Abstract
Advances in sequencing and high-throughput techniques have provided an unprecedented opportunity to interrogate human diseases on a genome-wide scale. The list of disease-causing mutations is expanding rapidly, and mutations affecting mRNA translation are no exception. Translation (protein synthesis) is one of the most complex processes in the cell. The orchestrated action of ribosomes, tRNAs and numerous translation factors decodes the information contained in mRNA into a polypeptide chain. The intricate nature of this process renders it susceptible to deregulation at multiple levels. In this Review, we summarize current evidence of translation deregulation in human diseases other than cancer. We discuss translation-related diseases on the basis of the molecular aberration that underpins their pathogenesis (including tRNA dysfunction, ribosomopathies, deregulation of the integrated stress response and deregulation of the mTOR pathway) and describe how deregulation of translation generates the phenotypic variability observed in these disorders.
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References
Shoffner, J. M. et al. Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNA(Lys) mutation. Cell 61, 931–937 (1990).This study provides the first link between mutation of a translation factor and an inherited human disease.
Lucas, C. L., Chandra, A., Nejentsev, S., Condliffe, A. M. & Okkenhaug, K. PI3Kdelta and primary immunodeficiencies. Nat. Rev. Immunol. 16, 702–714 (2016).
Piccirillo, C. A., Bjur, E., Topisirovic, I., Sonenberg, N. & Larsson, O. Translational control of immune responses: from transcripts to translatomes. Nat. Immunol. 15, 503–511 (2014).
Morita, M. et al. mTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translational regulation. Cell Metab. 18, 698–711 (2013).
Buffington, S. A., Huang, W. & Costa-Mattioli, M. Translational control in synaptic plasticity and cognitive dysfunction. Annu. Rev. Neurosci. 37, 17–38 (2014).
Bhat, M. et al. Targeting the translation machinery in cancer. Nat. Rev. Drug Discov. 14, 261–278 (2015).
Truitt, M. L. & Ruggero, D. New frontiers in translational control of the cancer genome. Nat. Rev. Cancer 16, 288–304 (2016).
Walsh, D., Mathews, M. B. & Mohr, I. Tinkering with translation: protein synthesis in virus-infected cells. Cold Spring Harb. Persp. Biol. 5, a012351 (2013).
Robichaud, N., Sonenberg, N., Ruggero, D. & Schneider, R. J. Translational control in cancer. Cold Spring Harb. Perspect. Biol. https://doi.org/10.1101/cshperspect.a032896 (2018).
Stern-Ginossar, N., Thompson, S. R., Mathews, M. B. & Mohr, I. Translational control in virus-infected cells. Cold Spring Harb. Perspect. Biol. https://doi.org/10.1101/cshperspect.a033001 (2018).
Hershey, J. W. B., Sonenberg, N. & Mathews, M. B. Principles of translational control. Cold Spring Harb. Persp. Biol. https://doi.org/10.1101/cshperspect.a032607 (2018).
Yan, X., Hoek, T. A., Vale, R. D. & Tanenbaum, M. E. Dynamics of translation of single mRNA molecules in vivo. Cell 165, 976–989 (2016).
Wu, B., Eliscovich, C., Yoon, Y. J. & Singer, R. H. Translation dynamics of single mRNAs in live cells and neurons. Science 352, 1430–1435 (2016).
Morisaki, T. et al. Real-time quantification of single RNA translation dynamics in living cells. Science 352, 1425–1429 (2016).
Wek, R. C. Role of eIF2alpha kinases in translational control and adaptation to cellular stress. Cold Spring Harbor Persp. Biol. 10, a032870 (2018).
Proud, C. G. Phosphorylation and signal transduction pathways in translational control. Cold Spring Harbor Persp. Biol. https://doi.org/10.1101/cshperspect.a033050 (2018).
Smits, P., Smeitink, J. & van den Heuvel, L. Mitochondrial translation and beyond: processes implicated in combined oxidative phosphorylation deficiencies. J. Biomed. Biotechnol. 2010, 737385 (2010).
Suomalainen, A. & Battersby, B. J. Mitochondrial diseases: the contribution of organelle stress responses to pathology. Nat. Rev. Mol. Cell Biol. 19, 77–92 (2018).
Iadevaia, V., Huo, Y., Zhang, Z., Foster, L. J. & Proud, C. G. Roles of the mammalian target of rapamycin, mTOR, in controlling ribosome biogenesis and protein synthesis. Biochem. Soc. Trans. 40, 168–172 (2012).
Braun, D. A. et al. Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly. Nat. Genet. 49, 1529–1538 (2017).
Eyries, M. et al. EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension. Nat. Genet. 46, 65–69 (2014).This paper reports the link between recessive mutations in GCN2 and PVOD.
Stessman, H. A. et al. Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Nat. Genet. 49, 515–526 (2017).
Goodenbour, J. M. & Pan, T. Diversity of tRNA genes in eukaryotes. Nucleic Acids Res. 34, 6137–6146 (2006).
Budde, B. S. et al. tRNA splicing endonuclease mutations cause pontocerebellar hypoplasia. Nat. Genet. 40, 1113–1118 (2008).This study provides the link between mutation in TSEN complex subunits and pontocerebellar hypoplasia.
Breuss, M. W. et al. Autosomal-recessive mutations in the tRNA splicing endonuclease subunit TSEN15 cause pontocerebellar hypoplasia and progressive microcephaly. Am. J. Hum. Genet. 99, 785 (2016).
Karaca, E. et al. Human CLP1 mutations alter tRNA biogenesis, affecting both peripheral and central nervous system function. Cell 157, 636–650 (2014).
Schaffer, A. E. et al. CLP1 founder mutation links tRNA splicing and maturation to cerebellar development and neurodegeneration. Cell 157, 651–663 (2014).
Birky, C. W. Jr The inheritance of genes in mitochondria and chloroplasts: laws, mechanisms, and models. Annu. Rev. Genet. 35, 125–148 (2001).
Song, S. et al. DNA precursor asymmetries in mammalian tissue mitochondria and possible contribution to mutagenesis through reduced replication fidelity. Proc. Natl Acad. Sci. USA 102, 4990–4995 (2005).
Neiman, M. & Taylor, D. R. The causes of mutation accumulation in mitochondrial genomes. Proc. Biol. Sci. 276, 1201–1209 (2009).
Schon, E. A. Mitochondrial genetics and disease. Trends Biochem. Sci. 25, 555–560 (2000).
Abbott, J. A., Francklyn, C. S. & Robey-Bond, S. M. Transfer RNA and human disease. Front. Genet. 5, 158 (2014).
Lombes, A. et al. Myoclonic epilepsy and ragged-red fibers with cytochrome oxidase deficiency: neuropathology, biochemistry, and molecular genetics. Ann. Neurol. 26, 20–33 (1989).
Yasukawa, T., Suzuki, T., Ueda, T., Ohta, S. & Watanabe, K. Modification defect at anticodon wobble nucleotide of mitochondrial tRNAs(Leu)(UUR) with pathogenic mutations of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. J. Biol. Chem. 275, 4251–4257 (2000).
Kirino, Y. et al. Codon-specific translational defect caused by a wobble modification deficiency in mutant tRNA from a human mitochondrial disease. Proc. Natl Acad. Sci. USA 101, 15070–15075 (2004).
Ravn, K. et al. An mtDNA mutation, 14453G→A, in the NADH dehydrogenase subunit 6 associated with severe MELAS syndrome. Eur. J. Hum. Genet. 9, 805–809 (2001).
Ghezzi, D. et al. Mutations of the mitochondrial-tRNA modifier MTO1 cause hypertrophic cardiomyopathy and lactic acidosis. Am. J. Hum. Genet. 90, 1079–1087 (2012).
Kopajtich, R. et al. Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis, and encephalopathy. Am. J. Hum. Genet. 95, 708–720 (2014).
Zeharia, A. et al. Acute infantile liver failure due to mutations in the TRMU gene. Am. J. Hum. Genet. 85, 401–407 (2009).
Tucker, E. J. et al. Mutations in MTFMT underlie a human disorder of formylation causing impaired mitochondrial translation. Cell Metab. 14, 428–434 (2011).
Liu, Y. et al. Mitochondrial tRNA mutations in Chinese hypertensive individuals. Mitochondrion 28, 1–7 (2016).
Huang, B., Johansson, M. J. & Bystrom, A. S. An early step in wobble uridine tRNA modification requires the Elongator complex. RNA 11, 424–436 (2005).
Anderson, S. L. et al. Familial dysautonomia is caused by mutations of the IKAP gene. Am. J. Hum. Genet. 68, 753–758 (2001).
Slaugenhaupt, S. A. et al. Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. Am. J. Hum. Genet. 68, 598–605 (2001).References 43 and 44 report that a mutation in ELP1 is responsible for familial dysautonomia.
Gold-von Simson, G. et al. Kinetin in familial dysautonomia carriers: implications for a new therapeutic strategy targeting mRNA splicing. Pediatr. Res. 65, 341–346 (2009).
Simpson, C. L. et al. Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration. Hum. Mol. Genet. 18, 472–481 (2009).
Cohen, J. S. et al. ELP2 is a novel gene implicated in neurodevelopmental disabilities. Am. J. Med. Genet. Part A 167, 1391–1395 (2015).
Edvardson, S. et al. tRNA N6-adenosine threonylcarbamoyltransferase defect due to KAE1/TCS3 (OSGEP) mutation manifest by neurodegeneration and renal tubulopathy. Eur. J. Hum. Genet. 25, 545–551 (2017).References 20 and 48 report the link between mutations in four subunits of the KEOPS–EKC complex and Galloway–Mowat syndrome.
Akizu, N. et al. AMPD2 regulates GTP synthesis and is mutated in a potentially treatable neurodegenerative brainstem disorder. Cell 154, 505–517 (2013).
Weitzer, S. & Martinez, J. The human RNA kinase hClp1 is active on 3′ transfer RNA exons and short interfering RNAs. Nature 447, 222–226 (2007).
Paushkin, S. V., Patel, M., Furia, B. S., Peltz, S. W. & Trotta, C. R. Identification of a human endonuclease complex reveals a link between tRNA splicing and pre-mRNA 3′ end formation. Cell 117, 311–321 (2004).
Sissler, M., Gonzalez-Serrano, L. E. & Westhof, E. Recent advances in mitochondrial aminoacyl-tRNA synthetases and disease. Trends Mol. Med. 23, 693–708 (2017).
Yao, P. & Fox, P. L. Aminoacyl-tRNA synthetases in medicine and disease. EMBO Mol. Med. 5, 332–343 (2013).
Robinson, J. C., Kerjan, P. & Mirande, M. Macromolecular assemblage of aminoacyl-tRNA synthetases: quantitative analysis of protein-protein interactions and mechanism of complex assembly. J. Mol. Biol. 304, 983–994 (2000).
Zhang, X. et al. Mutations in QARS, encoding glutaminyl-tRNA synthetase, cause progressive microcephaly, cerebral-cerebellar atrophy, and intractable seizures. Am. J. Hum. Genet. 94, 547–558 (2014).
Storkebaum, E. Peripheral neuropathy via mutant tRNA synthetases: Inhibition of protein translation provides a possible explanation. BioEssays 38, 818–829 (2016).
Wallen, R. C. & Antonellis, A. To charge or not to charge: mechanistic insights into neuropathy-associated tRNA synthetase mutations. Curr. Opin. Genet. Dev. 23, 302–309 (2013).
Motzik, A., Nechushtan, H., Foo, S. Y. & Razin, E. Non-canonical roles of lysyl-tRNA synthetase in health and disease. Trends Mol. Med. 19, 726–731 (2013).
He, W. et al. CMT2D neuropathy is linked to the neomorphic binding activity of glycyl-tRNA synthetase. Nature 526, 710–714 (2015).
Blocquel, D. et al. Alternative stable conformation capable of protein misinteraction links tRNA synthetase to peripheral neuropathy. Nucleic Acids Res. 45, 8091–8104 (2017).
Wakasugi, K. et al. A human aminoacyl-tRNA synthetase as a regulator of angiogenesis. Proc. Natl Acad. Sci. USA 99, 173–177 (2002).
Zhou, J. J. et al. Secreted histidyl-tRNA synthetase splice variants elaborate major epitopes for autoantibodies in inflammatory myositis. J. Biol. Chem. 289, 19269–19275 (2014).
Wei, N. et al. Oxidative stress diverts tRNA synthetase to nucleus for protection against DNA damage. Mol. Cell 56, 323–332 (2014).
Narla, A. & Ebert, B. L. Ribosomopathies: human disorders of ribosome dysfunction. Blood 115, 3196–3205 (2010).
Yelick, P. C. & Trainor, P. A. Ribosomopathies: global process, tissue specific defects. Rare Dis. 3, e1025185 (2015).
Draptchinskaia, N. et al. The gene encoding ribosomal protein S19 is mutated in Diamond–Blackfan anaemia. Nat. Genet. 21, 169–175 (1999).This study reports for the first time the involvement of a ribosomal gene ( RPS19 ) in human disease.
Gazda, H. T. et al. Frameshift mutation in p53 regulator RPL26 is associated with multiple physical abnormalities and a specific pre-ribosomal RNA processing defect in Diamond–Blackfan anemia. Hum. Mutat. 33, 1037–1044 (2012).
Mills, E. W. & Green, R. Ribosomopathies: there’s strength in numbers. Science 358 (2017). This review article provides a comprehensive discussion of current models explaining the tissue-specificity phenotype of ribosomopathies
Ludwig, L. S. et al. Altered translation of GATA1 in Diamond–Blackfan anemia. Nat. Med. 20, 748–753 (2014).
Sankaran, V. G. et al. Exome sequencing identifies GATA1 mutations resulting in Diamond–Blackfan anemia. J. Clin. Invest. 122, 2439–2443 (2012).References 69 and 70 uncover the importance of GATA1 expression in the pathogenesis of Diamond–Blackfan anaemia.
Ebert, B. L. et al. Identification of RPS14 as a 5q– syndrome gene by RNA interference screen. Nature 451, 335–339 (2008).
Ebert, B. L. Deletion 5q in myelodysplastic syndrome: a paradigm for the study of hemizygous deletions in cancer. Leukemia 23, 1252–1256 (2009).
Starczynowski, D. T. et al. Identification of miR-145 and miR-146a as mediators of the 5q– syndrome phenotype. Nat. Med. 16, 49–58 (2010).
Joslin, J. M. et al. Haploinsufficiency of EGR1, a candidate gene in the del(5q), leads to the development of myeloid disorders. Blood 110, 719–726 (2007).
Fonseca, B. D. et al. La-related protein 1 (LARP1) represses terminal oligopyrimidine (TOP) mRNA translation downstream of mTOR complex 1 (mTORC1). J. Biol. Chem. 290, 15996–16020 (2015).
Gentilella, A. et al. Autogenous control of 5′TOP mRNA stability by 40S ribosomes. Mol. Cell 67, 55–70 (2017).
Boultwood, J., Yip, B. H., Vuppusetty, C., Pellagatti, A. & Wainscoat, J. S. Activation of the mTOR pathway by the amino acid (l)-leucine in the 5q– syndrome and other ribosomopathies. Adv. Biol. Regul. 53, 8–17 (2013).
Pospisilova, D., Cmejlova, J., Hak, J., Adam, T. & Cmejla, R. Successful treatment of a Diamond–Blackfan anemia patient with amino acid leucine. Haematologica 92, e66–e67 (2007).
Knott, S. R. V. et al. Asparagine bioavailability governs metastasis in a model of breast cancer. Nature 554, 378–381 (2018).
Myers, K. C. et al. Variable clinical presentation of Shwachman–Diamond syndrome: update from the North American Shwachman–Diamond Syndrome Registry. J. Pediatr. 164, 866–870 (2014).
Warren, A. J. Molecular basis of the human ribosomopathy Shwachman–Diamond syndrome. Adv. Biol. Regul. 67, 109–127 (2018).
Ridanpaa, M. et al. Mutations in the RNA component of RNase MRP cause a pleiotropic human disease, cartilage-hair hypoplasia. Cell 104, 195–203 (2001).
Hermanns, P. et al. Consequences of mutations in the non-coding RMRP RNA in cartilage-hair hypoplasia. Hum. Mol. Genet. 14, 3723–3740 (2005).
McKusick, V. A., Eldridge, R., Hostetler, J. A., Ruangwit, U. & Egeland, J. A. Dwarfism in the Amish. Ii. Cartilage-hair hypoplasia. Bull. Johns Hopkins Hosp. 116, 285–326 (1965).
Goldfarb, K. C. & Cech, T. R. Targeted CRISPR disruption reveals a role for RNase MRP RNA in human preribosomal RNA processing. Genes Dev. 31, 59–71 (2017).
Armistead, J. et al. Mutation of a gene essential for ribosome biogenesis, EMG1, causes Bowen–Conradi syndrome. Am. J. Hum. Genet. 84, 728–739 (2009).
Marneros, A. G. BMS1 is mutated in aplasia cutis congenita. PLOS Genet. 9, e1003573 (2013).
Valdez, B. C., Henning, D., So, R. B., Dixon, J. & Dixon, M. J. The Treacher Collins syndrome (TCOF1) gene product is involved in ribosomal DNA gene transcription by interacting with upstream binding factor. Proc. Natl Acad. Sci. USA 101, 10709–10714 (2004).
Dauwerse, J. G. et al. Mutations in genes encoding subunits of RNA polymerases I and III cause Treacher Collins syndrome. Nat. Genet. 43, 20–22 (2011).This study demonstrates that Treacher Collins syndrome results from dysfunction of different components of Pol I and Pol III.
The Treacher Collins Syndrome Collaborative Group. Positional cloning of a gene involved in the pathogenesis of Treacher Collins syndrome. Nat. Genet. 12, 130–136 (1996).
Ruggero, D. et al. Dyskeratosis congenita and cancer in mice deficient in ribosomal RNA modification. Science 299, 259–262 (2003).
McCann, K. L. & Baserga, S. J. Genetics. Mysterious ribosomopathies. Science 341, 849–850 (2013).
Ruggero, D. & Shimamura, A. Marrow failure: a window into ribosome biology. Blood 124, 2784–2792 (2014).
Dai, M. S. & Lu, H. Inhibition of MDM2-mediated p53 ubiquitination and degradation by ribosomal protein L5. J. Biol. Chem. 279, 44475–44482 (2004).
Dai, M. S. et al. Ribosomal protein L23 activates p53 by inhibiting MDM2 function in response to ribosomal perturbation but not to translation inhibition. Mol. Cell. Biol. 24, 7654–7668 (2004).
Fang, S., Jensen, J. P., Ludwig, R. L., Vousden, K. H. & Weissman, A. M. Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53. J. Biol. Chem. 275, 8945–8951 (2000).
Lindstrom, M. S., Deisenroth, C. & Zhang, Y. Putting a finger on growth surveillance: insight into MDM2 zinc finger-ribosomal protein interactions. Cell Cycle 6, 434–437 (2007).
Rubbi, C. P. & Milner, J. Disruption of the nucleolus mediates stabilization of p53 in response to DNA damage and other stresses. EMBO J. 22, 6068–6077 (2003).
Lohrum, M. A., Ludwig, R. L., Kubbutat, M. H., Hanlon, M. & Vousden, K. H. Regulation of HDM2 activity by the ribosomal protein L11. Cancer Cell 3, 577–587 (2003).
McGowan, K. A. et al. Ribosomal mutations cause p53-mediated dark skin and pleiotropic effects. Nat. Genet. 40, 963–970 (2008).
Barlow, J. L. et al. A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q– syndrome. Nat. Med. 16, 59–66 (2010).
Donati, G., Montanaro, L. & Derenzini, M. Ribosome biogenesis and control of cell proliferation: p53 is not alone. Cancer Res. 72, 1602–1607 (2012).
Jones, N. C. et al. Prevention of the neurocristopathy Treacher Collins syndrome through inhibition of p53 function. Nat. Med. 14, 125–133 (2008).
Simsek, D. et al. The mammalian ribo-interactome reveals ribosome functional diversity and heterogeneity. Cell 169, 1051–1065 (2017).
Parks, M. M. et al. Variant ribosomal RNA alleles are conserved and exhibit tissue-specific expression. Sci. Adv. 4, eaao0665 (2018).
Khajuria, R. K. et al. Ribosome levels selectively regulate translation and lineage commitment in human hematopoiesis. Cell 173, 90–103 (2018).
Wang, W. et al. Ribosomal proteins and human diseases: pathogenesis, molecular mechanisms, and therapeutic implications. Med. Res. Rev. 35, 225–285 (2015).
Ron, D. & Walter, P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell Biol. 8, 519–529 (2007).
Ma, Y. & Hendershot, L. M. The unfolding tale of the unfolded protein response. Cell 107, 827–830 (2001).
Lin, J. H., Walter, P. & Yen, T. S. Endoplasmic reticulum stress in disease pathogenesis. Annu. Rev. Pathol. 3, 399–425 (2008).
Wolcott, C. D. & Rallison, M. L. Infancy-onset diabetes mellitus and multiple epiphyseal dysplasia. J. Pediatr. 80, 292–297 (1972).
Julier, C. & Nicolino, M. Wolcott–Rallison syndrome. Orphanet J. Rare Dis. 5, 29 (2010).
Harding, H. P. et al. Diabetes mellitus and exocrine pancreatic dysfunction in perk−/− mice reveals a role for translational control in secretory cell survival. Mol. Cell 7, 1153–1163 (2001).
Zhang, P. et al. The PERK eukaryotic initiation factor 2 alpha kinase is required for the development of the skeletal system, postnatal growth, and the function and viability of the pancreas. Mol. Cell. Biol. 22, 3864–3874 (2002).
Zhang, W. et al. PERK EIF2AK3 control of pancreatic beta cell differentiation and proliferation is required for postnatal glucose homeostasis. Cell Metab. 4, 491–497 (2006).
Feng, D., Wei, J., Gupta, S., McGrath, B. C. & Cavener, D. R. Acute ablation of PERK results in ER dysfunctions followed by reduced insulin secretion and cell proliferation. BMC Cell Biol. 10, 61 (2009).
Yu, Q. et al. Type I interferons mediate pancreatic toxicities of PERK inhibition. Proc. Natl Acad. Sci. USA 112, 15420–15425 (2015).
Senderek, J. et al. Mutations in SIL1 cause Marinesco–Sjogren syndrome, a cerebellar ataxia with cataract and myopathy. Nat. Genet. 37, 1312–1314 (2005).
Synofzik, M. et al. Absence of BiP co-chaperone DNAJC3 causes diabetes mellitus and multisystemic neurodegeneration. Am. J. Hum. Genet. 95, 689–697 (2014).
Poulton, C. J. et al. Microcephaly with simplified gyration, epilepsy, and infantile diabetes linked to inappropriate apoptosis of neural progenitors. Am. J. Hum. Genet. 89, 265–276 (2011).
Yang, H. et al. Functional characterization of 58-kilodalton inhibitor of protein kinase in protecting against diabetic retinopathy via the endoplasmic reticulum stress pathway. Mol. Vis. 17, 78–84 (2011).
Yan, W. et al. Control of PERK eIF2alpha kinase activity by the endoplasmic reticulum stress-induced molecular chaperone P58IPK. Proc. Natl Acad. Sci. USA 99, 15920–15925 (2002).
Roobol, A. et al. p58IPK is an inhibitor of the eIF2alpha kinase GCN2 and its localization and expression underpin protein synthesis and ER processing capacity. Biochem. J. 465, 213–225 (2015).
Ladiges, W. C. et al. Pancreatic beta-cell failure and diabetes in mice with a deletion mutation of the endoplasmic reticulum molecular chaperone gene P58IPK. Diabetes 54, 1074–1081 (2005).
Abdulkarim, B. et al. A missense mutation in PPP1R15B causes a syndrome including diabetes, short stature, and microcephaly. Diabetes 64, 3951–3962 (2015).
Kernohan, K. D. et al. Homozygous mutation in the eukaryotic translation initiation factor 2alpha phosphatase gene, PPP1R15B, is associated with severe microcephaly, short stature and intellectual disability. Hum. Mol. Genet. 24, 6293–6300 (2015).
Borck, G. et al. eIF2gamma mutation that disrupts eIF2 complex integrity links intellectual disability to impaired translation initiation. Mol. Cell 48, 641–646 (2012).
Skopkova, M. et al. EIF2S3 mutations associated with severe X-linked intellectual disability syndrome MEHMO. Hum. Mutat. 38, 409–425 (2017).
Moortgat, S. et al. Two novel EIF2S3 mutations associated with syndromic intellectual disability with severe microcephaly, growth retardation, and epilepsy. Am. J. Med. Genet. A 170, 2927–2933 (2016).
Bugiani, M., Boor, I., Powers, J. M., Scheper, G. C. & van der Knaap, M. S. Leukoencephalopathy with vanishing white matter: a review. J. Neuropathol. Exp. Neurol. 69, 987–996 (2010).
van der Knaap, M. S., Pronk, J. C. & Scheper, G. C. Vanishing white matter disease. Lancet Neurol. 5, 413–423 (2006).
Pierce, S. B. et al. Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome. Proc. Natl Acad. Sci. USA 108, 6543–6548 (2011).
Pierce, S. B. et al. Mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase, lead to premature ovarian failure and hearing loss in Perrault syndrome. Am. J. Hum. Genet. 92, 614–620 (2013).
Dallabona, C. et al. Novel (ovario) leukodystrophy related to AARS2 mutations. Neurology 82, 2063–2071 (2014).
Dooves, S. et al. Astrocytes are central in the pathomechanisms of vanishing white matter. J. Clin. Invest. 126, 1512–1524 (2016).
Dietrich, J. et al. EIF2B5 mutations compromise GFAP+ astrocyte generation in vanishing white matter leukodystrophy. Nat. Med. 11, 277–283 (2005).
Raini, G. et al. Mutant eIF2B leads to impaired mitochondrial oxidative phosphorylation in vanishing white matter disease. J. Neurochem. 141, 694–707 (2017).
Elroy-Stein, O. Mitochondrial malfunction in vanishing white matter disease: a disease of the cytosolic translation machinery. Neural Regen. Res. 12, 1610–1612 (2017).
Pietra, G. G. et al. Pathologic assessment of vasculopathies in pulmonary hypertension. J. Am. Coll. Cardiol. 43, 25S–32S (2004).
Montani, D. et al. Pulmonary veno-occlusive disease. Eur. Respiratory J. 47, 1518–1534 (2016).
Montani, D. et al. Clinical phenotypes and outcomes of heritable and sporadic pulmonary veno-occlusive disease: a population-based study. Lancet Respir. Med. 5, 125–134 (2017).
Hu, H. et al. Genetics of intellectual disability in consanguineous families. Mol. Psychiatry. https://doi.org/10.1038/s41380-017-0012-2 (2018).
Barbet, N. C. et al. TOR controls translation initiation and early G1 progression in yeast. Mol. Biol. Cell 7, 25–42 (1996).
Beretta, L., Gingras, A. C., Svitkin, Y. V., Hall, M. N. & Sonenberg, N. Rapamycin blocks the phosphorylation of 4E-BP1 and inhibits cap-dependent initiation of translation. EMBO J. 15, 658–664 (1996).References 143 and 144 show that TOR and mTOR control mRNA translation initiation.
Hsieh, A. C. et al. Genetic dissection of the oncogenic mTOR pathway reveals druggable addiction to translational control via 4EBP-eIF4E. Cancer Cell 17, 249–261 (2010).
Signer, R. A., Magee, J. A., Salic, A. & Morrison, S. J. Haematopoietic stem cells require a highly regulated protein synthesis rate. Nature 509, 49–54 (2014).
Shackelford, D. B. & Shaw, R. J. The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat. Rev. Cancer 9, 563–575 (2009).
Simanshu, D. K., Nissley, D. V. & McCormick, F. RAS proteins and their regulators in human disease. Cell 170, 17–33 (2017).
Fruman, D. A. et al. The PI3K pathway in human disease. Cell 170, 605–635 (2017).
Saxton, R. A. & Sabatini, D. M. mTOR signaling in growth, metabolism, and disease. Cell 168, 960–976 (2017).
Sato, A. mTOR, a potential target to treat autism spectrum disorder. CNS Neurol. Disord. Drug Targets 15, 533–543 (2016).
Wong, M. A critical review of mTOR inhibitors and epilepsy: from basic science to clinical trials. Expert Rev. Neurother. 13, 657–669 (2013).
Lipton, J. O. & Sahin, M. The neurology of mTOR. Neuron 84, 275–291 (2014).
Lee, J. H. et al. De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly. Nat. Genet. 44, 941–945 (2012).
Butler, M. G. et al. Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. J. Med. Genet. 42, 318–321 (2005).
Riviere, J. B. et al. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat. Genet. 44, 934–940 (2012).
Lim, J. S. et al. Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy. Nat. Med. 21, 395–400 (2015).
Crino, P. B. mTOR signaling in epilepsy: insights from malformations of cortical development. Cold Spring Harb. Persp. Med. 5, a022442 (2015).
Deau, M. C. et al. A human immunodeficiency caused by mutations in the PIK3R1 gene. J. Clin. Invest. 124, 3923–3928 (2014).
Angulo, I. et al. Phosphoinositide 3-kinase delta gene mutation predisposes to respiratory infection and airway damage. Science 342, 866–871 (2013).
Lucas, C. L. et al. Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110delta result in T cell senescence and human immunodeficiency. Nat. Immunol. 15, 88–97 (2014).
Tsujita, Y. et al. Phosphatase and tensin homolog (PTEN) mutation can cause activated phosphatidylinositol 3-kinase delta syndrome-like immunodeficiency. J. Allergy Clin. Immunol. 138, 1672–1680 (2016).
Li, J. et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275, 1943–1947 (1997).
Nelen, M. R. et al. Localization of the gene for Cowden disease to chromosome 10q22-23. Nat. Genet. 13, 114–116 (1996).
Liaw, D. et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat. Genet. 16, 64–67 (1997).
Caux, F. et al. Segmental overgrowth, lipomatosis, arteriovenous malformation and epidermal nevus (SOLAMEN) syndrome is related to mosaic PTEN nullizygosity. Eur. J. Hum. Genet. 15, 767–773 (2007).
Eng, C. PTEN: one gene, many syndromes. Hum. Mut. 22, 183–198 (2003).
Leslie, N. R. & Longy, M. Inherited PTEN mutations and the prediction of phenotype. Semin. Cell Dev. Biol. 52, 30–38 (2016).
Lindhurst, M. J. et al. A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N. Engl. J. Med. 365, 611–619 (2011).
Hussain, K. et al. An activating mutation of AKT2 and human hypoglycemia. Science 334, 474 (2011).
Nellist, M. et al. Germline activating AKT3 mutation associated with megalencephaly, polymicrogyria, epilepsy and hypoglycemia. Mol. Genet. Metab. 114, 467–473 (2015).
Boland, E. et al. Mapping of deletion and translocation breakpoints in 1q44 implicates the serine/threonine kinase AKT3 in postnatal microcephaly and agenesis of the corpus callosum. Am. J. Hum. Genet. 81, 292–303 (2007).
George, S. et al. A family with severe insulin resistance and diabetes due to a mutation in AKT2. Science 304, 1325–1328 (2004).
Kandt, R. S. et al. Linkage of an important gene locus for tuberous sclerosis to a chromosome 16 marker for polycystic kidney disease. Nat. Genet. 2, 37–41 (1992).
van Slegtenhorst, M. et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 277, 805–808 (1997).
Crino, P. B., Nathanson, K. L. & Henske, E. P. The tuberous sclerosis complex. N. Engl. J. Med. 355, 1345–1356 (2006).
Alfaiz, A. A. et al. TBC1D7 mutations are associated with intellectual disability, macrocrania, patellar dislocation, and celiac disease. Hum. Mutat. 35, 447–451 (2014).
Mirzaa, G. M. et al. Association of mTOR mutations with developmental brain disorders, including megalencephaly, focal cortical dysplasia, and pigmentary mosaicism. JAMA Neurol. 73, 836–845 (2016).
Bohn, G. et al. A novel human primary immunodeficiency syndrome caused by deficiency of the endosomal adaptor protein p14. Nat. Med. 13, 38–45 (2007).
Sancak, Y. et al. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141, 290–303 (2010).
Kim, E., Goraksha-Hicks, P., Li, L., Neufeld, T. P. & Guan, K. L. Regulation of TORC1 by Rag GTPases in nutrient response. Nat. Cell Biol. 10, 935–945 (2008).
Sancak, Y. et al. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320, 1496–1501 (2008).
Wolfson, R. L. & Sabatini, D. M. The dawn of the age of amino acid sensors for the mTORC1 pathway. Cell Metab. 26, 301–309 (2017).
Dibbens, L. M. et al. Mutations in DEPDC5 cause familial focal epilepsy with variable foci. Nat. Genet. 45, 546–551 (2013).
Ricos, M. G. et al. Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy. Ann. Neurol. 79, 120–131 (2016).
Basel-Vanagaite, L. et al. Biallelic SZT2 mutations cause infantile encephalopathy with epilepsy and dysmorphic corpus callosum. Am. J. Hum. Genet. 93, 524–529 (2013).
Baple, E. L. et al. Mutations in KPTN cause macrocephaly, neurodevelopmental delay, and seizures. Am. J. Hum. Genet. 94, 87–94 (2014).
Mc Cormack, A. et al. 12q14 microdeletions: additional case series with confirmation of a macrocephaly region. Case Rep. Genet. 2015, 192071 (2015).
Morita, M. et al. A novel 4EHP-GIGYF2 translational repressor complex is essential for mammalian development. Mol. Cell. Biol. 32, 3585–3593 (2012).
Chartier-Harlin, M. C. et al. Translation initiator EIF4G1 mutations in familial Parkinson disease. Am. J. Hum. Genet. 89, 398–406 (2011).
Dhungel, N. et al. Parkinson’s disease genes VPS35 and EIF4G1 interact genetically and converge on alpha-synuclein. Neuron 85, 76–87 (2015).
Nichols, N. et al. EIF4G1 mutations do not cause Parkinson’s disease. Neurobiol. Aging 36, 2444 (2015).
Cestra, G., Rossi, S., Di Salvio, M. & Cozzolino, M. Control of mRNA translation in ALS proteinopathy. Front. Mol. Neurosci. 10, 85 (2017).
Hagerman, R. J. et al. Fragile X syndrome. Nat. Rev. Dis. Primers 3, 17065 (2017).
Zu, T., Pattamatta, A. & Ranum, L. P. W. RAN translation in neurological diseases. Cold Spring Harb. Perspect. Biol. https://doi.org/10.1101/cshperspect.a033019 (2018).
Masvidal, L., Hulea, L., Furic, L., Topisirovic, I. & Larsson, O. mTOR-sensitive translation: cleared fog reveals more trees. RNA Biol. 14, 1299–1305 (2017).
Hay, N. & Sonenberg, N. Upstream and downstream of mTOR. Genes Dev. 18, 1926–1945 (2004).
Meyuhas, O. Synthesis of the translational apparatus is regulated at the translational level. Eur. J. Biochem. 267, 6321–6330 (2000).
Mergenthaler, P., Lindauer, U., Dienel, G. A. & Meisel, A. Sugar for the brain: the role of glucose in physiological and pathological brain function. Trends Neurosci. 36, 587–597 (2013).
Napoli, E., Duenas, N. & Giulivi, C. Potential therapeutic use of the ketogenic diet in autism spectrum disorders. Front. Pediatr. 2, 69 (2014).
Dy, A. B. C. et al. Metformin as targeted treatment in fragile X syndrome. Clin. Genet. 93, 216–222 (2018).
Lee, G. et al. Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. Nature 461, 402–406 (2009).
Wilhelm, M. et al. Mass-spectrometry-based draft of the human proteome. Nature 509, 582–587 (2014).
Acknowledgements
The authors thank E. Shoubridge, D. Ruggero, A. Shimamura, E. Storkebaum and S. J. Baserga for insightful discussions and input on this Review.
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S.T. and A.K. researched data for the article and made substantial contributions to the discussion of content; S.T., A.K., M.B.M. and N.S. wrote the article and reviewed and edited the manuscript before submission.
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Supplementary information
Glossary
- Aminoacyl-tRNA synthetases
-
(ARSs). Enzymes that catalyse the addition of an amino acid to the appropriate tRNA.
- 5-Taurinomethyluridine
-
(τm5U). A post-transcriptional modification of uridine at the wobble position of the mammalian mitochondrial tRNAs for Leu (UUR) and Trp.
- fMet-tRNAMet
-
A formylated form of the elongating Met-tRNAMet that is used as an initiator of tRNA in mammalian mitochondria.
- Threonylcarbamoyladenosine
-
(t6A). A universal tRNA modification at position 37 of tRNAs that decode ANN codons.
- Haploinsufficiency
-
A condition in diploid organisms where one gene copy is inactivated by mutation and the activity of the remaining copy is insufficient to maintain normal function.
- Clonal dominance
-
A condition in which a single clone of haematopoietic stem cells (HSCs) supersedes the other HSC clones.
- Overgrowth syndromes
-
A group of genetic diseases that are manifested as abnormal growth of the whole body or of body parts.
- Codon usage
-
The frequency with which a specific codon is used in the coding sequence of a mRNA or set of mRNAs.
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Tahmasebi, S., Khoutorsky, A., Mathews, M.B. et al. Translation deregulation in human disease. Nat Rev Mol Cell Biol 19, 791–807 (2018). https://doi.org/10.1038/s41580-018-0034-x
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DOI: https://doi.org/10.1038/s41580-018-0034-x
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