期刊
CLINICA CHIMICA ACTA
卷 488, 期 -, 页码 104-110出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.cca.2018.11.003
关键词
MNGIE; POLG; OPA1; mtDNA depletion; Pathogenic variants
资金
- Ministry of Higher Education and Scientific Research in Tunisia, University of Sfax
- Institut National de la Sante et de la Recherche Medicate (INSERM), France
- Centre National de la Recherche Scientifique (CNRS), France
- Universite d'Angers, France
- University Hospital of Angers, France
- Region Pays de Loire, France
- Angers Loire Metropole, France
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 POW 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.
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