Biallelic IARS Mutations Cause Growth Retardation with Prenatal Onset, Intellectual Disability, Muscular Hypotonia, and Infantile Hepatopathy

Am J Hum Genet. 2016 Aug 4;99(2):414-22. doi: 10.1016/j.ajhg.2016.05.027.

Robert Kopajtich ¹, Kei Murayama ², Andreas R Janecke ³, Tobias B Haack ¹, Maximilian Breuer ⁴, A S Knisely ⁵, Inga Harting ⁶, Toya Ohashi ⁷, Yasushi Okazaki ⁸, Daisaku Watanabe ⁹, Yoshimi Tokuzawa ¹⁰, Urania Kotzaeridou ⁴, Stefan Kölker ⁴, Sven Sauer ⁴, Matthias Carl ¹¹, Simon Straub ¹², Andreas Entenmann ¹², Elke Gizewski ¹³, René G Feichtinger ¹⁴, Johannes A Mayr ¹⁴, Karoline Lackner ¹⁵, Tim M Strom ¹, Thomas Meitinger ¹, Thomas Müller ¹², Akira Ohtake ¹⁶, Georg F Hoffmann ⁴, Holger Prokisch ¹, Christian Staufner ¹⁷

Affiliations

1 Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
2 Department of Metabolism, Chiba Children's Hospital, Chiba 266-0007, Japan; Chiba Cancer Center Research Institute, Chiba 260-8717, Japan.
3 Department of Pediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria; Division of Human Genetics, Medical University of Innsbruck, 6020 Innsbruck, Austria.
4 Department of General Pediatrics, Division of Neuropediatrics and Metabolic Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany.
5 Institute of Liver Studies, King's College Hospital, London SE5 9RS, UK; Institute of Pathology, Medical University of Graz, 8036 Graz, Austria.
6 Department of Neuroradiology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
7 Department of Pediatrics, The Jikei University School of Medicine, Tokyo 105-8461, Japan.
8 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.
9 Department of Large Animal Clinics, School of Veterinary Medicine, Kitasato University, Towada, Aomori 034-8628, Japan.
10 Division of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Saitama 350-1241, Japan.
11 Department of Cell and Molecular Biology, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany.
12 Department of Pediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria.
13 Department of Neuroradiology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
14 Department of Paediatrics, Paracelsus Medical University, SALK Salzburg, 5020 Salzburg, Austria.
15 Institute of Pathology, Medical University of Graz, 8036 Graz, Austria.
16 Department of Pediatrics, Faculty of Medicine, Saitama Medical University, Moroyama, Saitama 350-0495, Japan.
17 Department of General Pediatrics, Division of Neuropediatrics and Metabolic Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany. Electronic address: christian.staufner@med.uni-heidelberg.de.

PMID: 27426735 DOI: 10.1016/j.ajhg.2016.05.027

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.

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