Mitochondrial DNA depletion syndrome 11

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Description from OMIM

Mitochondrial DNA depletion syndrome-11 is an autosomal recessive mitochondrial disorder characterized by onset in childhood or adulthood of progressive external ophthalmoplegia (PEO), muscle weakness and atrophy, exercise intolerance, and respiratory insufficiency due to muscle weakness. More variable features include spinal deformity, emaciation, and cardiac abnormalities. Skeletal muscle biopsies show deletion and depletion of mitochondrial DNA (mtDNA) with variable defects in respiratory chain enzyme activities (summary by Kornblum et al., 2013). For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (603041).

Prevalence of clinical parameters (%)

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List of symptoms

Symptom/sign Organ system Percent affected Pubmed id Added on(yyyy-mm-dd) Edit/add reference
Ptosis nervous 100 % 23313956 2014-04-25
Ophthalmoplegia nervous 100 % 23313956 2014-04-25
Muscle weakness skeletal 100 % 23313956 2014-04-25
Myopathy skeletal 100 % 23313956 2014-04-25
Weight loss multi 100 % 23313956 2014-04-25
Exercise intolerance skeletal 100 % 23313956 2014-04-25
Muscle atrophy skeletal 100 % 23313956 2014-04-25
Kyphosis skeletal 83 % 23313956 2014-04-25
Respiratory failure respiratory 83 % 23313956 2014-04-25
Cerebellar atrophy nervous 75 % 23313956 2014-04-25
Mental retardation nervous 50 % 23313956 2014-04-25
Dysphagia nervous 50 % 23313956 2014-04-25
Increased blood CK circulatory 33 % 23313956 2014-04-25
Cerebral atrophy nervous 25 % 23313956 2014-04-25
Ataxia nervous 17 % 23313956 2014-04-25
Cardiac arrhythmia circulatory 17 % 23313956 2014-04-25
Psychiatric symptom nervous 17 % 23313956 2014-04-25

List of references:

Loss-of-function mutations in MGME1 impair mtDNA replication and cause multisystemic mitochondrial disease.
Cornelia Kornblum, Thomas J Nicholls, Tobias B Haack, Susanne Schöler, Viktoriya Peeva, Katharina Danhauser, Kerstin Hallmann, Gábor Zsurka, Joanna Rorbach, Arcangela Iuso, Thomas Wieland, Monica Sciacco, Dario Ronchi, Giacomo P Comi, Maurizio Moggio, Catarina M Quinzii, Salvatore DiMauro, Sarah E Calvo, Vamsi K Mootha, Thomas Klopstock, Tim M Strom, Thomas Meitinger, Michal Minczuk, Wolfram S Kunz, Holger Prokisch,

Known disease mechanisms in mitochondrial DNA (mtDNA) maintenance disorders alter either the mitochondrial replication machinery (POLG, POLG2 and C10orf2) or the biosynthesis pathways of deoxyribonucleoside 5'-triphosphates for mtDNA synthesis. However, in many of these disorders, the underlying genetic defect has yet to be discovered. Here, we identify homozygous nonsense and missense mutations in the orphan gene C20orf72 in three families with a mitochondrial syndrome characterized by external ophthalmoplegia, emaciation and respiratory failure. Muscle biopsies showed mtDNA depletion and multiple mtDNA deletions. C20orf72, hereafter MGME1 (mitochondrial genome maintenance exonuclease 1), encodes a mitochondrial RecB-type exonuclease belonging to the PD-(D/E)XK nuclease superfamily. We show that MGME1 cleaves single-stranded DNA and processes DNA flap substrates. Fibroblasts from affected individuals do not repopulate after chemically induced mtDNA depletion. They also accumulate intermediates of stalled replication and show increased levels of 7S DNA, as do MGME1-depleted cells. Thus, we show that MGME1-mediated mtDNA processing is essential for mitochondrial genome maintenance.

Nature genetics - Feb 2013