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• W2915233723 abstract "Aminoacyl-tRNA synthetases (ARSs) are essential enzymes responsible for charging tRNA molecules with cognate amino acids. Consistent with the essential function and ubiquitous expression of ARSs, mutations in 32 of the 37 ARS-encoding loci cause severe, early-onset recessive phenotypes. Previous genetic and functional data suggest a loss-of-function mechanism; however, our understanding of the allelic and locus heterogeneity of ARS-related disease is incomplete. Cysteinyl-tRNA synthetase (CARS) encodes the enzyme that charges tRNACys with cysteine in the cytoplasm. To date, CARS variants have not been implicated in any human disease phenotype. Here, we report on four subjects from three families with complex syndromes that include microcephaly, developmental delay, and brittle hair and nails. Each affected person carries bi-allelic CARS variants: one individual is compound heterozygous for c.1138C>T (p.Gln380∗) and c.1022G>A (p.Arg341His), two related individuals are compound heterozygous for c.1076C>T (p.Ser359Leu) and c.1199T>A (p.Leu400Gln), and one individual is homozygous for c.2061dup (p.Ser688Glnfs∗2). Measurement of protein abundance, yeast complementation assays, and assessments of tRNA charging indicate that each CARS variant causes a loss-of-function effect. Compared to subjects with previously reported ARS-related diseases, individuals with bi-allelic CARS variants are unique in presenting with a brittle-hair-and-nail phenotype, which most likely reflects the high cysteine content in human keratins. In sum, our efforts implicate CARS variants in human inherited disease, expand the locus and clinical heterogeneity of ARS-related clinical phenotypes, and further support impaired tRNA charging as the primary mechanism of recessive ARS-related disease. Aminoacyl-tRNA synthetases (ARSs) are essential enzymes responsible for charging tRNA molecules with cognate amino acids. Consistent with the essential function and ubiquitous expression of ARSs, mutations in 32 of the 37 ARS-encoding loci cause severe, early-onset recessive phenotypes. Previous genetic and functional data suggest a loss-of-function mechanism; however, our understanding of the allelic and locus heterogeneity of ARS-related disease is incomplete. Cysteinyl-tRNA synthetase (CARS) encodes the enzyme that charges tRNACys with cysteine in the cytoplasm. To date, CARS variants have not been implicated in any human disease phenotype. Here, we report on four subjects from three families with complex syndromes that include microcephaly, developmental delay, and brittle hair and nails. Each affected person carries bi-allelic CARS variants: one individual is compound heterozygous for c.1138C>T (p.Gln380∗) and c.1022G>A (p.Arg341His), two related individuals are compound heterozygous for c.1076C>T (p.Ser359Leu) and c.1199T>A (p.Leu400Gln), and one individual is homozygous for c.2061dup (p.Ser688Glnfs∗2). Measurement of protein abundance, yeast complementation assays, and assessments of tRNA charging indicate that each CARS variant causes a loss-of-function effect. Compared to subjects with previously reported ARS-related diseases, individuals with bi-allelic CARS variants are unique in presenting with a brittle-hair-and-nail phenotype, which most likely reflects the high cysteine content in human keratins. In sum, our efforts implicate CARS variants in human inherited disease, expand the locus and clinical heterogeneity of ARS-related clinical phenotypes, and further support impaired tRNA charging as the primary mechanism of recessive ARS-related disease. Aminoacyl-tRNA synthetases (ARSs) are essential, ubiquitously expressed enzymes that charge tRNA molecules with cognate amino acids in the cytoplasm and mitochondria.1Antonellis A. Green E.D. The role of aminoacyl-tRNA synthetases in genetic diseases.Annu. Rev. Genomics Hum. Genet. 2008; 9: 87-107Crossref PubMed Scopus (215) Google Scholar Mutations in 32 ARS loci have been implicated in recessive disease, and the associated phenotypes tend to involve a wide array of tissues.2Meyer-Schuman R. Antonellis A. Emerging mechanisms of aminoacyl-tRNA synthetase mutations in recessive and dominant human disease.Hum. Mol. Genet. 2017; 26: R114-R127Crossref PubMed Scopus (95) Google Scholar, 3Antonellis A. Oprescu S.N. Griffin L.B. Heider A. Amalfitano A. Innis J.W. Compound heterozygosity for loss-of-function FARSB variants in a patient with classic features of recessive aminoacyl-tRNA synthetase-related disease.Hum. Mutat. 2018; 39: 834-840Crossref PubMed Scopus (22) Google Scholar, 4Mendes M.I. Gutierrez Salazar M. Guerrero K. Thiffault I. Salomons G.S. Gauquelin L. Tran L.T. Forget D. Gauthier M.-S. Waisfisz Q. et al.Bi-allelic mutations in EPRS, encoding the glutamyl-prolyl-aminoacyl-trna synthetase, cause a hypomyelinating leukodystrophy.Am. J. Hum. Genet. 2018; 102: 676-684Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar The genotypes of subjects with ARS-mediated recessive disorders suggest a loss-of-function mechanism for disease pathogenesis but are also consistent with the presumbed lethality of complete loss of ARS function. Specifically, subjects are compound heterozygous for one missense mutation and one null allele, compound heterozygous for two missense mutations, or homozygous for a single missense mutation.2Meyer-Schuman R. Antonellis A. Emerging mechanisms of aminoacyl-tRNA synthetase mutations in recessive and dominant human disease.Hum. Mol. Genet. 2017; 26: R114-R127Crossref PubMed Scopus (95) Google Scholar Consistent with this notion, functional studies have revealed that recessive disease-associated ARS mutations cause reduced protein abundance in immunoblot assays,5Nakayama T. Wu J. Galvin-Parton P. Weiss J. Andriola M.R. Hill R.S. Vaughan D.J. El-Quessny M. Barry B.J. Partlow J.N. et al.Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy.Hum. Mutat. 2017; 38: 1348-1354Crossref PubMed Scopus (35) Google Scholar, 6Coughlin 2nd, C.R. Scharer G.H. Friederich M.W. Yu H.-C. Geiger E.A. Creadon-Swindell G. Collins A.E. Vanlander A.V. Coster R.V. Powell C.A. et al.Mutations in the mitochondrial cysteinyl-tRNA synthase gene, CARS2, lead to a severe epileptic encephalopathy and complex movement disorder.J. Med. Genet. 2015; 52: 532-540Crossref PubMed Scopus (49) Google Scholar, 7Oliveira R. Sommerville E.W. 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Genet. 2010; 87: 52-59Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar and/or diminished ability of the mutated gene to support cellular growth in yeast complementation assays.12Cassandrini D. Cilio M.R. Bianchi M. Doimo M. Balestri M. Tessa A. Rizza T. Sartori G. Meschini M.C. Nesti C. et al.Pontocerebellar hypoplasia type 6 caused by mutations in RARS2: Definition of the clinical spectrum and molecular findings in five patients.J. Inherit. Metab. Dis. 2013; 36: 43-53Crossref PubMed Scopus (61) Google Scholar, 13Diodato D. Melchionda L. Haack T.B. Dallabona C. Baruffini E. Donnini C. Granata T. Ragona F. Balestri P. Margollicci M. et al.VARS2 and TARS2 mutations in patients with mitochondrial encephalomyopathies.Hum. Mutat. 2014; 35: 983-989Crossref PubMed Scopus (71) Google Scholar, 21Pierce S.B. Chisholm K.M. Lynch E.D. Lee M.K. Walsh T. Opitz J.M. Li W. Klevit R.E. King M.-C. 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Quartararo J. Dallabona C. Carrara F. Moroni I. Donnini C. Garavaglia B. Zeviani M. Uziel G. A novel homozygous YARS2 mutation in two Italian siblings and a review of literature.JIMD Rep. 2015; 20: 95-101Crossref PubMed Scopus (16) Google Scholar As such, impaired protein translation as a consequence of decreased tRNA charging is the most likely molecular mechanism for ARS-mediated recessive disease.2Meyer-Schuman R. Antonellis A. Emerging mechanisms of aminoacyl-tRNA synthetase mutations in recessive and dominant human disease.Hum. Mol. Genet. 2017; 26: R114-R127Crossref PubMed Scopus (95) Google Scholar Here, we report on four affected individuals from three unrelated families. These individuals have similar clinical presentations (Table S1) and bi-allelic loss-of-function variants in cysteinyl-tRNA synthetase (CARS [MIM: 123859]). The appropriate, institute-specific review boards approved all studies, and informed consent was obtained from all subjects. The individual from family 1 (subject 1-3, Figure 1A) is of mixed European and French-Canadian descent and was enrolled in the NIH Undiagnosed Diseases Program. He was born at 33 weeks gestation to asymptomatic parents and presented with intrauterine growth retardation and microcephaly. In childhood he presented with failure to thrive, non-progressive cognitive delay, peripheral neuropathy, osteoporosis, proportionate short stature, recurrent hernias, mild aortic root dilatation, recurrent elbow dislocation, feeding difficulties, esophagitis requiring Nissen fundoplication, urinary retention, and chronic pain. At age 24 he was diagnosed with hypothalamic hypogonadism and delayed puberty, as well as type II diabetes mellitus. On examination he had dysmorphic features; a barrel-shaped trunk with wasting of the distal extremities; hypospadias with chordee; hyperextensible joints; myopia; central hypotonia but increased extremity tone; prominent lateral ventricles and sulci with mild cerebral atrophy upon brain MRI (Figures 2A–C); and fine, brittle hair (Figure 3A) and brittle nails (Figure S1A and S1B). Polarized light microscopy of hair shafts revealed moderate tiger-tail patterns compared to those of controls (Figures 4A and 4B ). Subject 1-3 is currently 34 years old and has mild motor, language, and cognitive disabilities.Figure 2Subjects with CARS Variants Present with Central Nervous System FeaturesShow full captionSagittal T1-weighted (A) and axial T2-weighted (B and C) imaging of subject 1-3 shows moderate cerebral atrophy, a thin corpus callosum (A; arrow), mild atrophy of the superior cerebellar vermis (A; arrowhead), thin cerebellar folia, incomplete falx cerebri, incomplete tentorium, and variant anatomy of the circle of Willis. Sagittal T1-weighted imaging on subject 2-4 shows thin splenium of corpus callosum (D; arrow) and mild atrophy of the vermis (D; arrowhead). T2-weighted axial images of subject 2-4 show moderate global cerebral atrophy, deep sulci (E), thin cerebellar folia (F), and decreased white-matter volume, but globally normal myelination (D–F).View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 3Subjects with CARS Variants Present with Brittle HairShow full captionPhotographs show the brittle scalp hair in subject 1-3 (A), subject 2-4 (B), subject 3-3 (C), and subject 3-4 (D).View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 4Subjects with CARS Variants Present with Hair-Shaft AbnormalitiesShow full captionPolarized light microscopy of hair shafts at the same magnification. Depicted are:(A) An unrelated, age-matched healthy subject.(B) Subject 1-3, showing moderate tiger-tail patterns.(C) Subject 2-4, showing trichorrhexis and tiger-tail patterns.(D) Subject 3-3, showing trichorrhexis and moderate tiger-tail patterns.Note the difference in shaft diameter between healthy (A) and affected (B–D) subjects.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Sagittal T1-weighted (A) and axial T2-weighted (B and C) imaging of subject 1-3 shows moderate cerebral atrophy, a thin corpus callosum (A; arrow), mild atrophy of the superior cerebellar vermis (A; arrowhead), thin cerebellar folia, incomplete falx cerebri, incomplete tentorium, and variant anatomy of the circle of Willis. Sagittal T1-weighted imaging on subject 2-4 shows thin splenium of corpus callosum (D; arrow) and mild atrophy of the vermis (D; arrowhead). T2-weighted axial images of subject 2-4 show moderate global cerebral atrophy, deep sulci (E), thin cerebellar folia (F), and decreased white-matter volume, but globally normal myelination (D–F). Photographs show the brittle scalp hair in subject 1-3 (A), subject 2-4 (B), subject 3-3 (C), and subject 3-4 (D). Polarized light microscopy of hair shafts at the same magnification. Depicted are: (A) An unrelated, age-matched healthy subject. (B) Subject 1-3, showing moderate tiger-tail patterns. (C) Subject 2-4, showing trichorrhexis and tiger-tail patterns. (D) Subject 3-3, showing trichorrhexis and moderate tiger-tail patterns. Note the difference in shaft diameter between healthy (A) and affected (B–D) subjects. The individual from family 2 (subject 2-4, Figure 1B) is of Dutch descent, has asymptomatic parents, and was born at 38 weeks’ gestation via elective cesarean section prompted by intrauterine growth retardation. As a result of a small atrial septal defect and failure to thrive, she was hospitalized for two months after birth. In childhood she developed restless behavior, poor sleep, mild dystonia, ataxic hand movements, poor coordination, and developmental delay. At age 30 she was diagnosed with diabetes mellitus. A CT scan of the head when she was 2 years old was normal. A brain MRI performed when she was 20 years old revealed areas of apparent delayed myelination; decreased white-matter volume; prominence of cerebellar folia; a small corpus striatum; hypoplasia of the corpus callosum; and mild, globally diffuse cerebral and cerebellar atrophy (Figures 2D–2F). The quality of the MRI and the lack of a repeat MRI did not allow distinction between hypomyelination and demyelination. On examination she had microcephaly; fine facial features; fragile nails; and sparse, brittle, and thin hair (Figure 3B). Light microscopy of hair shafts revealed trichoschisis and trichorrhexis nodosa, polarized microscopy showed weak but consistent tiger tail banding (Figure 4C), and scanning electron microscopy showed longitudinal grooves (data not shown). Subject 2-4 is currently 35 years old and has a moderate level of motor, language, and cognitive disability. Family 3 includes two affected siblings (subjects 3-3 and 3-4, Figure 1C) who are of Dutch descent and were born to asymptomatic parents. Both subjects presented with developmental delay, mild spastic ataxia, a wide-based gait, pyramidal signs, liver steatosis, and thin hair (Figures 3C and 3D). Polarized microscopy of hair shafts revealed trichorrhexis and moderate tiger-tail patterns in subject 3-3 (Figure 4D) and mild tiger-tail patterns in subject 3-4 (data not shown). Subject 3-3 was observed from infancy because of unexplained failure to thrive, cholestasis, and fat malabsorption and had complex partial and generalized seizures. Subject 3-4 presented at two months with congenital nystagmus and high myopia; at nine months she had repeated convulsions associated with fever and was diagnosed with hepatomegaly and steatosis. Brain CT of subject 3-3 revealed hemiatrophy and a wide right ventricle (data not shown). Subject 3-3 is currently 25 years old and has a moderate level of motor, language, and cognitive disability. Subject 3-4 is currently 20 years old and has a mild level of motor, language, and cognitive disability. Tiger-tail structural anomalies are typical of individuals affected by trichothiodystrophy (TTD);34Cheng S. Stone J. de Berker D. Trichothiodystrophy and fragile hair: The distinction between diagnostic signs and diagnostic labels in childhood hair disease.Br. J. Dermatol. 2009; 161: 1379-1383Crossref PubMed Scopus (9) Google Scholar indeed, this was the initial clinical diagnosis of subject 2-4. Because TTD is often caused by DNA-repair defects, thorough analysis of DNA-repair capacity was performed on skin fibroblasts from subjects 1-3, 2-4, and 3-3. This analysis did not reveal any defects (Figure S2). To identify candidate variants for the unexplained phenotypes observed in our subjects, we performed exome sequencing (ES) on all affected individuals and their unaffected parents (Figure 1A–1C). In Family 1, ES was performed using the Illumina HiSeq2000 platform and the TrueSeq capture kit as previously described.35Bentley D.R. Balasubramanian S. Swerdlow H.P. Smith G.P. Milton J. Brown C.G. Hall K.P. Evers D.J. Barnes C.L. Bignell H.R. et al.Accurate whole human genome sequencing using reversible terminator chemistry.Nature. 2008; 456: 53-59Crossref PubMed Scopus (2519) Google Scholar, 36Gahl W.A. Markello T.C. Toro C. Fajardo K.F. Sincan M. Gill F. Carlson-Donohoe H. Gropman A. Pierson T.M. Golas G. et al.The National Institutes of Health Undiagnosed Diseases Program: insights into rare diseases.Genet. Med. 2012; 14: 51-59Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar, 37Gnirke A. Melnikov A. Maguire J. Rogov P. LeProust E.M. Brockman W. Fennell T. Giannoukos G. Fisher S. Russ C. et al.Solution hybrid selection with ultra-long oligonucleotides for massively parallel targeted sequencing.Nat. Biotechnol. 2009; 27: 182-189Crossref PubMed Scopus (1039) Google Scholar, 38Teer J.K. Bonnycastle L.L. Chines P.S. Hansen N.F. Aoyama N. Swift A.J. Abaan H.O. Albert T.J. Margulies E.H. Green E.D. et al.NISC Comparative Sequencing ProgramSystematic comparison of three genomic enrichment methods for massively parallel DNA sequencing.Genome Res. 2010; 20: 1420-1431Crossref PubMed Scopus (177) Google Scholar Sequence data were aligned to the human reference genome (hg19), and variants were filtered with VarSifter39Teer J.K. Green E.D. Mullikin J.C. Biesecker L.G. VarSifter: visualizing and analyzing exome-scale sequence variation data on a desktop computer.Bioinformatics. 2012; 28 (web39): 599-600Crossref PubMed Scopus (117) Google Scholar on the basis of allele frequencies in the NIH-UDP cohort.36Gahl W.A. Markello T.C. Toro C. Fajardo K.F. Sincan M. Gill F. Carlson-Donohoe H. Gropman A. Pierson T.M. Golas G. et al.The National Institutes of Health Undiagnosed Diseases Program: insights into rare diseases.Genet. Med. 2012; 14: 51-59Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar, 40Gahl W.A. Tifft C.J. The NIH Undiagnosed Diseases Program: lessons learned.JAMA. 2011; 305: 1904-1905Crossref PubMed Scopus (88) Google Scholar, 41Markello T.C. Han T. Carlson-Donohoe H. Ahaghotu C. Harper U. Jones M. Chandrasekharappa S. Anikster Y. Adams D.R. Gahl W.A. Boerkoel C.F. NISC Comparative Sequencing ProgramRecombination mapping using Boolean logic and high-density SNP genotyping for exome sequence filtering.Mol. Genet. Metab. 2012; 105: 382-389Crossref PubMed Scopus (12) Google Scholar In families 2 and 3, trio ES was performed after DNA enrichment with Agilent Sureselect Exome V4 Capture and subsequently run on the HiSeq platform (101bp paired-end, Illumina) with an average depth coverage of 50×–100×; sequences were mapped with BWA. Variants were detected with the Genome Analysis Toolkit, and the VCF files were filtered with Cartagenia software (version 3.0.7). A summary of the ES analysis is provided in Table S2. Analysis of ES data revealed that all four affected individuals are homozygous or compound heterozygous for CARS variants (Table 1 and Figure 1). Variant analysis by ES in family 1 revealed additional candidate disease-causing variants in DEAF1 (MIM: 602635), SOX30 (MIM: 606698), and PTPN13 (MIM: 600267). In family 2, ES analysis revealed no additional candidate variants. In family 3, ES analysis revealed candidate variants in ZNF185 (MIM: 300381). Importantly, the phenotypic similarity among subjects is consistent with the finding that all three families carry CARS variants, which were the only common candidates identified via ES; it should be noted that the research groups studying these families were connected via GeneMatcher42Sobreira N. Schiettecatte F. Boehm C. Valle D. Hamosh A. New tools for Mendelian disease gene identification: PhenoDB variant analysis module; and GeneMatcher, a web-based tool for linking investigators with an interest in the same gene.Hum. Mutat. 2015; 36: 425-431Crossref PubMed Scopus (111) Google Scholar on the basis of the detection of CARS variants.Table 1CARS Variants Identified in Subjects with Recessive DiseaseSubjectNucleotide ChangeaHuman nucleotide positions cor" @default.
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