Table 1.
Nuclear genes involved in mtDNA instability
| Gene | Localization | MIM number | Disease | Inheritance | Phenotype | Age of onset |
|---|---|---|---|---|---|---|
| MNF2 | 1p36.22 | 609,260 | Charcot-Marie-Tooth disease, axonal, type 2A2A (CMT2A2A) | AD | CMT disease is a group of progressive neurologic disorders characterized by peripheral neuropathy and optic atrophy. Damage of the peripheral nerves results in loss of sensation (touch, pain, heat, and sound) and muscle weakness in the feet, legs, and hands | infancy |
| 1p36.23 | 617,087 | Charcot-Marie-Tooth disease, axonal, type 2A2B (CMT2A2B) | AR | infancy | ||
| 1p36.24 | 601,152 | Hereditary motor and sensory neuropathy VIA (CMT6A) | AD | childhood or adulthood | ||
| DGUOK | 2p13.1 | 251,880 | Mitochondrial DNA depletion syndrome 3 (hepatocerebral type) | AR | Genetic disorder characterized by multisystemic neurological abnormalities including muscle weakness, PEO, liver failure and lactic acidosis | infancy |
| 2p13.2 | 617,068 | Portal hypertension, noncirrhotic | AR | Disorder, relatively benign, is characterized by onset of high blood pressure in the hepatic portal system associated with hepatosplenomegaly. | childhood or adulthood | |
| 2p13.3 | 617,070 | Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4 | AR | Disorder characterized by adult onset of eye muscle weakness and proximal limb muscle weakness | adulthood | |
| MPV17 | 2p23.3 | 256,810 | Mitochondrial DNA depletion syndrome 6 (hepatocerebral type) | AR | Infantile onset disorder which affects liver and muscles. | infancy |
| RNASEH1 | 2p25.3 | 616,479 | Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2 | AR | Disorder characterized by adult onset of PEO, proximal limb muscle weakness and symptoms of spinocerebellar ataxia | adulthood |
| MFF | 2q36.3 | 617,086 | Encephalopathy due to defective mitochondrial and peroxisomal fission 2 | AR | Encephalopathy, including delayed psychomotor development, hypotonia and muscle weakness | childhood |
| OPA1 | 3q29 | 616,896 | Mitochondrial DNA depletion syndrome 14 (encephalocardiomyopathic type) | 0 | Encephalocardiomyopathy. | infancy |
| 3q30 | 210,000 | Behr syndrome | AR | Optic atrophy associated with neurological manifestations including myoclonic epilepsy, progressive spastic paraplegia, dysarthria, extra-pyramidal tract signs, ataxia, urinary incontinence, mental retardation, posterior column sensory loss or muscle contractures (predominant in the lower limbs) | early childhood | |
| 3q31 | 165,500 | Optic atrophy 1 | AD | Optic atrophy with onset of visual impairment in early childhood | early childhood | |
| 3q32 | 125,250 | Optic atrophy plus syndrome | AD | Optic atrophy with PEO and ataxia (and wide range of intermediate phenotypes) | childhood | |
| PRIMPOL | 4q35.1 | 615,420 | Myopia 22, autosomal dominant | AD | Eye abnormality where light focuses in front of the retina and causes nearsightedness. | early childhood |
| SLC25A4 | 4q35.1 | 617,184 | Mitochondrial DNA depletion syndrome 12A (cardiomyopathic type) AD | AD | Disorders characterized by cardiomyopathy or hypertrophic cardiomyopathy and muscle weakness | infancy |
| 4q35.2 | 615,418 | Mitochondrial DNA depletion syndrome 12B (cardiomyopathic type) AR | AR | childhood | ||
| 4q35.3 | 609,283 | Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2 | AD | Disorder characterized by weakness of the external eye muscles, limb muscle weakness and exercise intolerance | adulthood | |
| RRM2B | 8q22.3 | 612,075 | Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy) | AR | Mitochondrial neurogastrointestinal encephalopathy (MNGIE). Disease affects the digestive and nervous system | infancy |
| 8q22.4 | 612,075 | Mitochondrial DNA depletion syndrome 8B (MNGIE type) | ||||
| 8q22.5 | 613,077 | Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 5 | AD | Autosomal dominant progressive external ophthalmoplegia (adPEO) | adulthood | |
| TFAM | 10q21.1 | 617,156 | Mitochondrial DNA depletion syndrome 15 (hepatocerebral type) | AR | First symptoms occur at or soon after birth including hypoglycemia, hyperbilirubinemia, jaundice etc. | infancy |
| DNA2 | 10q21.3 | 615,807 | Seckel syndrome 8 | AR | Also known as bird-headed dwarfism, disorder characterized by growth and mental retardation | infancy |
| 10q21.4 | 615,156 | Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 6 | AD | Adult onset PEO with limb-girdle muscle weakness predominantly affecting the lower limb | childhood or adulthood | |
| TWNK | 10q24.31 | 271,245 | Mitochondrial DNA depletion syndrome 7 (hepatocerebral type) | AR | Neurodegenerative disease characterized by hypotonia, ataxia, ophthalmoplegia, hearing loss, seizures, and sensory axonal neuropathy | childhood or adulthood |
| 10q24.32 | 616,138 | Perrault syndrome 5 | AR | Neurological disorder with a characteristic feature of hearing loss caused by abnormalities in the inner ear | childhood | |
| 10q24.33 | 609,286 | Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3 | AD | Clinical features of this disease include adult onset of weakness of the external eye muscles and exercise intolerance | adulthood | |
| DNM1L | 12p11.21 | 614,388 | Encephalopahty, lethal, due to defective mitochondrial peroxisomal fission 1 | AD, AR | Encephalopathy with hypotonia and delayed psychomotor development | childhood |
| POLG | 15q26.1 | 203,700 | Mitochondrial DNA depletion syndrome 4A (Alpers type) | AR | Alpers syndrome is the clinical triad of psychomotor retardation, intractable epilepsy, and liver failure in infants and young children | infancy to young children |
| 15q26.2 | 613,662 | Mitochondrial DNA depletion syndrome 4B (MNGIE type) | AR | Progressive multisystem disorder clinically characterized by chronic gastrointestinal dysmotility, PEO, axonal sensory ataxic neuropathy and muscle weakness | childhood or adulthood | |
| 15q26.3 | 607,459 | Mitochondrial recessive ataxia syndrome (includes SANDO and SCAE) | AR | SANDO is characterized by sensory ataxic neuropathy, dysarthria, and ophthalmoparesis. | adulthood | |
| 15q26.4 | 157,640 | Progressive external ophthalmoplegia, autosomal dominant 1 | AD | PEO and muscle weakness, may include hearing loss, ataxia and parkinsonism | adulthood | |
| 15q26.5 | 258,450 | Progressive external ophthalmoplegia, autosomal recessive 1 | AR | adulthood | ||
| TK2 | 16q21 | 617,069 | Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3 | AR | Adult-onset progressive external ophthalmoplegia, sometimes with progressive proximal muscle weakness | adulthood |
| 16q22 | 609,560 | Mitochondrial DNA depletion syndrome 2 (myopathic type) | AR | Childhood onset of muscle weakness and a slowly progressive myopathy | infancy or childchood | |
| SPG7 | 16q24.3 | 607,259 | Spastic paraplegia 7 | AD, AR | Disease characterized by spasticity of limbs sometimes with additional neurologic features | adulthood |
| POLG2 | 17q23.3 | 610,131 | Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4 | AD | PEO and variably affected skeletal muscle, the nervous system, the liver, and the gastrointestinal tract | infancy to adulthood |
| MGME1 | 20p11.23 | 615,084 | Mitochondrial DNA depletion syndrome 11 | AR | Disorder characterized by PEO, muscle weakness and atrophy | childhood or adulthood |
| TYMP | 22q13.33 | 603,041 | Mitochondrial DNA depletion syndrome 1 (MNGIE type) | AR | Progressive multisystem disorder clinically characterized by PEO, gastrointestinal dysmotility, cachexia, diffuse leukoencephalopathy and peripheral neuropathy | adulthood |
AR – autosomal recessive, AD – autosomal dominant