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Genetic mutations associated with mitochondrial myopathies

Genetic mutations associated with mitochondrial myopathies
Mitochondrial DNA mutations
Mutations in genes encoding respiratory chain proteins
Complex I (ND1 and ND4 cause a pure myopathy; ND5 causes a myopathy with MELAS/LHON/MERRF)
Complex III (Cytochrome b causes exercise intolerance/myalgia and rarely causes cardiomyopathy or multisystem disorder)
Complex IV (COX I, COXII, COXIII) causes exercise intolerance/myoglobinuria, but can also cause severe encephalomyopathy (all three), or MELAS (COX III only)
Mutations affecting protein synthesis
Mutations in transfer RNA most commonly cause MELAS or MERRF, and can also cause isolated myopathy, CPEO, or respiratory muscle weakness
Mutations in ribosomal RNA cause aminoglycoside-related deafness and cardiomyopathy but not skeletal myopathy
Large scale deletions/duplications most often cause sporadic CPEO/Kearns-Sayre syndrome and less commonly cause Pearson syndrome
Nuclear DNA mutations
Mutations in genes encoding respiratory chain proteins
Coenzyme Q10 deficiency can cause isolated myopathy or rapidly fatal encephalomyopathy of infancy with nephrotic syndrome
Complex I mutations (NDUFS1, 2, 3, 4, 6, 7, 8, NDUFV1, 2, NDUFA1, 2, 11) and complex II mutations (SDHA) can cause autosomal recessive Leigh syndrome
Complex II mutations (SDHB, SDHC, SDHD) can cause paraganglioma and sarcoma
Complex III mutations (UQCRB, UQCRQ) can cause lactic acidosis, hypoglycemia, and psychomotor retardation
Complex IV mutations (COX6B1, COX4I2) can cause infantile encephalopathy, anemia, and pancreatic dysfunction
Mutations in nuclear genes encoding proteins required for assembly or function of the respiratory chain proteins
Complex I mutations (NDUFAF1, 2, 3, 4, C20orf7, C8orf38, C6orf66) can cause variable disorders including Leigh syndrome and lethal infantile encephalopathy
Complex II mutations (SDHAF1, 2) can cause infantile leukoencephalopathy and paraganglioma
Complex III mutation (BCS1L) can cause GRACILE syndrome
Complex IV mutations (SURF 1, COX10, COX15, SCO1, SCO2) can cause Leigh syndrome and infantile cardioencephalomyopathy
Complex V mutations (ATPAF2, ATP5A1, ATP5E, TMEM70) can cause encephalopathy and 3-methylglutaconic aciduria
Nuclear gene defects affecting mitochondrial protein synthesis (causing multiple deletions or depletion of mitochondrial DNA)
Mutations in POLG, C10orf2 (encodes twinkle helicase), RRM2B, SLC25A4, POLG2, and DGUOK can cause autosomal dominant or recessive CPEO
Mutations in TK2, SUCLA2, SUCLA2, SUCLG1, RRM2B, and DGUOK can cause congenital encephalomyopathy and muscular dystrophy-like encephalomyopathy; TK2 mutations can also cause a slowly progressive generalized myopathy
Nuclear gene mutations causing defects of mitochondrial dynamics (fusion/fission)
Mutations in OPA1 can cause bilateral optic neuropathies and may be accompanied by sensorineural hearing loss; MFN2 mutations can cause an axonal form of Charcot-Marie-Tooth disease
Nuclear gene defects affecting mitochondrial proteins implicated in apoptosis
Mutations in AIF1 can cause multiple mtDNA deletions or mtDNA depletion and present with a mitochondrial encephalomyopathy; FASTKD2 may also present with a mitochondrial encephalomyopathy; APOPT1 mutations can cause a leukodystrophy
Nuclear gene mutations resulting in defects of the lipid milieu
TAZ mutations can cause Barth syndrome, an X-linked mitochondrial myopathy, cardiomyopathy, neutropenia, and short stature
SERAC1 mutations can cause MEGDEL
Nuclear gene defects affecting mitochondrial metabolic pathways other than the respiratory chain
Defects of mitochondrial substrate transport include CPT 1A deficiency, which results mainly in hepatic disease; CPT 2 deficiency most commonly produces a syndrome of recurrent rhabdomyolysis
Defects in mitochondrial substrate utilization include trifunctional protein deficiency, which causes neuropathy, myopathy, and recurrent rhabdomyolysis
Nuclear gene mutations causing defects in iron-sulfur cluster assembly/homeostasis
Defects in ISCU are associated with myopathy, exercise intolerance, and recurrent rhabdomyolysis
This table is not all-inclusive but rather lists some of the more common or more important genes associated with mitochondrial disease phenotypes in humans.
Barth syndrome: X-linked cardiomyopathy, mitochondrial myopathy and cyclic neutropenia; CPEO: chronic progressive external ophthalmoplegia; GRACILE syndrome: growth retardation, amino aciduria, cholestasis, iron overload, lactic acidosis and early death; Kearns-Sayre syndrome: CPEO with pigmentary retinopathy and onset before age 20; Leigh syndrome: subacute necrotizing encephalomyelopathy; LHON: Leber hereditary optic neuropathy; MEGDEL: 3-methylglutaconic aciduria with deafness, encephalopathy and Leigh-like syndrome; MELAS: mitochondrial encephalopathy with lactic acidosis and stroke-like episodes; MERRF: myoclonic epilepsy with ragged red fibers; Pearson syndrome: sideroblastic anemia and pancreatic dysfunction; RNA: ribonucleic acid; CPT: carnitine palmitoyltransferase; ISCU: iron-sulfur cluster assembly.
Data from:
  • DiMauro S, Hirano M. Mitochondrial encephalomyopathies: an update. Neuromuscul Disord 2005; 15:276.
  • DiMauro S. Mitochondrial myopathies. Curr Opin Rheumatol 2006; 18:636.
  • DiMauro S, Schon EA, Carelli V, Hirano M. The clinical maze of mitochondrial neurology. Nat Rev Neurol 2013; 9:429.
  • Lightowlers RN, Taylor RW, Turnbull DM. Mutations causing mitochondrial disease: What is new and what challenges remain? Science 2015; 349:1494.
  • Nardin RA, Johns DR. Mitochondrial dysfunction and neuromuscular disease. Muscle Nerve 2001; 24:170.
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