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Uusimaa, J, Evans, J, Smith, C, Butterworth, A, Craig, K, Ashley, N, Liao, C, Carver, J, Diot, A, Macleod, L, Hargreaves, IP, Al-Hussaini, A, Faqeih, E, Asery, A, Al Balwi, M, Eyaid, W, Al-Sunaid, A, Kelly, D, van Mourik, I, Ball, S , Jarvis, J, Mulay, A, Hadzic, N, Samyn, M, Baker, A, Rahman, S, Stewart, H, Morris, AAM, Seller, A, Fratter, C, Taylor, RW and Poulton, J (2013) Clinical, biochemical, cellular and molecular characterization of mitochondrial DNA depletion syndrome due to novel mutations in the MPV17 gene. European Journal of Human Genetics, 22 (2). pp. 184-191. ISSN 1018-4813
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Clinical, biochemical, cellular and molecular characterization of mitochondrial DNA depletion syndrome due to novel mutation.pdf - Published Version Available under License Creative Commons Attribution. Download (997kB) | Preview |
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.
| Item Type: | Article |
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| Uncontrolled Keywords: | 0604 Genetics, 1103 Clinical Sciences |
| Subjects: | Q Science > QH Natural history > QH301 Biology Q Science > QH Natural history > QH426 Genetics R Medicine > RM Therapeutics. Pharmacology |
| Divisions: | Pharmacy & Biomolecular Sciences |
| Publisher: | Nature Publishing Group |
| Related URLs: | |
| Date Deposited: | 22 Sep 2020 10:23 |
| Last Modified: | 04 Sep 2021 06:39 |
| DOI or ID number: | 10.1038/ejhg.2013.112 |
| URI: | https://researchonline.ljmu.ac.uk/id/eprint/13683 |
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