MPV17 – Mitochondrial DNA Depletion Syndrome 6 (Hepatocerebral Type)

MPV17 encodes a mitochondrial inner membrane protein essential for deoxynucleotide import and mtDNA maintenance. Biallelic MPV17 mutations cause an autosomal recessive hepatocerebral mitochondrial DNA depletion syndrome, presenting with infantile liver failure, failure to thrive, lactic acidosis, and later neurologic involvement including peripheral neuropathy. A Navajo patient homozygous for c.149G>A (p.Arg50Gln) was diagnosed via quantitative mtDNA analysis and MPV17 sequencing (PMID:28209105).

An initial study of Navajo neurohepatopathy identified six affected individuals from five families, all homozygous for c.149G>A (p.Arg50Gln), confirming a founder effect (PMID:16909392). Four Korean children from unrelated families exhibited diverse MPV17 variants, including frameshift and missense alleles, all in the homozygous or compound heterozygous state (PMID:27536553). A comprehensive review described 100 affected individuals carrying 48 distinct pathogenic MPV17 variants, with missense changes representing ~50% of alleles and biallelic missense genotypes (e.g., homozygous p.Arg50Gln, p.Pro98Leu, p.Arg41Gln) correlating with milder phenotypes (PMID:29282788).

The MPV17 variant spectrum includes 39 missense, multiple nonsense and frameshift (e.g., c.293del (p.Pro98fs), c.360G>A (p.Trp120Ter)), splice-site (c.70+5G>A), and small deletion alleles. Recurrent alleles such as c.149G>A (p.Arg50Gln) support a population-specific founder effect in Navajo patients.

Functional studies across models demonstrate concordance with human disease. An AAV-mediated, liver-specific MPV17 expression in Mpv17–/– mice restored mtDNA copy number, OXPHOS activity, and prevented ketogenic diet–induced liver failure (PMID:24247928). A minigene splicing assay confirmed pathogenicity of intronic c.70+5G>A (PMID:20614188). Yeast Sym1 ortholog assays showed that patient missense mutations disrupt a high-molecular-weight complex essential for mtDNA stability (PMID:30273399), and electrophysiological characterization revealed MPV17 as a non-selective channel regulating mitochondrial membrane potential (PMID:25861990).

The mechanism of pathogenicity is loss of MPV17 function (haploinsufficiency in a recessive context) leading to tissue-specific mtDNA depletion, energy failure, and secondary ROS accumulation. There is no compelling human evidence refuting the association; however, a canine MPV17 truncation model exhibits no overt phenotype, suggesting species-specific compensatory mechanisms (PMID:26353863).

Collectively, over 100 probands from >50 families, multi-family segregation, and robust functional concordance establish a definitive gene-disease relationship. MPV17 sequencing is clinically indicated in early-onset hepatocerebral mitochondrial DNA depletion syndromes, informing diagnosis and potential gene therapy approaches.

Key Take-home: MPV17 deficiency is definitively associated with autosomal recessive hepatocerebral mitochondrial DNA depletion syndrome and warrants targeted genetic testing to guide management and emerging gene-based therapies.

References

• Acta gastro-enterologica Belgica | 2016 | Navajo Neurohepatopathy: A Case Report and Literature Review Emphasizing Clinicopathologic Diagnosis PMID:28209105
• American Journal of Human Genetics | 2006 | Navajo neurohepatopathy is caused by a mutation in the MPV17 gene. PMID:16909392
• Molecular Genetics and Metabolism Reports | 2016 | MPV17 mutations in patients with hepatocerebral mitochondrial DNA depletion syndrome. PMID:27536553
• Human Mutation | 2018 | MPV17-related mitochondrial DNA maintenance defect: New cases and review of clinical, biochemical, and molecular aspects. PMID:29282788
• Molecular Therapy | 2014 | AAV-mediated liver-specific MPV17 expression restores mtDNA levels and prevents diet-induced liver failure. PMID:24247928
• Journal of Inherited Metabolic Disease | 2010 | Functional splicing assay supporting that c.70 + 5G > A mutation in the MPV17 gene is disease causing. PMID:20614188
• PLoS One | 2018 | Pathological alleles of MPV17 modeled in the yeast Saccharomyces cerevisiae orthologous gene SYM1 reveal their inability to take part in a high molecular weight complex. PMID:30273399
• The Journal of Biological Chemistry | 2015 | The Human Mitochondrial DNA Depletion Syndrome Gene MPV17 Encodes a Non-selective Channel That Modulates Membrane Potential. PMID:25861990
• Biology Open | 2015 | Canine MPV17 truncation without clinical manifestations. PMID:26353863

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