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A Loss‐of‐Function Variant in the Human Histidyl‐t RNA Synthetase ( HARS ) Gene is Neurotoxic In Vivo
dc.contributor.authorVester, Aiméeen_US
dc.contributor.authorVelez‐ruiz, Gisselleen_US
dc.contributor.authorMcLaughlin, Heather M.en_US
dc.contributor.authorNisc Comparative Sequencing Program, nisc Comparative Sequencing Programen_US
dc.contributor.authorLupski, James R.en_US
dc.contributor.authorTalbot, Kevinen_US
dc.contributor.authorVance, Jeffery M.en_US
dc.contributor.authorZüchner, Stephanen_US
dc.contributor.authorRoda, Ricardo H.en_US
dc.contributor.authorFischbeck, Kenneth H.en_US
dc.contributor.authorBiesecker, Leslie G.en_US
dc.contributor.authorNicholson, Garthen_US
dc.contributor.authorBeg, Asim A.en_US
dc.contributor.authorAntonellis, Anthonyen_US
dc.date.accessioned2013-01-03T19:45:33Z
dc.date.available2014-03-03T15:09:23Zen_US
dc.date.issued2013-01en_US
dc.identifier.citationVester, Aimée ; Velez‐ruiz, Gisselle ; McLaughlin, Heather M.Nisc Comparative Sequencing Program, nisc Comparative Sequencing Program ; Lupski, James R.; Talbot, Kevin; Vance, Jeffery M.; Züchner, Stephan ; Roda, Ricardo H.; Fischbeck, Kenneth H.; Biesecker, Leslie G.; Nicholson, Garth; Beg, Asim A.; Antonellis, Anthony; (2013). "A Lossâ ofâ Function Variant in the Human Histidylâ t RNA Synthetase ( HARS ) Gene is Neurotoxic In Vivo." Human Mutation 34(1): 191-199. <http://hdl.handle.net/2027.42/95567>en_US
dc.identifier.issn1059-7794en_US
dc.identifier.issn1098-1004en_US
dc.identifier.urihttps://hdl.handle.net/2027.42/95567
dc.description.abstractAminoacyl‐t RNA synthetases ( ARS s) are ubiquitously expressed enzymes responsible for ligating amino acids to cognate t RNA molecules. Mutations in four genes encoding an ARS have been implicated in inherited peripheral neuropathy with an axonal pathology, suggesting that all ARS genes are relevant candidates for disease in patients with related phenotypes. Here, we present results from a mutation screen of the histidyl‐t RNA synthetase ( HARS ) gene in a large cohort of patients with peripheral neuropathy. These efforts revealed a rare missense variant (c.410G>A/p.Arg137Gln) that resides at a highly conserved amino acid, represents a loss‐of‐function allele when evaluated in yeast complementation assays, and is toxic to neurons when expressed in a worm model. In addition to the patient with peripheral neuropathy, p.Arg137Gln HARS was detected in three individuals by genome‐wide exome sequencing. These findings suggest that HARS is the fifth ARS locus associated with axonal peripheral neuropathy. Implications for identifying ARS alleles in human populations and assessing them for a role in neurodegenerative phenotypes are discussed.en_US
dc.publisherWiley Periodicals, Inc.en_US
dc.publisherCold Spring Harbor Laboratory Pressen_US
dc.subject.otherHARSen_US
dc.subject.otherPeripheral Neuropathyen_US
dc.subject.otherAminoacyl‐T RNA Synthetasesen_US
dc.subject.otherNeurotoxicityen_US
dc.titleA Loss‐of‐Function Variant in the Human Histidyl‐t RNA Synthetase ( HARS ) Gene is Neurotoxic In Vivoen_US
dc.typeArticleen_US
dc.rights.robotsIndexNoFollowen_US
dc.subject.hlbsecondlevelGeneticsen_US
dc.subject.hlbtoplevelHealth Sciencesen_US
dc.subject.hlbtoplevelScienceen_US
dc.description.peerreviewedPeer Revieweden_US
dc.identifier.pmid22930593en_US
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/95567/1/humu22210.pdf
dc.identifier.doi10.1002/humu.22210en_US
dc.identifier.sourceHuman Mutationen_US
dc.identifier.citedreferenceMello C, Fire A. 1995. DNA transformation. Methods Cell Biol 48: 451 – 482.en_US
dc.identifier.citedreferenceBrenner S. 1974. The genetics of Caenorhabditis elegans. Genetics 77: 71 – 94.en_US
dc.identifier.citedreferenceCader MZ, Ren J, James PA, Bird LE, Talbot K, Stammers DK. 2007. Crystal structure of human wildtype and S581L‐mutant glycyl‐t RNA synthetase, an enzyme underlying distal spinal muscular atrophy. FEBS Lett 581: 2959 – 2964.en_US
dc.identifier.citedreferenceCheng J, Randall A, Baldi P. 2006. Prediction of protein stability changes for single‐site mutations using support vector machines. Proteins 62: 1125 – 1132.en_US
dc.identifier.citedreferenceDubourg O, Azzedine H, Yaou RB, Pouget J, Barois A, Meininger V, Bouteiller D, Ruberg M, Brice A, LeGuern E. 2006. The G526R glycyl‐t RNA synthetase gene mutation in distal hereditary motor neuropathy type V. Neurology 66: 1721 – 1726.en_US
dc.identifier.citedreferenceDyck PJ, Lambert EH. 1968. Lower motor and primary sensory neuron diseases with peroneal muscular atrophy. II. Neurologic, genetic, and electrophysiologic findings in various neuronal degenerations. Arch Neurol 18: 619 – 625.en_US
dc.identifier.citedreferenceEdvardson S, Shaag A, Kolesnikova O, Gomori JM, Tarassov I, Einbinder T, Saada A, Elpeleg O. 2007. Deleterious mutation in the mitochondrial arginyl‐transfer RNA synthetase gene is associated with pontocerebellar hypoplasia. Am J Hum Genet 81: 857 – 862.en_US
dc.identifier.citedreferenceFreist W, Verhey JF, Ruhlmann A, Gauss DH, Arnez JG. 1999. Histidyl‐t RNA synthetase. Biol Chem 380: 623 – 646.en_US
dc.identifier.citedreferenceGotz A, Tyynismaa H, Euro L, Ellonen P, Hyotylainen T, Ojala T, Hamalainen RH, Tommiska J, Raivio T, Oresic M, Karikoski R, Tammela O, et al., 2011. Exome sequencing identifies mitochondrial alanyl‐t RNA synthetase mutations in infantile mitochondrial cardiomyopathy. Am J Hum Genet 88: 635 – 642.en_US
dc.identifier.citedreferenceGreen ED, Birren B, Klapholz S, Myers RM, Riethman H, Roskams J. 1999. Genome analysis: a laboratory manual. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press.en_US
dc.identifier.citedreferenceHe W, Zhang HM, Chong YE, Guo M, Marshall AG, Yang XL. 2011. Dispersed disease‐causing neomorphic mutations on a single protein promote the same localized conformational opening. Proc Natl Acad Sci USA 108: 12307 – 12312.en_US
dc.identifier.citedreferenceHobert O. 2002. PCR fusion‐based approach to create reporter gene constructs for expression analysis in transgenic C. elegans. Biotechniques 32: 728 – 730.en_US
dc.identifier.citedreferenceJordanova A, Irobi J, Thomas FP, Van Dijck P, Meerschaert K, Dewil M, Dierick I, Jacobs A, De Vriendt E, Guergueltcheva V, Rao CV, Tournev I, et al., 2006. Disrupted function and axonal distribution of mutant tyrosyl‐t RNA synthetase in dominant intermediate C harcot– M arie– T ooth neuropathy. Nat Genet 38: 197 – 202.en_US
dc.identifier.citedreferenceLarkin MA, Blackshields G, Brown NP, Chenna R, McGettigan PA, McWilliam H, Valentin F, Wallace IM, Wilm A, Lopez R, Thompson JD, Gibson TJ, et al., 2007. C lustal W and C lustal X version 2.0. Bioinformatics 23: 2947 – 2948.en_US
dc.identifier.citedreferenceLatour P, Thauvin‐Robinet C, Baudelet‐Mery C, Soichot P, Cusin V, Faivre L, Locatelli MC, Mayencon M, Sarcey A, Broussolle E, Camu W, David A, et al., 2010. A major determinant for binding and aminoacylation of t RNA (Ala) in cytoplasmic A lanyl‐t RNA synthetase is mutated in dominant axonal C harcot– M arie– T ooth disease. Am J Hum Genet 86: 77 – 82.en_US
dc.identifier.citedreferenceLupski JR, Belmont JW, Boerwinkle E, Gibbs RA. 2011. Clan genomics and the complex architecture of human disease. Cell 147: 32 – 43.en_US
dc.identifier.citedreferenceMartyn CN, Hughes RA. 1997. Epidemiology of peripheral neuropathy. J Neurol Neurosurg Psychiatr 62: 310 – 318.en_US
dc.identifier.citedreferenceMcIntire SL, Reimer RJ, Schuske K, Edwards RH, Jorgensen EM. 1997. Identification and characterization of the vesicular GABA transporter. Nature 389: 870 – 876.en_US
dc.identifier.citedreferenceMcLaughlin HM, Sakaguchi R, Giblin W, Wilson TE, Biesecker L, Lupski JR, Talbot K, Vance JM, Zuchner S, Lee YC, Kennerson M, Hou YM, et al., 2012. A recurrent loss‐of‐function alanyl‐t RNA synthetase ( AARS ) mutation in patients with C harcot– M arie– T ooth disease type 2N ( CMT 2 N ). Hum Mutat 33: 244 – 253.en_US
dc.identifier.citedreferenceMcLaughlin HM, Sakaguchi R, Liu C, Igarashi T, Pehlivan D, Chu K, Iyer R, Cruz P, Cherukuri PF, Hansen NF, Mullikin JC, NISC Comparative Sequencing Program, et al., 2010. Compound heterozygosity for loss‐of‐function lysyl‐t RNA synthetase mutations in a patient with peripheral neuropathy. Am J Hum Genet 87: 560 – 566.en_US
dc.identifier.citedreferenceMello CC, Kramer JM, Stinchcomb D, Ambros V. 1991. Efficient gene transfer in C.elegans: extrachromosomal maintenance and integration of transforming sequences. EMBO J 10: 3959 – 3970.en_US
dc.identifier.citedreferenceMiller KG, Alfonso A, Nguyen M, Crowell JA, Johnson CD, Rand JB. 1996. A genetic selection for Caenorhabditis elegans synaptic transmission mutants. Proc Natl Acad Sci USA 93: 12593 – 12598.en_US
dc.identifier.citedreferenceMotley WW, Seburn KL, Nawaz MH, Miers KE, Cheng J, Antonellis A, Green ED, Talbot K, Yang XL, Fischbeck KH, Burgess RW. 2011. C harcot– M arie– T ooth‐linked mutant GARS is toxic to peripheral neurons independent of wild‐type GARS levels. PLoS Genet 7: e1002399.en_US
dc.identifier.citedreferenceNangle LA, Zhang W, Xie W, Yang XL, Schimmel P. 2007. C harcot– M arie– T ooth disease‐associated mutant t RNA synthetases linked to altered dimer interface and neurite distribution defect. Proc Natl Acad Sci USA 104: 11239 – 11244.en_US
dc.identifier.citedreferencePierce SB, Chisholm KM, Lynch ED, Lee MK, Walsh T, Opitz JM, Li W, Klevit RE, King MC. 2011. Mutations in mitochondrial histidyl t RNA synthetase HARS 2 cause ovarian dysgenesis and sensorineural hearing loss of P errault syndrome. Proc Natl Acad Sci USA 108: 6543 – 6548.en_US
dc.identifier.citedreferenceRiley LG, Cooper S, Hickey P, Rudinger‐Thirion J, McKenzie M, Compton A, Lim SC, Thorburn D, Ryan MT, Giege R, Bahlo M, Christodoulou J. 2010. Mutation of the mitochondrial tyrosyl‐t RNA synthetase gene, YARS 2, causes myopathy, lactic acidosis, and sideroblastic anemia— MLASA syndrome. Am J Hum Genet 87: 52 – 59.en_US
dc.identifier.citedreferenceScheper GC, van der Klok T, van Andel RJ, van Berkel CG, Sissler M, Smet J, Muravina TI, Serkov SV, Uziel G, Bugiani M, Schiffmann R, Krageloh‐Mann I, et al., 2007. Mitochondrial aspartyl‐t RNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation. Nat Genet 39: 534 – 539.en_US
dc.identifier.citedreferenceSchuske K, Beg AA, Jorgensen EM. 2004. The GABA nervous system in C. elegans. Trends Neurosci 27: 407 – 414.en_US
dc.identifier.citedreferenceSeburn KL, Nangle LA, Cox GA, Schimmel P, Burgess RW. 2006. An active dominant mutation of glycyl‐t RNA synthetase causes neuropathy in a C harcot– M arie– T ooth 2D mouse model. Neuron 51: 715 – 726.en_US
dc.identifier.citedreferenceSivakumar K, Kyriakides T, Puls I, Nicholson GA, Funalot B, Antonellis A, Sambuughin N, Christodoulou K, Beggs JL, Zamba‐Papanicolaou E, Ionasescu V, Dalakas MC, et al., 2005. Phenotypic spectrum of disorders associated with glycyl‐t RNA synthetase mutations. Brain 128: 2304 – 2314.en_US
dc.identifier.citedreferenceSteenweg ME, Ghezzi D, Haack T, Abbink TE, Martinelli D, van Berkel CG, Bley A, Diogo L, Grillo E, Te Water Naude J, Strom TM, Bertini E, et al., 2012. Leukoencephalopathy with thalamus and brainstem involvement and high lactate ‘ LTBL ’ caused by EARS 2 mutations. Brain 135: 1387 – 1394.en_US
dc.identifier.citedreferenceStorkebaum E, Leitao‐Goncalves R, Godenschwege T, Nangle L, Mejia M, Bosmans I, Ooms T, Jacobs A, Van Dijck P, Yang XL, Shimmel P, Norga K, et al., 2009. Dominant mutations in the tyrosyl‐t RNA synthetase gene recapitulate in D rosophila features of human C harcot– M arie– T ooth neuropathy. Proc Natl Acad Sci USA 106: 11782 – 11787.en_US
dc.identifier.citedreferenceXie W, Nangle LA, Zhang W, Schimmel P, Yang XL. 2007. Long‐range structural effects of a C harcot– M arie– T ooth disease‐causing mutation in human glycyl‐t RNA synthetase. Proc Natl Acad Sci USA 104: 9976 – 9981.en_US
dc.identifier.citedreferenceAntonellis A, Ellsworth RE, Sambuughin N, Puls I, Abel A, Lee‐Lin SQ, Jordanova A, Kremensky I, Christodoulou K, Middleton LT, Sivakumar K, Ionasescu V, et al., 2003. Glycyl t RNA synthetase mutations in C harcot– M arie– T ooth disease type 2D and distal spinal muscular atrophy type V. Am J Hum Genet 72: 1293 – 1299.en_US
dc.identifier.citedreferenceAntonellis A, Green ED. 2008. The role of aminoacyl‐t RNA synthetases in genetic diseases. Annu Rev Genomics Hum Genet 9: 87 – 107.en_US
dc.identifier.citedreferenceAntonellis A, Lee‐Lin SQ, Wasterlain A, Leo P, Quezado M, Goldfarb LG, Myung K, Burgess S, Fischbeck KH, Green ED. 2006. Functional analyses of glycyl‐t RNA synthetase mutations suggest a key role for t RNA ‐charging enzymes in peripheral axons. J Neurosci 26: 10397 – 10406.en_US
dc.identifier.citedreferenceBayat V, Thiffault I, Jaiswal M, Tetreault M, Donti T, Sasarman F, Bernard G, Demers‐Lamarche J, Dicaire MJ, Mathieu J, Vanasse M, Bouchard JP, et al., 2012. Mutations in the mitochondrial methionyl‐t RNA synthetase cause a neurodegenerative phenotype in flies and a recessive ataxia ( ARSAL ) in humans. PLoS Biol 10: e1001288.en_US
dc.identifier.citedreferenceBelostotsky R, Ben‐Shalom E, Rinat C, Becker‐Cohen R, Feinstein S, Zeligson S, Segel R, Elpeleg O, Nassar S, Frishberg Y. 2011. Mutations in the mitochondrial seryl‐t RNA synthetase cause hyperuricemia, pulmonary hypertension, renal failure in infancy and alkalosis, HUPRA syndrome. Am J Hum Genet 88: 193 – 200.en_US
dc.identifier.citedreferenceBiesecker LG, Mullikin JC, Facio FM, Turner C, Cherukuri PF, Blakesley RW, Bouffard GG, Chines PS, Cruz P, Hansen NF, Teer JK, Maskeri B, et al., 2009. The C lin S eq P roject: piloting large‐scale genome sequencing for research in genomic medicine. Genome Res 19: 1665 – 1674.en_US
dc.identifier.citedreferenceBoeke JD, LaCroute F, Fink GR. 1984. A positive selection for mutants lacking orotidine‐5′‐phosphate decarboxylase activity in yeast: 5‐fluoro‐orotic acid resistance. Mol Gen Genet 197: 345 – 346.en_US
dc.owningcollnameInterdisciplinary and Peer-Reviewed


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