Original Article

Journal of Child Neurology 1-7 ª The Author(s) 2014 Congenital Visual Impairment and Progressive Reprints and permission: sagepub.com/journalsPermissions.nav Microcephaly Due to Lysyl–Transfer DOI: 10.1177/0883073814553272 Ribonucleic Acid (RNA) Synthetase (KARS) jcn.sagepub.com Mutations: The Expanding Phenotype of Aminoacyl–Transfer RNA Synthetase Mutations in Human Disease

Hugh J. McMillan, MD, MSc1, Peter Humphreys, MDCM1, Amanda Smith, PhD1, Jeremy Schwartzentruber, MSc2, Pranesh Chakraborty, MD1, Dennis E. Bulman, PhD1, Chandree L. Beaulieu, MSc1, FORGE Canada Consortium1, Jacek Majewski, PhD3, Kym M. Boycott, MD, PhD1, and Michael T. Geraghty, MBBS, MSc1

Abstract Aminoacyl–transfer ribonucleic acid (RNA) synthetases (ARSs) are a group of required for the first step of protein translation. Each aminoacyl–transfer RNA synthetase links a specific amino acid to its corresponding transfer RNA component within the cytoplasm, mitochondria, or both. Mutations in ARSs have been linked to a growing number of diseases. Lysyl–transfer RNA synthetase (KARS) links the amino acid lysine to its cognate transfer RNA. We report 2 siblings with severe infantile visual loss, progressive microcephaly, developmental delay, seizures, and abnormal subcortical white matter. Exome sequencing identified mutations within the KARS (NM_005548.2):c.1312C>T; p.Arg438Trp and c.1573G>A; p.Glu525Lys occurring within a highly conserved region of the catalytic domain. Our patients’ phenotype is remarkably similar to a phenotype recently reported in glutaminyl–transfer RNA synthetase (QARS), another bifunctional ARS gene. This finding expands the phenotypic spectrum associated with mutations in KARS and draws attention to aminoacyl–transfer RNA synthetase as a group of enzymes that are increasingly being implicated in human disease.

Keywords lysyl-tRNA synthetase, aminoacyl–tRNA, microcephaly, epilepsy, vision disorders

Received July 06, 2014. Received revised July 06, 2014. Accepted for publication September 07, 2014.

Background Aminoacyl–transfer ribonucleic acid (RNA) synthetases (ARSs) are a group of enzymes that are responsible for the first step of protein translation. Each of the 37 aminoacyl– transfer RNA synthetase enzymes links a specific amino acid 1 to its corresponding transfer RNA, a process referred to as Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada aminoacylation or charging. Aminoacylation must occur 2 McGill University and Genome Quebec Innovation Centre, Montre´al, before protein translation can begin. Aminoacyl–transfer Quebec, Canada RNA synthetases are divided into 1 of 3 groups depending 3 Department of Human Genetics, McGill University, Montre´al, Quebec, on the site where transfer RNA aminoacylation occurs: cyto- Canada plasm, mitochondria, or both (ie, bifunctional).1 Each ami- Corresponding Author: noacyl–transfer RNA synthetase has a unique 4-letter Hugh J. McMillan, MD, MSc, Neurology, Children’s Hospital of Eastern Ontario, designation where the first letter corresponds to the amino 401 Smyth Rd, Ottawa, Ontario, Canada K1H 8L1. acid it associates with, followed by ‘‘ARS’’; for example, the Email: [email protected]

Downloaded from jcn.sagepub.com at UNIV OF WESTERN ONTARIO on February 17, 2015 2 Journal of Child Neurology convention for alanyl–transfer RNA synthetase is AARS. In normal. Although an electroretinogram was normal at age thecaseofaminoacyl–transfer RNA synthetase functioning 4 months, visual evoked potentials were absent. Magnetic reso- within the mitochondria, the suffix 2 is applied (ie, AARS2). nance imaging (MRI) brain at age 9 months revealed moderate, The 3 bifunctional aminoacyl–transfer RNA synthetases symmetrical thinning of the central cerebral white matter and include lysyl–transfer RNA synthetase (KARS), glycyl–trans- the corpus callosum. On neurologic assessment at age 9 months, fer RNA synthetase (GARS), and glutaminyl–transfer RNA his weight was 10.4 kg (90th percentile) and his head circum- synthetase (QARS). ference was 43.0 cm (2nd percentile). No abnormalities beyond Aminoacyl–transfer RNA synthetases have been linked to a his visual loss were apparent. A hearing test at age 12 months growing number of neurologic disorders with an expanding range was normal. Pregnancy had been significant only for noniden- of phenotypes. Several ARSs have been linked to Charcot-Marie- tical twin gestation. Antenatal ultrasounds were normal. He and Tooth disease, including AARS,2 YARS,3 GARS,4 and KARS.5 The his twin sister were delivered via planned Caesarean section at initial ARS mutations were predominantly autosomal dominant2-4 41 weeks. His birth weight was 2.87 kg (3rd to 10th percentile). although autosomal recessive inheritance is now increasingly Family history noted his nonconsanguineous parents and twin recognized, particularly with severe and earlier-onset pheno- sister to be well. There was a progressive decline in head types.6 Next-generation sequencing is an effective tool that has growth velocity after age 9 months: 44.0 cm at 21 months and advanced our understanding of clinical phenotypes associated 45.2 cm at 3.5 years (both well below the 2nd percentile). He with ARS mutations. Next-generation sequencing permits in- developed seizures at age 2 years characterized by 30 to 60 sec- parallel sequencing of all protein-encoding regions within a onds of behavioral arrest, blank stare, and chewing movements . Although exons constitute only about 1% to of lips. Electroencephalogram (EEG) showed generalized spike 2% of the human genome, they contain 85% of Mendelian and wave discharges. His seizures were well controlled with disease-causing mutations,7 making this technique highly advan- phenobarbital and later valproic acid. Baseline and surveillance tageous when investigating patients with rare clinical presenta- transaminase levels were normal. Developmentally, he demon- tions,8 phenotypes associated with significant genetic strated global developmental delay. He sat unsupported at age 8 heterogeneity (eg, spinocerebellar ataxia, Charcot-Marie-Tooth months and rolled front-to-back at age 10 months. He could disease, type 2), or a broad differential diagnosis.8 As this technol- transition from crawl to sit at age 14 months and started to ogy becomes increasing affordable and available, there is a con- cruise at age 22 months. At the age of 5 years, he had less than comitant increase in testing opportunities for patients with such 10 words and could understand some simple instructions. Bio- clinical presentations.8 As a result, our understanding of aminoa- chemical testing revealed normal serum creatine kinase, lac- cyl–transfer RNA synthetase related disease has thus expanded tate, plasma amino acids, 7 dehydrocholesterol, very-long- considerably, with mutations now identified in 19 of the 37 ARS chain fatty acids, transferrin isoelectric focusing, vitamin B12, , particularly ARSs that are active within mitochondria. The karyotype, and microarray (Baylor College, range of clinical phenotypes associated with ARS mutations has v5.0, in 2006). Urine organic acids were unremarkable. Repeat similarly expanded and now includes microcephaly, seizures, leu- brain MRI at age 20 months revealed some progress of myeli- koencephalopathy, peripheral neuropathy, vision and hearing nation; however, symmetric abnormalities were still noted in impairment, and/or hepatic failure. the deep white matter. MR spectroscopy of the basal ganglia We report 2 siblings who presented with visual impair- was normal. At his most recent neurologic follow-up at the age ment from birth, progressive microcephaly, epilepsy, and of 10 years, his EEG continued to show persistent focal and severe cognitive impairment due to 2 mutations in the generalized epileptiform discharges although his seizures bifunctional ARS, lysyl–transfer RNA synthetase (KARS). remained clinically under good control. KARS mutations have been linked to autosomal recessive A younger sister was born 3 years after the twins. Pregnancy syndromic peripheral neuropathy phenotype5 and nonsyn- was uncomplicated, and she was delivered at 40 weeks. Birth dromic hearing impairment.9 Our patients’ symptoms were weight was 3.46 kg (just below the 50th percentile) and birth more severe than those noted in previous patients with head circumference was 33.5 cm (just above the 10th percentile). mutations in KARS, yet were strikingly similar to those At age 5 weeks, her parents noted her to have the same impair- recently reported in another bifunctional ARS, glutaminyl– ment of visual fixation and nystagmus that had been noted in her transfer RNA synthetase (QARS).6 older brother. Neurologic examination noted her head circumfer- ence to be 37.4 cm (below the 2nd percentile). At age 4 months, her visual impairment was less severe than her brother’s; she Cases could visually fixate and follow a nearby face. She would also A boy was referred to Pediatric Ophthalmology at 6 weeks of reach for objects in front of her. She had an intact smile and was age because of concern regarding visual impairment. He was cooing and laughing. Neurologic exam was otherwise unremark- not visually fixating and lacked a social smile. Severe visual able. Routine EEG at age 10 months was normal. Hearing test at loss and gross searching pendular nystagmus were noted. He 2 years of age was normal. Video EEG was performed at 2 years was unable to visually fixate or follow with either eye. Eye because of episodes of nighttime screaming. Generalized epilep- examination revealed no significant refractive error and his tiform discharges were noted although no clinical correlate was optic nerve and retina appeared normal. Pupillary response was seen. By age 2.5 years, her head circumference was 44.0 cm,

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Figure 1. Magnetic resonance imaging (MRI) of the brain of the younger affected sister revealed (A) T1-weighted sagittal image at age 4 months to show an intact but thin corpus callosum. (B) T1-weighted sagittal image at age 5.3 years showed interval improvement of corpus callosal thickness; however, T2 fluid-attenuated inversion recovery axial image showed an abnormal pattern of myelination for the patient’s age. MR spectroscopy was unremarkable. (C) Normal T2 fluid-attenuated inversion recovery axial image of an unrelated 5.4-year-old developmentally normal boy (imaging was requested as part of workup of primary generalized epilepsy) shows age-appropriate myelination. even farther below the 2nd percentile. At age 4 years, she had project with the goal of identifying novel genes for rare events that were clinically consistent with complex partial sei- childhood diseases. Institutional Research Ethics Board zures; she slumped over and stared blankly for 2 minutes with approval was obtained (Children’s Hospital of Eastern postictal confusion for an additional 30 to 40 minutes. Valproic Ontario), as was free and informed consent from the family acid was started with good clinical effect. Global developmental prior to enrolment. DNA was extracted from whole blood delay was noted although she pulled to stand and cruised at age by standard protocols. DNA from the 2 affected siblings was 16 months and began walking with ankle foot orthoses after subjected to exome capture and high-throughput sequencing. 3 years of age. At age 5 years, she was nonverbal but could com- Target enrichment was achieved using the Agilent SureSelect municate using a picture exchange communication system. 50Mb(V3)AllExonKitandfollowedbysequencing(Illu- Repeat MRI of the brain at age 5.3 years showed symmetrical mina HiSeq), generating >16 Gbp of 100-base-pair, paired- loss of subcortical white matter volume, deep sulcation, and end reads per sample. Read alignment, variant calling, and hypogenesis of the corpus callosum (Figure 1). annotation were done as outlined for previous FORGE proj- ects (8) with a pipeline based on BWA, Picard, Annovar, and custom annotation scripts. Variants were compared to Exome Sequencing and Analysis those previously seen in dbSNP132, the 1000-genomes data With no clear molecular diagnosis, the family was enrolled set (2012/04 release), or the 6500 NHLBI exomes (Exome in the FORGE Canada Consortium, a nationwide collaborative Variant Server (EVS), NHLBI GO Exome Sequencing Project

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Figure 2. Sanger sequencing and segregation. (A) Pedigree of family with KARS mutations showing segregation of the 2 mutations found: c.1312C>T; p.Arg438Trp and c.1573G>A; pGlu525Lys. Patients 1 and 2 (solid circles) are compound heterozygous confirmed to have inherited 1 allele from their unaffected father and mother (half shaded). (B) Sanger sequencing validation of KARS mutations identified by exome sequencing. (C) Conservation of the arginine residue at position 438 and glutamic acid residue at position 525 in the KARS protein.

(ESP), Seattle, Washington, data downloaded 2012-10-03), as Discussion well as in approximately 1000 exomes previously sequenced Aminoacyl–transfer RNA synthetases have been linked to at the McGill University and Genome Quebec Innovation an increasing number of disease phenotypes, particularly Centre. those with signs and symptoms suggestive of mitochondrial Given the presumed recessive mode of inheritance, dele- disease. Recent advances in genomic sequencing, particu- terious homozygous or compound heterozygous rare var- larly exome sequencing, have been instrumental in the iden- iants shared by the affected siblings were sought. No rare tification of many individuals harboring mutations in the (<3% allele frequency) homozygous single-nucleotide var- ARS genes. ARS mutations present a challenge to clinicians iants or indels were detected in the siblings, nor were any because of phenotypic variability and the lack of a reliable homozygous or large de novo copy number variations. We biomarker such as lactic acid which would raise clinical next considered genes with multiple heterozygous rare var- suspicion of this group of diseases. In the past few years, iants present in both siblings, but excluded genes where the reports have emerged linking 19 of the 37 ARS genes to same 2 variants were seen in an individual sample from our human disease phenotypes, which range considerably in set of control exomes. Only the KARS gene remained as a their severity as well as the range of organ and system candidate. The 2 variants identified were confirmed and involvement (Table 1). segregated using Sanger sequencing (Figure 2). The parents Lysyl–transfer RNA synthetase (KARS) was first linked to were each heterozygous for 1 of the mutations an autosomal recessive syndromic peripheral neuropathy phe- (NM_005548.2):c.1312C>T; p.Arg438Trp was inherited notype.5 The clinical phenotype of the reported patient from the father and c.1573G>A; p.Glu525Lys was inherited included intermediate Charcot-Marie-Tooth, developmental from the mother. The 2 KARS variants, c.1312C>T; delay, self-abusive behavior, dysmorphic features, and a ves- p.Arg438Trp and c.1573G>A; pGlu525Lys, occur at highly tibular schwannoma. Exome sequencing identified compound conserved positions (Figure 2) and are predicted to be either heterozygous mutations; c.398T>A; p.Leu133His and possibly damaging or damaging (respectively) by both SIFT c.524_525insTT; p.Tyr173SerfsX7.5 The missense mutation (scores 0.26 and 0.00, respectively)10 and PolyPhen2 (scores was found to show a marked reduction in KARS 0.73 and 1.00, respectively).11

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Table 1. Human Aminoacyl-Transfer Ribonucleic Acid (ARS) Synthetase Associated With Disease.

Gene Name Clinical phenotype(s) Reference

Cytoplasmic AARS Alanyl-tRNA synthetase Charcot-Marie-Tooth 2 CARS Cysteinyl-tRNA synthetase Not reported DARS Aspartyl-tRNA synthetase Hypomyelination; brainstem and spinal cord involvement 12 EARS Glutamyl-prolyl-tRNA synthetase Not reported FARSA Phenylalanyl-tRNA synthetase (a) Not reported FARSB Phenylalanyl -tRNA synthetase (b) Not reported HARS Histidyl-tRNA synthetase Progressive visual impairment (optic disk pallor, nystagmus) 13 IARS Isoleucyl-tRNA synthetase Not reported LARS Leucyl-tRNA synthetase Infantile syndromic liver failure 14 MARS Methionyl-tRNA synthetase Infantile syndromic liver failure 15 NARS Asparaginyl-tRNA synthetase Not reported RARS Arginyl-tRNA synthetase Not reported SARS Seryl-tRNA synthetase Not reported TARS Threonyl-tRNA synthetase Not reported VARS Valyl-tRNA synthetase Not reported WARS Tryptophanyl-tRNA synthetase Not reported YARS Tyrosyl-tRNA synthetase Charcot-Marie-Tooth 3 Mitochondrial AARS2 Alanyl-tRNA synthetase 2 Fatal infantile hypertrophic mitochondrial cardiomyopathy 16 CARS2 Cysteinyl-tRNA synthetase 2 Not reported DARS2 Aspartyl-tRNA synthetase 2 Leukoencephalopathy (þ brainstem and spinal cord) 17 Exercise-induced episodic ataxia 18 EARS2 Glutamyl-tRNA synthetase 2 Leukoencephalopathy, lactic acidosis, deep gray nuclei abnormality 19 FARS2 Phenylalanyl-tRNA synthetase 2 Fatal infantile Alpers encephalopathy 20 HARS2 Histidyl-tRNA synthetase 2 Ovarian dysgenesis sensorineural hearing loss 21 IARS2 Isoleucyl-tRNA synthetase 2 Not reported LARS2 Leucyl-tRNA synthetase 2 Ovarian dysgenesis sensorineural hearing loss 22 MARS2 Methionyl-tRNA synthetase 2 Spastic ataxia with leukoencephalopathy 23 NARS2 Asparaginyl-tRNA synthetase 2 Not reported PARS2 Prolyl-tRNA synthetase 2 Not reported RARS2 Arginyl-tRNA synthetase 2 Pontocerebellar hypoplasia 24 SARS2 Seryl-tRNA synthetase 2 Hyperuricemia, pulmonary hypertension, renal failure 25 TARS2 Threonyl-tRNA synthetase 2 Not reported VARS2 Valyl-tRNA synthetase 2 Not reported WARS2 Tryptophanyl-tRNA synthetase 2 Not reported YARS2 Tyrosyl-tRNA synthetase 2 Myopathy, lactic acidosis, and sideroblastic anemia 26 Bifunctional GARS Glycyl-tRNA synthetase Charcot-Marie-Tooth/distal spinal muscular atrophy 4 Myalgia, high lactate, leukoencephalopathy, cardiomyopathy 27 KARS Lysyl-tRNA synthetase Nonsyndromic hearing impairment 9 Charcot-Marie-Tooth phenotype 5 Congenital visual impairment, progressive microcephaly and (this series) cognitive impairment QARS Glutaminyl-tRNA synthetase Progressive microcephaly, infantile seizures, cerebral and 6 cerebellar atrophy

Abbreviation: tRNA, transfer ribonucleic acid. kinetics, and the frame-shift mutation was found to represent a however, it did not affect enzyme kinetics and thus is of less loss-of-function allele. Each mutation occurred within the clear significance.5 anticodon-binding domain (Figure 3), although the frame- Autosomal recessive nonsyndromic hearing loss was the shift mutation also predicted disrupted transcription of the second clinical phenotype linked to mutations in KARS. Using KARS catalytic domain, which is essential for charging of its exome sequencing, 2 separate KARS mutations were identified cognate transfer RNA.5 A second patient with a phenotype in 3 consanguineous families; c.1129G>A; p.Asp377Asn and resembling hereditary neuropathy with liability to pressure c.517T>C; p.Tyr173His.9 The p.Tyr173His mutation occurred palsy, inherited in an autosomal dominant pattern, was found in the KARS anticodon domain at the same codon as that previ- to have a sequence variant in KARS (c.906C>G; p.Ile302Met); ously reported in the patient (above) with a syndromic form of

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Author Note x ** x O O This work was selected for study by the FORGE Canada Steering Committee which consists of K. Boycott (University of Ottawa), J. Friedman (University of British Columbia), J. Michaud (University 597 1 124 234 of Montreal), F. Bernier (University of Calgary), M. Brudno (Univer- RNA Ancodon Catalyc sity of Toronto), B. Fernandez (Memorial University), B. Knoppers binding binding domain mof domain (McGill University), M. Samuels (Universite´ de Montre´al), and S. Scherer (University of Toronto). Figure 3. Mammalian lysyl–transfer ribonucleic acid (RNA) synthetase (KARS) gene showing previously reported mutations and associated Acknowledgments clinical phenotypes: (1) autosomal recessive syndromic peripheral The authors would like to thank the family for their cooperation and neuropathy phenotype (*) linked to p.Leu133His and p.Tyr173- permission to publish these findings. This work was selected for study SerfsX75; (2) nonsyndromic hearing loss (x) due to p.Tyr173His and 9 by the FORGE Canada Steering Committee which consists of K. Boy- p.Asp377Asn and; (3) optic atrophy, progressive microcephaly, and cott (University of Ottawa), J. Friedman (University of British Colum- cognitive impairment (O); p.Arg438Trp and p.Glu525Lys (this report). bia), J. Michaud (University of Montreal), F. Bernier (University of Calgary), M. Brudno (University of Toronto), B. Fernandez (Memor- ial University), B. Knoppers (McGill University), M. Samuels (Uni- versite´de Montre´al), and S. Scherer (University of Toronto). peripheral neuropathy.5 The p.Asp377Asn mutation occurred in the catalytic domain. Each mutation segregated in an autoso- Author Contributions mal recessive manner; affected individuals were homozygous while unaffected family members were carriers or normal. HJM and MTG wrote the manuscript. MTG, PC, and KMB designed and coordinated the study. PH and MTG provided subspecialist con- Each mutation occurred at highly conserved positions within sultation services, serial clinical examinations, and diagnostic testing. the KARS gene and were predicted to be deleterious by SIFT, 9 AS and DEB completed Sanger sequencing, modeling and conserva- LRT and PolyPhen-2 modeling. tion of KARS mutations. JS and JM carried out analysis of the next- The patients reported here have compound heterozygous generation sequencing data. All authors read and approved the final mutations in the KARS catalytic domain. We hypothesize that manuscript. the severe clinical phenotype of our patients, namely, early- onset visual impairment, progressive microcephaly, seizures, Declaration of Conflicting Interests and severe cognitive impairment is a reflection of the critical The authors declared no potential conflicts of interest with respect to function of the catalytic domain for the function of the KARS the research, authorship, and/or publication of this article. enzyme. The clinical phenotype of our patients is more severe than that previously attributed to mutations in KARS; however, Funding it is remarkably similar to that recently described in patients The authors disclosed receipt of the following financial support for the with QARS mutations which is another bifunctional aminoa- research, authorship, and/or publication of this article: Funding was cyl–transfer RNA synthetase enzyme.6 Mutations in HARS 13 provided by the Government of Canada through Genome Canada, the have been linked to progressive visual loss, whereas many Canadian Institutes of Health Research (CIHR) and the Ontario other ARS mutations have been associated with clinical and Genomics Institute (OGI-049). Funding was also provided by Genome neuroimaging evidence of cortical and/or white matter abnorm- Que´bec and Genome British Columbia. KMB is supported by a Clin- ality.6,12,17,19,23 Further research is necessary to understanding ical Investigatorship Award from the CIHR Institute of Genetics. why significant variability exists in disease phenotype among individuals who have mutations at different locations within Ethical Approval the same ARS gene. Functional studies in yeast may help Members of the study family consisted of the proband, his affected sis- delineate critical areas within the KARS enzyme that may give ter as well as his unaffected mother, father, and twin sister. Parents rise to more severe disease phenotypes. Aminoacyl transfer provided informed consent for themselves and their children to be RNA synthetases are also being increasingly recognized as enrolled in the Finding of Rare Disease Genes (FORGE) Canada having important secondary functions that include regulation study. The Research Ethics Board (REB) of the Children’s Hospital of transcription, translation, splicing, and apoptosis28; impact of Eastern Ontario approved this study in accordance with the on such functions may also explain some of the observed phe- Declaration of Helsinki (CHEO REB # 11/04E). A copy of the written notypic variability. consent is available for review by the Editor of this journal. Aminoacyl transfer RNA synthetase mutations are emerging as a recognizable cause of rare childhood and adult diseases. As References more children with cognitive impairment associated with sei- 1. Antonellis A, Green ED. The role of aminoacyl-tRNA synthetases zures, microcephaly, and other neurologic symptoms are eval- in genetic diseases. Annu Rev Genom Hum Genet. 2008;9:87-107. uated using exome sequencing, we will gain a more precise 2. Latour P, Thauvin-Robinet C, Baudelet-Mery C, et al. A major understanding of how prevalent ARS mutations are in this determinant for binding and aminoacylation of tRNA(Ala) in patient population. cytoplasmic Alanyl-tRNA synthetase is mutated in dominant

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