. 2020 Aug 6;107(2):311-324.

doi: 10.1016/j.ajhg.2020.06.016. Epub 2020 Jul 31.

De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects

Andreea Manole¹, Stephanie Efthymiou¹, Emer O'Connor¹, Marisa I Mendes², Matthew Jennings³, Reza Maroofian¹, Indran Davagnanam⁴, Kshitij Mankad⁵, Maria Rodriguez Lopez⁶, Vincenzo Salpietro¹, Ricardo Harripaul⁷, Lauren Badalato⁸, Jagdeep Walia⁸, Christopher S Francklyn⁹, Alkyoni Athanasiou-Fragkouli¹, Roisin Sullivan¹, Sonal Desai¹⁰, Kristin Baranano¹⁰, Faisal Zafar¹¹, Nuzhat Rana¹¹, Muhammed Ilyas¹², Alejandro Horga¹, Majdi Kara¹³, Francesca Mattioli¹⁴, Alice Goldenberg¹⁵, Helen Griffin³, Amelie Piton¹⁴, Lindsay B Henderson¹⁶, Benyekhlef Kara¹⁷, Ayca Dilruba Aslanger¹⁷, Joost Raaphorst¹⁸, Rolph Pfundt¹⁹, Ruben Portier²⁰, Marwan Shinawi²¹, Amelia Kirby²², Katherine M Christensen²², Lu Wang²³, Rasim O Rosti²³, Sohail A Paracha²⁴, Muhammad T Sarwar²⁴, Dagan Jenkins²⁵; SYNAPS Study Group²⁶; Jawad Ahmed²⁴, Federico A Santoni²⁷, Emmanuelle Ranza²⁸, Justyna Iwaszkiewicz²⁹, Cheryl Cytrynbaum³⁰, Rosanna Weksberg³⁰, Ingrid M Wentzensen¹⁶, Maria J Guillen Sacoto¹⁶, Yue Si¹⁶, Aida Telegrafi¹⁶, Marisa V Andrews²¹, Dustin Baldridge²¹, Heinz Gabriel³¹, Julia Mohr³¹, Barbara Oehl-Jaschkowitz³², Sylvain Debard³³, Bruno Senger³³, Frédéric Fischer³³, Conny van Ravenwaaij³⁴, Annemarie J M Fock³⁴, Servi J C Stevens³⁵, Jürg Bähler⁶, Amina Nasar⁸, John F Mantovani³⁶, Adnan Manzur²⁵, Anna Sarkozy²⁵, Desirée E C Smith², Gajja S Salomons², Zubair M Ahmed³⁷, Shaikh Riazuddin³⁸, Saima Riazuddin³⁷, Muhammad A Usmani³⁷, Annette Seibt³⁹, Muhammad Ansar⁴⁰, Stylianos E Antonarakis⁴¹, John B Vincent⁷, Muhammad Ayub⁸, Mona Grimmel⁴², Anne Marie Jelsig⁴³, Tina Duelund Hjortshøj⁴³, Helena Gásdal Karstensen⁴³, Marybeth Hummel⁴⁴, Tobias B Haack⁴⁵, Yalda Jamshidi⁴⁶, Felix Distelmaier³⁹, Rita Horvath³, Joseph G Gleeson²³, Hubert Becker³³, Jean-Louis Mandel¹⁴, David A Koolen¹⁹, Henry Houlden⁴⁷

Affiliations

¹ Department of Neuromuscular Disorders, University College London (UCL) Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
² Metabolic Unit, Department of Clinical Chemistry, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam Gastroenterology and Metabolism, Amsterdam, 1081 the Netherlands.
³ Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0QQ UK.
⁴ Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
⁵ Department of Neuroradiology, Great Ormond Street Hospital for Children, London, WC1N 3JH, UK.
⁶ Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London (UCL), London, WC1E 6BT, UK.
⁷ Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, ON, M5T 1R8, Canada; Institute of Medical Science and Department of Psychiatry, University of Toronto, Toronto, ON, M5T 1R8, Canada.
⁸ Department of Pediatrics, Queen's University, Kingston, ON, K7L 2V7, Canada.
⁹ Department of Biochemistry, University of Vermont College of Medicine, Burlington, VT 05405, USA.
¹⁰ Department of Neurology and Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
¹¹ Department of Pediatrics, Multan Hospital, Multan, 60000, Pakistan.
¹² University of Islamabad, Islamabad, 45320, Pakistan.
¹³ Department of Pediatrics, Tripoli Children's Hospital, Tripoli, Libya.
¹⁴ Institute for Genetics and Molecular and Cellular Biology (IGBMC), University of Strasbourg, CNRS UMR7104, INSERM U1258, Illkirch, 67404, France.
¹⁵ Département de Génétique, centre de référence anomalies du développement et syndromes malformatifs, CHU de Rouen, Inserm U1245, UNIROUEN, Normandie Université, Centre Normand de Génomique et de Médecine Personnalisée, Rouen, 76031, France.
¹⁶ GeneDx, 207 Perry Parkway Gaithersburg, MD 20877, USA.
¹⁷ Bezmiâlem Vakıf Üniversitesi, Istanbul, 34093, Turkey.
¹⁸ Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500HB Nijmegen, the Netherlands; Department of Neurology, Amsterdam Neuroscience Institute, Amsterdam University Medical Center, 1105AZ Amsterdam, the Netherlands.
¹⁹ Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500HB Nijmegen, the Netherlands.
²⁰ Department of Neurology, Medisch Spectrum Twente, 7512KZ Enschede, the Netherlands.
²¹ Department of Pediatrics, Divisions of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.
²² Division of Medical Genetics, SSM Health Cardinal Glennon Children's Hospital, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
²³ Howard Hughes Medical Institute, University of California San Diego and Rady Children's Hospital, La Jolla, CA 92130, USA.
²⁴ Institute of Basic Medical Sciences, Khyber Medical University, 25100 Peshawar, Pakistan.
²⁵ Institute of Child Health, Guilford Street and Dubowitz Neuromuscular Centre, Great Ormond Street Hospital for Children, London, WC1N 3JH, UK.
²⁶ SYNAPS Study Group, see Supplemental Information for the study group members who contributed clinical cases and data.
²⁷ Department of Genetic Medicine and Development, University of Geneva, 1206 Geneva, Switzerland; Department of Endocrinology, Diabetes, and Metabolism, University Hospital of Lausanne, 1011 Lausanne, Switzerland.
²⁸ Department of Genetic Medicine and Development, University of Geneva, 1206 Geneva, Switzerland; Service of Genetic Medicine, University Hospitals of Geneva, 1205 Geneva, Switzerland; Medigenome, The Swiss Institute of Genomic Medicine, Geneva, CH-1207, Switzerland.
²⁹ Swiss Institute of Bioinformatics, Molecular Modeling Group, Batiment Genopode, Unil Sorge, Lausanne, CH-1015, Switzerland.
³⁰ Hospital for Sick Children, Division of Clinical and Metabolic Genetics, 555 University Ave., Toronto, M5G 1X8, Canada.
³¹ CeGaT GmbH and Praxis für Humangenetik Tuebingen, Tuebingen, 72076, Germany.
³² Biomedical Centre Cardinal-Wendel-Straße 14, 66424 Hamburg, Germany.
³³ University of Strasbourg, CNRS, GMGM UMR 7156, Strasbourg, 67083, France.
³⁴ University of Groningen, University Medical Center Groningen, Department of Neurology, Groningen, 9713, the Netherlands.
³⁵ Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, 6211, the Netherlands.
³⁶ Division of Child Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
³⁷ Department of Biochemistry and Molecular Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
³⁸ Jinnah Burn and Reconstructive Surgery Center, Allama Iqbal Medical College, University of Health Sciences, Lahore 54550, Pakistan.
³⁹ Department of General Pediatrics, Heinrich-Heine-University, Moorenstr. 5, 40225 Düsseldorf, Germany.
⁴⁰ Department of Genetic Medicine and Development, University of Geneva, 1206 Geneva, Switzerland; Institute of Molecular and Clinical Ophthalmology Basel, Basel Switzerland.
⁴¹ Department of Genetic Medicine and Development, University of Geneva, 1206 Geneva, Switzerland; Service of Genetic Medicine, University Hospitals of Geneva, 1205 Geneva, Switzerland; iGE3 Institute of Genetics and Genomics of Geneva, 1211 Geneva, Switzerland.
⁴² Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tübingen, Germany.
⁴³ Department of Clinical Genetics, University Hospital of Copenhagen, Rigshospitalet, 2100, Denmark.
⁴⁴ Department of Pediatrics, Section of Medical Genetics, West Virginia University, Morgantown, WV 26506-9600, USA.
⁴⁵ Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tübingen, Germany; Centre for Rare Diseases, University of Tuebingen, 72076 Tübingen, Germany.
⁴⁶ Genetics Centre, Molecular and Clinical Sciences Institute, St George's University of London, London, SW17 0RE, UK.
⁴⁷ Department of Neuromuscular Disorders, University College London (UCL) Institute of Neurology, Queen Square, London, WC1N 3BG, UK. Electronic address: h.houlden@ucl.ac.uk.

PMID: 32738225
PMCID: PMC7413890
DOI: 10.1016/j.ajhg.2020.06.016

De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects

Andreea Manole et al. Am J Hum Genet. 2020.

. 2020 Aug 6;107(2):311-324.

doi: 10.1016/j.ajhg.2020.06.016. Epub 2020 Jul 31.

Authors

Affiliations

¹ Department of Neuromuscular Disorders, University College London (UCL) Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
² Metabolic Unit, Department of Clinical Chemistry, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam Gastroenterology and Metabolism, Amsterdam, 1081 the Netherlands.
³ Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0QQ UK.
⁴ Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
⁵ Department of Neuroradiology, Great Ormond Street Hospital for Children, London, WC1N 3JH, UK.
⁶ Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London (UCL), London, WC1E 6BT, UK.
⁷ Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, ON, M5T 1R8, Canada; Institute of Medical Science and Department of Psychiatry, University of Toronto, Toronto, ON, M5T 1R8, Canada.
⁸ Department of Pediatrics, Queen's University, Kingston, ON, K7L 2V7, Canada.
⁹ Department of Biochemistry, University of Vermont College of Medicine, Burlington, VT 05405, USA.
¹⁰ Department of Neurology and Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
¹¹ Department of Pediatrics, Multan Hospital, Multan, 60000, Pakistan.
¹² University of Islamabad, Islamabad, 45320, Pakistan.
¹³ Department of Pediatrics, Tripoli Children's Hospital, Tripoli, Libya.
¹⁴ Institute for Genetics and Molecular and Cellular Biology (IGBMC), University of Strasbourg, CNRS UMR7104, INSERM U1258, Illkirch, 67404, France.
¹⁵ Département de Génétique, centre de référence anomalies du développement et syndromes malformatifs, CHU de Rouen, Inserm U1245, UNIROUEN, Normandie Université, Centre Normand de Génomique et de Médecine Personnalisée, Rouen, 76031, France.
¹⁶ GeneDx, 207 Perry Parkway Gaithersburg, MD 20877, USA.
¹⁷ Bezmiâlem Vakıf Üniversitesi, Istanbul, 34093, Turkey.
¹⁸ Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500HB Nijmegen, the Netherlands; Department of Neurology, Amsterdam Neuroscience Institute, Amsterdam University Medical Center, 1105AZ Amsterdam, the Netherlands.
¹⁹ Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500HB Nijmegen, the Netherlands.
²⁰ Department of Neurology, Medisch Spectrum Twente, 7512KZ Enschede, the Netherlands.
²¹ Department of Pediatrics, Divisions of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.
²² Division of Medical Genetics, SSM Health Cardinal Glennon Children's Hospital, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
²³ Howard Hughes Medical Institute, University of California San Diego and Rady Children's Hospital, La Jolla, CA 92130, USA.
²⁴ Institute of Basic Medical Sciences, Khyber Medical University, 25100 Peshawar, Pakistan.
²⁵ Institute of Child Health, Guilford Street and Dubowitz Neuromuscular Centre, Great Ormond Street Hospital for Children, London, WC1N 3JH, UK.
²⁶ SYNAPS Study Group, see Supplemental Information for the study group members who contributed clinical cases and data.
²⁷ Department of Genetic Medicine and Development, University of Geneva, 1206 Geneva, Switzerland; Department of Endocrinology, Diabetes, and Metabolism, University Hospital of Lausanne, 1011 Lausanne, Switzerland.
²⁸ Department of Genetic Medicine and Development, University of Geneva, 1206 Geneva, Switzerland; Service of Genetic Medicine, University Hospitals of Geneva, 1205 Geneva, Switzerland; Medigenome, The Swiss Institute of Genomic Medicine, Geneva, CH-1207, Switzerland.
²⁹ Swiss Institute of Bioinformatics, Molecular Modeling Group, Batiment Genopode, Unil Sorge, Lausanne, CH-1015, Switzerland.
³⁰ Hospital for Sick Children, Division of Clinical and Metabolic Genetics, 555 University Ave., Toronto, M5G 1X8, Canada.
³¹ CeGaT GmbH and Praxis für Humangenetik Tuebingen, Tuebingen, 72076, Germany.
³² Biomedical Centre Cardinal-Wendel-Straße 14, 66424 Hamburg, Germany.
³³ University of Strasbourg, CNRS, GMGM UMR 7156, Strasbourg, 67083, France.
³⁴ University of Groningen, University Medical Center Groningen, Department of Neurology, Groningen, 9713, the Netherlands.
³⁵ Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, 6211, the Netherlands.
³⁶ Division of Child Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
³⁷ Department of Biochemistry and Molecular Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
³⁸ Jinnah Burn and Reconstructive Surgery Center, Allama Iqbal Medical College, University of Health Sciences, Lahore 54550, Pakistan.
³⁹ Department of General Pediatrics, Heinrich-Heine-University, Moorenstr. 5, 40225 Düsseldorf, Germany.
⁴⁰ Department of Genetic Medicine and Development, University of Geneva, 1206 Geneva, Switzerland; Institute of Molecular and Clinical Ophthalmology Basel, Basel Switzerland.
⁴¹ Department of Genetic Medicine and Development, University of Geneva, 1206 Geneva, Switzerland; Service of Genetic Medicine, University Hospitals of Geneva, 1205 Geneva, Switzerland; iGE3 Institute of Genetics and Genomics of Geneva, 1211 Geneva, Switzerland.
⁴² Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tübingen, Germany.
⁴³ Department of Clinical Genetics, University Hospital of Copenhagen, Rigshospitalet, 2100, Denmark.
⁴⁴ Department of Pediatrics, Section of Medical Genetics, West Virginia University, Morgantown, WV 26506-9600, USA.
⁴⁵ Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tübingen, Germany; Centre for Rare Diseases, University of Tuebingen, 72076 Tübingen, Germany.
⁴⁶ Genetics Centre, Molecular and Clinical Sciences Institute, St George's University of London, London, SW17 0RE, UK.
⁴⁷ Department of Neuromuscular Disorders, University College London (UCL) Institute of Neurology, Queen Square, London, WC1N 3BG, UK. Electronic address: h.houlden@ucl.ac.uk.

PMID: 32738225
PMCID: PMC7413890
DOI: 10.1016/j.ajhg.2020.06.016

Abstract

Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function.

Keywords: aminoacyl-tRNA synthetase; developmental delay; epilepsy; neurodevelopment; neuropathy; next generation sequencing.

PubMed Disclaimer

Conflict of interest statement

Maria J. Guillen Sacoto, Lindsay B. Henderson, Yue Si, Aida Telegrafi, and Ingrid M. Wentzensen are employees of GeneDx. The other authors declare no competing interests.

Figures

**Figure 1**
*AsnRS1* Protein Structure and Function (A) AA asparagine (Asn) is ligated to tRNA^Asn and catalyzed by AsnRS1 and ATP to produce Asn-tRNA (Asn), AMP, and pyrophosphate. (B) *NARS1* mutations and their predicted functional effect. (C) Schematic representation of human ARS1 primary structure. Three main domains are depicted: the unique domain (UNE-N), the anticodon binding domain (ABD), and the catalytic domain (CAT). The nature and position of the mutants are shown above the primary structure, *de novo* boxed in red, and the positions of the domains are indicated below, including motif 1 (involved in *AsnRS1* dimerization) and motifs 2 and 3 (which form the active site). (D) Bar graph summarizing proportions of various clinical findings affecting individuals with *NARS1* mutations.

**Figure 2**
Pedigrees of the 21 Families and 32 Affected Individuals Identified in This Study with *de novo* and Bi-allelic Mutations in *NARS1* Filled symbols represent affected individuals and double bars represent consanguinity in the family. −/−, +/−, and +/+ represent wild-type, heterozygous, and homozygous variants, respectively.

**Figure 3**
Radiological Findings of Individuals in Our Cohort Set 1: Individual homozygous for c.32G>C (p.Arg11Pro). Upper row images (coronal T2-WI [1A] and axial T1-WI [1B]) at the age of 10 months show severely delayed myelination and fronto-temporal atrophy. Lower row images (axial T2-WI [1C] and axial T1-WI [1D]) repeated at the age of 18 months show progressive and global brain atrophy with an emerging pattern of severe hypomyelination. Set 2: An additional homozygous c.32G>C (p.Arg11Pro) individual. Upper row images (axial T2-WI [2A] and axial T1-WI [2B]) at the age of 8 months show mild fronto-temporal underdevelopment and severely delayed myelination. Lower row images (axial T2-WI [2C] and axial T1-W1 [2D]) repeated at the age of 2 years shows progressive and global brain atrophy along with severe hypomyelination. Set 3: Individual homozygous for c.50C>T (p.Thr17Met). Axial fluid-attenuated inversion recovery (FLAIR) images at the age of 9 months show global atrophy involving the cerebral and cerebellar hemispheres along with severe hypomyelination. Set 4: MRI images of an individual with the homozygous c.1633C>T (p.Arg545Cyc) variant. Coronal T1-WI (4A), axial T2-WI (4B), and sagittal T1-WI (4C) at the age of 4 years; coronal T1-WI (4D), axial T2-WI (4E), and sagittal T1-WI (4F) at the age of 11 years; and coronal T2-WI (4G), axial FLAIR (4H), and sagittal T2-WI (4I) at the age of 20 years. These demonstrate normal intracranial appearances across the three different ages. This individual had an upper thoracic scoliosis, which was operatively corrected at the age of 4, demonstrated on the sagittal T2-WI of the spine (4J) and frontal projection radiograph of the chest/thoracic spine (4K).

**Figure 4**
Protein Levels of AsnRS1 Are Reduced in Individual-Derived Cells (A) RT-PCR of the *de novo* c.1600C>T (p.Arg534^∗) variant in P2 and parents (B) western blotting and (C) quantification graph of individuals with *NARS1* mutations compared with controls. Ctrl = control, P10 = homozygous c.1633C>T (p.Arg545Cys), P26 = homozygous c.50C>T (p.Thr17Met), P29 = compound heterozygous (c.1067A>C (p.Asp356Ala) and c.203dupA (p.Met69Aspfs^∗4) (F denotes father of individuals), P24 = homozygous c.32G>C (p.Arg11Pro).

**Figure 5**
BN-PAGE and iNPC RNA-Sequencing (A) iNPCs from P26 (c.50C>T [p.Thr17Met]) and P29 (c.203dupA [p.Met69Aspfs^∗4] and c.1067A>C [p.Asp356Ala]) exhibit increased expression of most iNPC markers (sox1, sox2, nestin, snail1, pax6, DKK3, twist2, and Musashi-1) compared to fibroblast (fbb) as measured by qPCR, shown with hierarchal clustering. (B) Heatmap with hierarchal clustering generated using all gene counts from RNaseq distinction of control (Ctrl1 a–c, Ctrl2 a–c) and individual-derived (P26 a–b, P29 a–c) iNPCs. (C) Volcano plot showing log2 of fold change in NARS mutant iNPCs compared to controls and −log10 (adjusted p value). (D) BN-PAGE western blot showing reduced levels of the AsnRS1 dimer in individuals P26 and P29 and fathers compared to control, but not for individual P10. (E) Quantification of BN-PAGE western blot AsnRS1 dimer formation, showing significantly (^∗∗∗p < 0.001) reduced levels of the AsnRS1 in individuals P26 and P29 and fathers compared to control but not change for P10. P26 = homozygous c.50C>T (p.Thr17Met), P29 = c.203dupA (p.Met69Aspfs^∗4), c.1067A>C (p.Asp356Ala), P10 = c.1633C>T (p.Arh545Cys), father of P26 = heterozygous c.50C>T (p.Thr17Met), father of P29 = c.1067A>C (p.Asp356Ala).

**Figure 6**
Molecular Modeling of the NARS1 p.Arg545Cys Homozygous Variant The crystal structure is based on *B.malayi* AsnRS1. AsnRS1 is a homodimer; one AsnRS1 monomer is given in yellow and one in orange. Analog of the transition state presented in the surface representation, C terminus in dark blue, Asp230 and Asp226 in cyan, Arg545 and Arg545Cys in magenta. (A) Interaction between *AsnRS1* and tRNA with residues on the helical linker. (B–E) Zoom in on the C terminus helical linker region, (B) and (E) show loss of molecular interaction and folding of the p.Arg545Cys variant (^∗).

**Figure 7**
Reduced Asparaginyl-tRNA Synthetase Activity in Individuals with Homozygous *NARS1* Variants c.1600C>T (p.Arg534^∗) (P2), c.1633C>T (p.Arg545Cys) (P9 and P20), c.32G>C (p.Arg11Pro) (P24), c.50C>T (p.Thr17Met) (P26), and c.1067A>C (p.Asp356Ala)/c.203dupA (p.M69Aspfs^∗4) (P29) *NARS1* variants in comparison to the average of three unrelated fibroblast cell lines. (All cell lines are fibroblast except P2, which is a lymphoblast cell line. Control values for lymphoblast are similar to fibroblasts.) n = 9, p value FDR < 0.01.

See this image and copyright information in PMC

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De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects

Affiliations

De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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