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.

Mitochondrial DNA Depletion and Deletions in Paediatric Patients with Neuromuscular Diseases: Novel Phenotypes

“…Similar encephalopathic phenotypes have been described in MDDS caused by several mtDNA maintenance genes including in SUCLA2 and SUCLG1 (Ostergaard et al 2007a, b;Carrozzo et al 2007;Elpeleg et al 2005), DGUOK (Mandel et al 2001;Dimmock et al 2008) and RRM2B (Bornstein et al 2008;Acham-Roschitz et al 2009;Kollberg et al 2009). Patient 1 was also found with generalized aminoaciduria that has previously been described in MDDS patients (Uusimaa et al 2014). Patient 2 presented with a novel early-onset and fatal MDDS phenotype including encephalopathy, optic atrophy, pigmentary retinopathy, sensorineural hearing impairment and pathologic ER membranes in histologically disordered muscle with accumulation of glycogen and extracellular collagen fibres (Fig.…”

Renal manifestations of genetic mitochondrial disease

“…The renal phenotype is most characteristic of renal tubular dysfunction, [72][73][74][75][76][77][78] but renal failure has also been described. 79 …”

The Human Mitochondrial DNA Depletion Syndrome Gene MPV17 Encodes a Non-selective Channel That Modulates Membrane Potential

“…Remarkably, these mice showed signs of premature aging: gray coat color early in adulthood, age-dependent glomerulosclerosis, sensorineural deafness (6 -9), and cataract. 5 The recent findings where liver-specific expression of human MPV17 in Mpv17 Ϫ/Ϫ mice restored mtDNA copy number and oxidative phosphorylation proficiency and prevented ketogenic diet-induced liver failure (10) underscore the link between MPV17 function and MPV17-related MDDS.…”

“…Clinically, this infantile onset disease is characterized by developmental delay, liver dysfunction, sensory and motor neuropathy, and other manifestations (1,2). So far, more than 30 mutations of the nuclear encoded gene for the small (18-kDa) inner mitochondrial membrane protein MPV17 (4) have been described (5). In line with this, severe mtDNA depletion in the liver, brain, and skeletal muscle was also detected in Mpv17 Ϫ/Ϫ mice (4, 6 -8).…”