title: Clinical, biochemical, cellular and molecular characterization of mitochondrial DNA depletion syndrome due to novel mutations in the MPV17 gene.
abstract: Mitochondrial DNA (mtDNA) depletion syndromes (MDS) are severe autosomal recessive disorders associated with decreased mtDNA copy number in clinically affected tissues. The hepatocerebral form (mtDNA depletion in liver and brain) has been associated with mutations in the POLG, PEO1 (Twinkle), DGUOK and MPV17 genes, the latter encoding a mitochondrial inner membrane protein of unknown function. The aims of this study were to clarify further the clinical, biochemical, cellular and molecular genetic features associated with MDS due to MPV17 gene mutations. We identified 12 pathogenic mutations in the MPV17 gene, of which 11 are novel, in 17 patients from 12 families. All patients manifested liver disease. Poor feeding, hypoglycaemia, raised serum lactate, hypotonia and faltering growth were common presenting features. mtDNA depletion in liver was demonstrated in all seven cases where liver tissue was available. Mosaic mtDNA depletion was found in primary fibroblasts by PicoGreen staining. These results confirm that MPV17 mutations are an important cause of hepatocerebral mtDNA depletion syndrome, and provide the first demonstration of mosaic mtDNA depletion in human MPV17 mutant fibroblast cultures. We found that a severe clinical phenotype was associated with profound tissue-specific mtDNA depletion in liver, and, in some cases, mosaic mtDNA depletion in fibroblasts.
authors.affiliation: 1] Nuffield Department of Obstetrics and Gynaecology, University of Oxford The Women's Centre, Oxford, UK [2] Institute of Clinical Medicine/Paediatrics, University of Oulu, Clinical Research Center, Oulu University Hospital, Oulu, Finland.
authors.forename: Johanna
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authors.lastname: Uusimaa
authors.affiliation: Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Trust, Oxford, UK.
authors.forename: Julie
authors.initials: J
authors.lastname: Evans
authors.affiliation: Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Trust, Oxford, UK.
authors.forename: Conrad
authors.initials: C
authors.lastname: Smith
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Newcastle University, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Butterworth
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Newcastle University, UK.
authors.forename: Kate
authors.initials: K
authors.lastname: Craig
authors.affiliation: Nuffield Department of Obstetrics and Gynaecology, University of Oxford The Women's Centre, Oxford, UK.
authors.forename: Neil
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authors.lastname: Ashley
authors.affiliation: Nuffield Department of Obstetrics and Gynaecology, University of Oxford The Women's Centre, Oxford, UK.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Liao
authors.affiliation: Nuffield Department of Obstetrics and Gynaecology, University of Oxford The Women's Centre, Oxford, UK.
authors.forename: Janet
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authors.lastname: Carver
authors.affiliation: Nuffield Department of Obstetrics and Gynaecology, University of Oxford The Women's Centre, Oxford, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Diot
authors.affiliation: Nuffield Department of Obstetrics and Gynaecology, University of Oxford The Women's Centre, Oxford, UK.
authors.forename: Lorna
authors.initials: L
authors.lastname: Macleod
authors.affiliation: Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Iain
authors.initials: I
authors.lastname: Hargreaves
authors.affiliation: Department of Pediatrics, King Fahad Medical City, Riyadh, Saudi Arabia.
authors.forename: Abdulrahman
authors.initials: A
authors.lastname: Al-Hussaini
authors.affiliation: Department of Pediatrics, King Fahad Medical City, Riyadh, Saudi Arabia.
authors.forename: Eissa
authors.initials: E
authors.lastname: Faqeih
authors.affiliation: Department of Pediatrics, King Fahad Medical City, Riyadh, Saudi Arabia.
authors.forename: Ali
authors.initials: A
authors.lastname: Asery
authors.affiliation: Department of Pathology and Laboratory Medicine, King Abdulaziz Medical City, Riyadh, Saudi Arabia.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Al Balwi
authors.affiliation: Department of Pediatrics, King Abdulaziz Medical City, King Saud Bin Abdulaziz University for Health & Science, Riyadh, Saudi Arabia.
authors.forename: Wafaa
authors.initials: W
authors.lastname: Eyaid
authors.affiliation: Department of Pediatrics, King Abdulaziz Medical City, King Saud Bin Abdulaziz University for Health & Science, Riyadh, Saudi Arabia.
authors.forename: Areej
authors.initials: A
authors.lastname: Al-Sunaid
authors.affiliation: Paediatric Liver Unit, Birmingham Children's Hospital, Birmingham, UK.
authors.forename: Deirdre
authors.initials: D
authors.lastname: Kelly
authors.affiliation: Paediatric Liver Unit, Birmingham Children's Hospital, Birmingham, UK.
authors.forename: Indra
authors.initials: I
authors.lastname: van Mourik
authors.affiliation: Department of Newborn Screening and Biochemical Genetics, Birmingham Children's Hospital, Birmingham, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ball
authors.affiliation: Clinical Genetics Unit, Birmingham Women's Hospital, Birmingham, UK.
authors.forename: Joanna
authors.initials: J
authors.lastname: Jarvis
authors.affiliation: Maternity Services, Manor Hospital, Walsall, UK.
authors.forename: Arundhati
authors.initials: A
authors.lastname: Mulay
authors.affiliation: Paediatric Liver Centre, King's College Hospital, London, UK.
authors.forename: Nedim
authors.initials: N
authors.lastname: Hadzic
authors.affiliation: Paediatric Liver Centre, King's College Hospital, London, UK.
authors.forename: Marianne
authors.initials: M
authors.lastname: Samyn
authors.affiliation: Paediatric Liver Centre, King's College Hospital, London, UK.
authors.forename: Alastair
authors.initials: A
authors.lastname: Baker
authors.affiliation: Mitochondrial Research Group, UCL Institute of Child Health, London, UK.
authors.forename: Shamima
authors.initials: S
authors.lastname: Rahman
authors.affiliation: Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Stewart
authors.affiliation: Willink Biochemical Genetics Unit, St Mary's Hospital, Manchester, UK.
authors.forename: Andrew Am
authors.initials: AA
authors.lastname: Morris
authors.affiliation: Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Trust, Oxford, UK.
authors.forename: Anneke
authors.initials: A
authors.lastname: Seller
authors.affiliation: Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Trust, Oxford, UK.
authors.forename: Carl
authors.initials: C
authors.lastname: Fratter
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Newcastle University, UK.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.affiliation: Nuffield Department of Obstetrics and Gynaecology, University of Oxford The Women's Centre, Oxford, UK.
authors.forename: Joanna
authors.initials: J
authors.lastname: Poulton
mesh_terms: D016022:Case-Control Studies; D002478:Cells, Cultured; D002675:Child, Preschool; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000473:pathology; D018628:Gene Dosage; D050259:Genes, Mitochondrial; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D028361:Mitochondrial Diseases / Q000235:genetics / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics*; D020125:Mutation, Missense; D017354:Point Mutation
chemical_list: D018389:Codon, Nonsense; D004272:DNA, Mitochondrial; C530370:MPV17 protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins