MPV17 – Mitochondrial DNA Depletion Syndrome

MPV17 encodes a small inner mitochondrial membrane protein essential for maintenance of mitochondrial DNA (mtDNA) copy number. Biallelic loss-of-function variants in MPV17 cause the hepatocerebral form of mitochondrial DNA depletion syndrome (MDS), an autosomal recessive disorder characterized by infantile‐onset liver failure, hypoglycemia, lactic acidosis and neurological regression (PMID:16582910). Clinical presentation typically occurs in the first year of life and progresses rapidly to multi-organ dysfunction.

Initial reports identified disease-segregating mutations in three unrelated families, establishing MPV17 as a novel MDS locus (PMID:16582910). Subsequent case series described three children homozygous for nonsense and missense mutations (p.Trp120Ter, p.Gly24Trp) with two-stage disease—rapid hepatic failure followed by neurologic involvement— confirming autosomal recessive inheritance (PMID:18695062). A multi-center study reported eight additional patients, expanding the spectrum to include splice-site (c.186+2T>C) and in-frame deletion (p.Lys88del) variants and confirming early fatal course without liver transplantation (PMID:20074988).

To date, 13 distinct MPV17 mutations have been documented in 21 patients from 12 families (PMID:20074988). Additional cohorts contributed 7 patients with novel truncating and missense alleles (PMID:24321534) and 4 ethnically diverse cases presenting with isolated infantile liver failure (PMID:17694548). Consistent autosomal recessive segregation in consanguineous and non-consanguineous families, with heterozygous carrier parents and affected siblings, supports robust genetic evidence.

Variant spectrum includes splice-site (c.70+5G>A), nonsense (c.360G>A (p.Trp120Ter)), frameshift and missense alleles (c.121C>T (p.Arg41Trp)). One commonly reported missense, c.121C>T (p.Arg41Trp), has been identified homozygously in a patient with acute flaccid paralysis and leukoencephalopathy, with parental heterozygous carrier status confirming recessive transmission (PMID:28673863).

Functional studies demonstrate that intronic c.70+5G>A abolishes correct splicing in minigene assays (PMID:20614188). Mpv17 knockout mice develop diet‐induced liver failure, and adeno-associated virus‐mediated hepatic MPV17 expression restores mtDNA levels and prevents liver pathology (PMID:24247928). Yeast Sym1 models of MPV17 missense alleles disrupt high-molecular-weight complexes and compromise oxidative phosphorylation and mtDNA stability (PMID:30273399).

No significant conflicting reports have been published. The consistency of genotype–phenotype correlations, population genetic data, and concordant functional assays support a Definitive gene–disease relationship.

Key Take-home: Biallelic MPV17 mutations cause autosomal recessive hepatocerebral MDS; early genetic testing enables prenatal diagnosis, family counseling, and informs liver transplant decisions.

References

• Nature genetics • 2006 • MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion PMID:16582910
• Archives of neurology • 2008 • Hepatocerebral form of mitochondrial DNA depletion syndrome: novel MPV17 mutations PMID:18695062
• Molecular genetics and metabolism • 2010 • MPV17-associated hepatocerebral mitochondrial DNA depletion syndrome: new patients and novel mutations PMID:20074988
• 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
• Molecular therapy • 2014 • AAV-mediated liver-specific MPV17 expression restores mtDNA levels and prevents diet-induced liver failure PMID:24247928
• Journal of pediatrics • 2014 • Clinical and molecular characteristics of mitochondrial DNA depletion syndrome associated with neonatal cholestasis and liver failure PMID:24321534

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