Journal
EUROPEAN JOURNAL OF HUMAN GENETICS
Volume 22, Issue 2, Pages 184-191Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ejhg.2013.112
Keywords
MPV17; mitochondrial DNA depletion; hepatocerebral disease; neonatal liver disease
Funding
- MRC
- Wellcome Trust
- Angus Memorial Mitochondrial Fund
- Foundation for Paediatric Research
- Sigrid Juselius Foundation
- Academy of Finland [138566]
- Wellcome Trust Strategic Award [906919]
- Great Ormond Street Hospital Children's Charity
- Great Ormond Street Hospital Childrens Charity [V1260] Funding Source: researchfish
- Medical Research Council [G0800674, MR/K000608/1, MR/J010448/1] Funding Source: researchfish
- MRC [MR/J010448/1, MR/K000608/1, G0800674] Funding Source: UKRI
- Academy of Finland (AKA) [138566, 138566] Funding Source: Academy of Finland (AKA)
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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 mitochondria] 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.
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