bioinformatic analysis was also performed in addition to mtDNA deletion screening and mtDNA copy number quantification in blood of the two patients which were carried out by solf clipping program and qPCR respectively. RESULTS: Next-generation re-sequencing revealed a novel homozygous c.2391G > T POLG mutation (p.M797I) co-occurring with the hypomorphic c.1311A > G OPA1 variant (p.I437M). Analysis of the mitochondrial genome in the two patients disclosed mtDNA depletion in blood, but no deletion. Bio-informatics investigations supported the pathogenicity of the novel POLG mutation that is located in the C-terminal subdomain and might change POLG 3D structure, stability and function. CONCLUSION: The novel homozygous p.M797IPOLG mutation is responsible for MNGIE combined to optic atrophy and mtDNA depletion in the two patients.