Table 2.
Diseases Caused by Mutations in Genes Involved in Cytoplasmic Translation Elongation
| Gene | Inheritance | Function | Disease/Clinical Presentation | References |
|---|---|---|---|---|
| Human Diseases | ||||
| EEF1A2 | De novo | Delivery of aminoacyl-tRNA (aa-tRNA) to ribosome during elongation | Progressive microcephaly with epilepsy, intellectual disability, autistic-like behavior | Inui et al., 2016; Lam et al., 2016; de Ligt et al., 2012; Lopes et al., 2016; Nakajima et al., 2015; Veeramah et al., 2013 |
| EEF2 | Dominant | Translocation of ribosome after peptide bond formation | Spinocerebellar ataxia 26 | Hekman et al., 2012 |
| AARS, GARS, HARS, MARS, YARS | Dominant | Cytoplasmic tRNA synthetases | Charcot-Marie-Tooth disease and other peripheral neuropathies | Reviewed in Meyer-Schuman and Antonellis, 2017 |
| AARS, DARS, HARS, KARS, QARS, RARS | Recessive | Cytoplasmic tRNA synthetases | Neurodegenerative disorders including peripheral neuropathy, progressive microcephaly, Usher’s syndrome, leukoencephalopathy | Kodera et al., 2015; McLaughlin et al., 2010; Meyer-Schuman and Antonellis, 2017; Nakayama et al., 2017; Puffenberger et al., 2012; Simons et al., 2015; Taft et al., 2013; Wolf et al., 2014; Zhang et al., 2014a |
| POLR1C, POLR3A, POLR3B | Recessive | RNA polymerase III subunits | Leukodystrophy with accompanying neurodegeneration | Azmanov et al., 2016; Bernard et al., 2011; Saitsu et al., 2011; Shimojima et al., 2014; Tétreault et al., 2011; Thiffault et al., 2015 |
| TRNT1 | Recessive | Nucleotidyltransferase responsible for CCA addition to 3’ end of tRNAs | Microcephaly, cortical atrophy, sensorineural deafness, photoreceptor loss | Chakraborty et al., 2014; DeLuca et al., 2016; Sasarman et al., 2015 |
| KAE1/OSGEP | Recessive | Biosynthesis of N6- threonylcarbamoyladenosine (t6A) modification on tRNAs | Microcephaly, cerebellar atrophy, renal defects | Edvardson et al., 2017 |
| CLP1, TSEN2, TSEN15, TSEN34, TSEN54 | Recessive | Splicing of intron-containing tRNAs | Pontocerebellar hypoplasia | Bierhals et al., 2013; Breuss et al., 2016; Karaca et al., 2014; Namavar et al., 2011; Schaffer et al., 2014 |
| ANG | Dominant | Stress-induced cleavage of tRNAs | Amyotrophic lateral sclerosis, Parkinson’s disease | Aparicio-Erriu and Prehn, 2012; Chen et al., 2014; Van Es et al., 2011; Fernández-Santiago et al., 2009; Greenway et al., 2006; Wu et al., 2007 |
| NSUN2 | Recessive | Cytosine-5 methylation (m5C) of tRNA | Microcephaly, cortical atrophy, intellectual disability | Abbasi-Moheb et al., 2012; Komara et al., 2015; Martinez et al., 2012) |
| GTPBP2 | Recessive | Ribosome recycling factor | Cerebellar atrophy, retinal degeneration, intellectual disability | Jaberi et al., 2015 |
| Mouse Models | ||||
| Eef1a2 | Recessive | Delivery of aa-tRNA to ribosome during elongation | wasted phenotype–motor neuron loss and muscle wasting | Chambers et al., 1998 |
| Aars | Recessive | Cytoplasmic alanyl tRNA synthetase | sticky phenotype–Purkinje cell degeneration, and unkempt appearance of fur | Lee et al., 2006 |
| Clp1 | Recessive | Splicing of intron-containing tRNAs | Clp1 kinase dead–motor neuron loss and microcephaly | Hanada et al., 2013 |
| Nsun2 | Recessive | Cytosine-5 methylation (m5C) of tRNA | Apoptosis of cortical, hippocampal, and striatal neurons; microcephaly | Blanco et al., 2014 |
| Gtpbp2, n-Tr20 | Recessive | Ribosome recycling factor, tRNAArgUCU | Ataxia; degeneration of cerebellum, cortex, hippocampus, and retina | Ishimura et al., 2014, Ishimura et al.,2016 |
| Ltn1 | Recessive | E3 ubiquitin ligase, degradation of aberrant nascent chains | lister phenotype–progressive neurodegeneration, locomotor abnormalities | Chu et al., 2009 |