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Eur J Hum Genet. 2014 Feb;22(2):184-91. doi: 10.1038/ejhg.2013.112. Epub 2013 May 29.

Clinical, biochemical, cellular and molecular characterization of mitochondrial DNA depletion syndrome due to novel mutations in the MPV17 gene.

Author information

1
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.
2
Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Trust, Oxford, UK.
3
Wellcome Trust Centre for Mitochondrial Research, Newcastle University, UK.
4
Nuffield Department of Obstetrics and Gynaecology, University of Oxford The Women's Centre, Oxford, UK.
5
Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK.
6
Department of Pediatrics, King Fahad Medical City, Riyadh, Saudi Arabia.
7
Department of Pathology and Laboratory Medicine, King Abdulaziz Medical City, Riyadh, Saudi Arabia.
8
Department of Pediatrics, King Abdulaziz Medical City, King Saud Bin Abdulaziz University for Health & Science, Riyadh, Saudi Arabia.
9
Paediatric Liver Unit, Birmingham Children's Hospital, Birmingham, UK.
10
Department of Newborn Screening and Biochemical Genetics, Birmingham Children's Hospital, Birmingham, UK.
11
Clinical Genetics Unit, Birmingham Women's Hospital, Birmingham, UK.
12
Maternity Services, Manor Hospital, Walsall, UK.
13
Paediatric Liver Centre, King's College Hospital, London, UK.
14
Mitochondrial Research Group, UCL Institute of Child Health, London, UK.
15
Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford, UK.
16
Willink Biochemical Genetics Unit, St Mary's Hospital, Manchester, UK.

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.

PMID:
23714749
PMCID:
PMC3895632
DOI:
10.1038/ejhg.2013.112
[Indexed for MEDLINE]
Free PMC Article

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