title: Biallelic IARS Mutations Cause Growth Retardation with Prenatal Onset, Intellectual Disability, Muscular Hypotonia, and Infantile Hepatopathy.
abstract: tRNA synthetase deficiencies are a growing group of genetic diseases associated with tissue-specific, mostly neurological, phenotypes. In cattle, cytosolic isoleucyl-tRNA synthetase (IARS) missense mutations cause hereditary weak calf syndrome. Exome sequencing in three unrelated individuals with severe prenatal-onset growth retardation, intellectual disability, and muscular hypotonia revealed biallelic mutations in IARS. Studies in yeast confirmed the pathogenicity of identified mutations. Two of the individuals had infantile hepatopathy with fibrosis and steatosis, leading in one to liver failure in the course of infections. Zinc deficiency was present in all affected individuals and supplementation with zinc showed a beneficial effect on growth in one.
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Kopajtich
authors.affiliation: Department of Metabolism, Chiba Children's Hospital, Chiba 266-0007, Japan; Chiba Cancer Center Research Institute, Chiba 260-8717, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Murayama
authors.affiliation: Department of Pediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria; Division of Human Genetics, Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Andreas R
authors.initials: AR
authors.lastname: Janecke
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Haack
authors.affiliation: Department of General Pediatrics, Division of Neuropediatrics and Metabolic Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Breuer
authors.affiliation: Institute of Liver Studies, King's College Hospital, London SE5 9RS, UK; Institute of Pathology, Medical University of Graz, 8036 Graz, Austria.
authors.forename: A S
authors.initials: AS
authors.lastname: Knisely
authors.affiliation: Department of Neuroradiology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Harting
authors.affiliation: Department of Pediatrics, The Jikei University School of Medicine, Tokyo 105-8461, Japan.
authors.forename: Toya
authors.initials: T
authors.lastname: Ohashi
authors.affiliation: Division of Translational Research, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Saitama 350-1241, Japan; Division of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Saitama 350-1241, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Okazaki
authors.affiliation: Department of Large Animal Clinics, School of Veterinary Medicine, Kitasato University, Towada, Aomori 034-8628, Japan.
authors.forename: Daisaku
authors.initials: D
authors.lastname: Watanabe
authors.affiliation: Division of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Saitama 350-1241, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Tokuzawa
authors.affiliation: Department of General Pediatrics, Division of Neuropediatrics and Metabolic Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Urania
authors.initials: U
authors.lastname: Kotzaeridou
authors.affiliation: Department of General Pediatrics, Division of Neuropediatrics and Metabolic Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kölker
authors.affiliation: Department of General Pediatrics, Division of Neuropediatrics and Metabolic Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Sauer
authors.affiliation: Department of Cell and Molecular Biology, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Carl
authors.affiliation: Department of Pediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Simon
authors.initials: S
authors.lastname: Straub
authors.affiliation: Department of Pediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Entenmann
authors.affiliation: Department of Neuroradiology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Elke
authors.initials: E
authors.lastname: Gizewski
authors.affiliation: Department of Paediatrics, Paracelsus Medical University, SALK Salzburg, 5020 Salzburg, Austria.
authors.forename: René G
authors.initials: RG
authors.lastname: Feichtinger
authors.affiliation: Department of Paediatrics, Paracelsus Medical University, SALK Salzburg, 5020 Salzburg, Austria.
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Mayr
authors.affiliation: Institute of Pathology, Medical University of Graz, 8036 Graz, Austria.
authors.forename: Karoline
authors.initials: K
authors.lastname: Lackner
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.affiliation: Department of Pediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Müller
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Saitama Medical University, Moroyama, Saitama 350-0495, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ohtake
authors.affiliation: Department of General Pediatrics, Division of Neuropediatrics and Metabolic Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Georg F
authors.initials: GF
authors.lastname: Hoffmann
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.affiliation: Department of General Pediatrics, Division of Neuropediatrics and Metabolic Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany. Electronic address: christian.staufner@med.uni-heidelberg.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Staufner
mesh_terms: D000293:Adolescent; D000483:Alleles; D000818:Animals; D002648:Child; D002675:Child, Preschool; D019587:Dietary Supplements; D005234:Fatty Liver / Q000235:genetics; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics*; D005355:Fibrosis / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000235:genetics*; D007533:Isoleucine-tRNA Ligase / Q000172:deficiency / Q000235:genetics*; D008107:Liver Diseases / Q000151:congenital* / Q000235:genetics*; D017093:Liver Failure / Q000235:genetics; D008297:Male; D009123:Muscle Hypotonia / Q000151:congenital* / Q000235:genetics*; D009154:Mutation; D013577:Syndrome; D015027:Zebrafish / Q000235:genetics; D015032:Zinc / Q000008:administration & dosage / Q000172:deficiency / Q000627:therapeutic use
chemical_list: D007533:Isoleucine-tRNA Ligase; D015032:Zinc