MPV17 – Mitochondrial Disease

MPV17 encodes an inner mitochondrial membrane protein essential for mitochondrial DNA (mtDNA) maintenance and is implicated in autosomal recessive mitochondrial disease (MONDO:0044970). A South African cohort identified a founder homozygous truncating variant in MPV17 in infantile neurohepatopathy, highlighting the gene’s role in hepatocerebral mitochondrial pathology.

Clinical Validity and Genetic Evidence

Autosomal recessive inheritance is established by homozygosity for the MPV17 truncating allele in multiple unrelated families. In a cohort of 42 nuclear DNA–positive mitochondrial disease patients, 38 probands were homozygous for c.106C>T (p.Gln36Ter) (PMID:33115810), one of the largest nuclear founder groups reported in the literature. No segregation data beyond proband genotypes are available.

Variant Spectrum and Founder Effect

The predominant variant in this cohort is c.106C>T (p.Gln36Ter), a nonsense mutation resulting in early protein truncation. Additional MPV17 variants across reports include missense, splice‐site, and frameshift changes, underscoring allelic heterogeneity. The high frequency of the c.106C>T allele suggests a strong founder effect in the South African population.

Functional and Experimental Evidence

A Mpv17–/– mouse model exhibits diet‐induced liver failure that is rescued by liver‐specific AAV‐mediated human MPV17 expression, restoring mtDNA copy number and oxidative phosphorylation proficiency (PMID:24247928). Electrophysiological studies demonstrate MPV17 forms a nonselective mitochondrial inner‐membrane channel modulating membrane potential and reactive oxygen species production (PMID:25861990).

Mechanism and Disease Modeling

MPV17 deficiency leads to mtDNA depletion, impaired deoxynucleotide homeostasis, and oxidative injury. Yeast ortholog studies confirm pathogenic missense alleles disrupt high molecular weight complex formation, compromising mtDNA stability. These findings converge on a loss‐of‐function mechanism causing hepatic and neurological manifestations.

Conclusion and Clinical Utility

Collectively, genetic and experimental data provide a Strong level of clinical validity for MPV17 in mitochondrial disease, with Moderate genetic evidence and Strong functional evidence. The recurrent founder c.106C>T (p.Gln36Ter) variant warrants targeted testing in populations of Sub‐Saharan African descent. MPV17 variant screening enables accurate diagnosis, genetic counseling, and the development of gene‐replacement therapies.

Key Take-Home: MPV17 truncating variants cause autosomal recessive mitochondrial disease via mtDNA depletion; founder screening and functional rescue affirm the gene’s clinical utility.

References

• — • 2020 • Genetic spectrum of mitochondrial disease in South Africa PMID:33115810
  
• Molecular Therapy • 2014 • AAV-mediated liver-specific MPV17 expression restores mtDNA levels and prevents diet-induced liver failure PMID:24247928
  
• Journal of Biological Chemistry • 2015 • The Human Mitochondrial DNA Depletion Syndrome Gene MPV17 Encodes a Non-selective Channel That Modulates Membrane Potential PMID:25861990

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