Table 1.
ARS loci implicated in dominant and recessive human disease phenotypes
| Gene | Locus | Location of Protein Function | Mode of Inheritance | Disease Phenotype(s) | Unique variants | References |
|---|---|---|---|---|---|---|
| AARS | 16q22 | Cytoplasm | Autosomal Recessive | Early-onset epileptic encephalopathy with myelination defect | 2 | (2) |
| Microcephaly with hypomyelination, epileptic encephalopathy, and spasticity | 2 | (3) | ||||
| Autosomal Dominant | Charcot-Marie-Tooth disease type 2N | 3 | (4,5–7) | |||
| Distal hereditary motor neuropathy | 1 | (8) | ||||
| AARS2 | 6p21.1 | Mitochondria | Autosomal Recessive | Leukoencephalopathy with ovarian failure | 19 | (9–13) |
| Cardiomyopathy | 2 | (14) | ||||
| Multiple respiratory chain complex defects | 4 | (15) | ||||
| CARS2 | 13q34 | Mitochondria | Autosomal Recessive | Epileptic encephalopathy | 2 | (16) |
| Progressive myoclonic epilepsy | 2 | (17) | ||||
| DARS | 2q21.3 | Cytoplasm | Autosomal Recessive | Hypomyelination with brain stem and spinal cord involvement and leg spasticity | 2 | (18) |
| DARS2 | 1q25.1 | Mitochondria | Autosomal Recessive | Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation | 11 | (19–24) |
| EARS2 | 16p12.2 | Mitochondria | Autosomal Recessive | Leukoencephalopathy with thalamus and brainstem involvement and high lactate | 20 | (25–30) |
| Neonatal lactic acidosis, recurrent hypoglycemia, agenesis of corpus callosum | 2 | (31) | ||||
| Multiple respiratory chain complex defects | 3 | (15) | ||||
| FARS2 | 6p25.1 | Mitochondria | Autosomal Recessive | Hereditary spastic paraplegia | 1 | (32) |
| Alpers syndrome | 5 | (33,34) | ||||
| Early onset epilepsy | 5 | (35–37) | ||||
| Global delay, dysarthria and tremor | 2 | (38) | ||||
| GARS | 7p15 | Mitochondria and Cytoplasm | Autosomal Recessive | Systemic mitochondrial disease | 2 | (39) |
| Cardiomyopathy | 1 | (15) | ||||
| Autosomal Dominant | Charcot-Marie-Tooth disease type 2D | 4 | (40–43) | |||
| Distal hereditary motor neuropathy | 10 | (40,41,43–47) | ||||
| HARS | 5q31.3 | Cytoplasm | Autosomal Recessive | Usher syndrome | 1 | (48) |
| Autosomal Dominant | Charcot-Marie-Tooth disease type 2W | 5 | (49,50) | |||
| Distal hereditary motor neuropathy | 2 | (50) | ||||
| HARS2 | 5q31.3 | Mitochondria | Autosomal Recessive | Perrault syndrome | 2 | (51) |
| IARS | 9q22.31 | Cytoplasm | Autosomal Recessive | Prenatal growth retardation, neonatal cholestasis, muscular hypotonia, intellectual disability, infantile hepatopathy | 8 | (52,53) |
| IARS2 | 1q41 | Mitochondria | Autosomal Recessive | Cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, skeletal dysplasia syndrome; Leigh syndrome | 4 | (54,55) |
| KARS | 16q23.1 | Mitochondria and Cytoplasm | Autosomal Recessive | Nonsyndromic hearing loss (DFNB89) | 2 | (56) |
| Recessive intermediate Charcot-Marie-Tooth disease type B, dysmorphic features, developmental delay, self-abusive behavior, vestibular Schwannoma | 2 | (57) | ||||
| Visual impairment, microcephaly, developmental delay, seizures | 2 | (58) | ||||
| LARS | 5q32 | Cytoplasm | Autosomal Recessive | Infantile hepatopathy | 4 | (59,60) |
| LARS2 | 3p21.31 | Mitochondria | Autosomal Recessive | Perrault syndrome | 5 | (61,62) |
| Hydrops, lactic acidosis, sideroblastic anemia, multisystem failure | 2 | (63) | ||||
| MARS | 12q13.3 | Cytoplasm | Autosomal Recessive | Interstitial lung disease and liver disease | 7 | (64–66) |
| Autosomal Dominant | Charcot-Marie-Tooth disease type 2U | 2 | (67,68) | |||
| MARS2 | 2q33.1 | Cytoplasm | Autosomal Recessive | Developmental delay, sensorineural hearing loss | 2 | (69) |
| Autosomal recessive spastic ataxia with leukoencephalopathy | 2 | (70) | ||||
| NARS2 | 11q14.1 | Mitochondria | Autosomal Recessive | Alpers syndrome | 1 | (71) |
| Developmental delay, intellectual disability, epilepsy, myopathy | 6 | (72,73) | ||||
| Nonsyndromic deafness | 1 | (74) | ||||
| Leigh syndrome | 2 | (74) | ||||
| PARS2 | 3p21.31 | Mitochondria | Autosomal Recessive | Alpers syndrome | 2 | (71) |
| Infantile-onset developmental delay and epilepsy | 2 | (72) | ||||
| QARS | 3p21.31 | Cytoplasm and Mitochondria | Autosomal Recessive | Progressive microcephaly, cerebral-cerebellar atrophy, hypomyelination, intractable seizures, developmental delay | 6 | (75,76) |
| RARS | 5q34 | Cytoplasm | Autosomal Recessive | Hypomyelination | 5 | (77) |
| RARS2 | 6q16.1 | Mitochondria | Autosomal Recessive | Pontocerebellar hypoplasia | 14 | (78–84) |
| Early onset epileptic encephalopathy | 2 | (85) | ||||
| Lactic acidosis with or without neurological symptoms (microcephaly, seizures, developmental delay) | 1 | (86) | ||||
| Intellectual disability | 1 | (87) | ||||
| SARS | 1p13.3 | Cytoplasm | Autosomal Recessive | Intellectual disability, ataxia, microcephaly, speech impairment, aggressive behavior | 1 | (88) |
| SARS2 | 19q13.2 | Mitochondria | Autosomal Recessive | Hyperuricemia, pulmonary hypertension, renal failure, and alkalosis | 2 | (89,90) |
| TARS2 | 1q21.2 | Mitochondria | Autosomal Recessive | Axial hypotonia and severe psychomotor delay | 2 | (91) |
| VARS | 6p21.33 | Cytoplasm | Autosomal Recessive | Severe developmental delay, microcephaly, seizures | 2 | (92) |
| VARS2 | 6p21.33 | Mitochondria | Autosomal Recessive | Microcephaly and epilepsy | 1 | (91) |
| Encephalocardiomyopathy | 2 | (93) | ||||
| Multiple respiratory chain complex defects | 2 | (15) | ||||
| WARS | 14q32.2 | Cytoplasm | Autosomal Dominant | Distal hereditary motor neuropathy | 1 | (94) |
| WARS2 | 1p12 | Mitochondria | Autosomal Recessive | Intellectual disability, ataxia, microcephaly, speech impairment, aggressive behavior | 2 | (88) |
| YARS | 1p35.1 | Cytoplasm | Autosomal Recessive | Multisystem disease, developmental delay, failure to thrive | 2 | (95) |
| Autosomal Dominant | Dominant intermediate Charcot-Marie-Tooth disease type C | 5 | (96,97) | |||
| YARS2 | 12p11.21 | Mitochondria | Autosomal Recessive | Myopathy, lactic acidosis, sideroblastic anemia, cardiomyopathy, respiratory insufficiency | 7 | (98–103) |
| Multiple respiratory chain complex defects | 1 | (15) |