MGME1 – mitochondrial DNA depletion syndrome 11

Biallelic loss-of-function variants in MGME1 underlie autosomal recessive mitochondrial DNA depletion syndrome 11. To date, two unrelated probands have been reported with homozygous frameshift and nonsense variants. The first individual harbored c.359del (p.Pro120LeufsTer2) presenting early-onset cerebellar ataxia, progressive external ophthalmoplegia, emaciation, respiratory failure, microcephaly, cerebellar atrophy, delayed speech and fundus albipunctatus (PMID:28711739). A second case carried c.862C>T (p.Gln288Ter) with chronic progressive external ophthalmoplegia, frequent falls, pes planus, diffuse hypotonia, cerebellar atrophy, mild respiratory involvement, and learning difficulty (PMID:37429773). No additional segregation data are available, yielding a Limited evidence level based on two unrelated probands and consistent clinical features.

Structural and biochemical studies have elucidated MGME1 as a mitochondria-specific DNase essential for correct mtDNA maintenance. High-resolution HsMGME1–DNA complex structures combined with in vitro cleavage assays define a two-cation catalytic mechanism underpinning directional DNA processing, congruent with loss-of-function pathogenicity (PMID:30247721). There are no reported conflicting data. Overall, current genetic and experimental findings support a Limited clinical validity for MGME1 in mitochondrial DNA depletion syndrome 11. Further cases and segregation analyses are needed. Key take-home: MGME1 should be included in diagnostic panels for early-onset cerebellar ataxia and mitochondrial depletion syndromes when biallelic truncating variants are identified.

References

• European journal of medical genetics • 2017 • Homozygous c.359del variant in MGME1 is associated with early onset cerebellar ataxia. PMID:28711739
• Neuromuscular disorders : NMD • 2023 • A case of mitochondrial DNA depletion syndrome type 11 - expanding the genotype and phenotype. PMID:37429773
• Nucleic acids research • 2018 • Structural insights into DNA degradation by human mitochondrial nuclease MGME1. PMID:30247721

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