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Am J Hum Genet. 2018 Jul 5;103(1):100-114. doi: 10.1016/j.ajhg.2018.06.006.

Bi-allelic Mutations in Phe-tRNA Synthetase Associated with a Multi-system Pulmonary Disease Support Non-translational Function.

Author information

1
IAS HKUST - Scripps R&D Laboratory, Institute for Advanced Study, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China; Pangu Biopharma, Edinburgh Tower, The Landmark, 15 Queen's Road Central, Hong Kong, China; aTyr Pharma, 3545 John Hopkins Court, Suite 250, San Diego, CA 92121, USA.
2
IAS HKUST - Scripps R&D Laboratory, Institute for Advanced Study, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China; Pangu Biopharma, Edinburgh Tower, The Landmark, 15 Queen's Road Central, Hong Kong, China.
3
Department of Medicine, Columbia University, New York, NY 10032, USA; National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
4
Dr. von Hauner Children's Hospital, Division of Pediatric Pneumology, University Hospital Munich, German Center for Lung Research (DZL), Lindwurmstr. 4, 80337 München, Germany.
5
Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
6
Institute of Human Genetics, Technical University Munich, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
7
aTyr Pharma, 3545 John Hopkins Court, Suite 250, San Diego, CA 92121, USA.
8
IAS HKUST - Scripps R&D Laboratory, Institute for Advanced Study, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
9
Department of Pediatrics, Columbia University, New York, NY 10032, USA; Goryeb Children's Hospital, Atlantic Health System, Morristown, NJ 07960, USA.
10
Department of Pediatrics, Columbia University, New York, NY 10032, USA.
11
Department of Pathology, Weill Cornell Medicine, New York, NY 10065, USA.
12
Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY 10032, USA.
13
GeneDx, Gaithersburg, MD 20877, USA.
14
Center for Human Genetics and Laboratory Diagnostics (AHC) Dr. Klein, Dr. Rost and Colleagues, Lochhamer Str. 29, 82152 Martinsried, Germany.
15
Department of Pediatrics and Adolescent Medicine, University Medical Center, Medical Faculty, University of Freiburg, 79085 Freiburg, Germany.
16
Bristol Royal Hospital for Children, University Hospitals Bristol NHS Foundation Trust, Bristol BS2 8BJ, UK.
17
Royal Devon & Exeter NHS Foundation Trust, Exeter EX2 5DW, UK.
18
Institute of Human Genetics, Technical University Munich, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Ingolstädter Landstr. 1, 85764 Neuherberg, Germany; Institut für Neurogenomik, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
19
Klinikum Bielefeld Mitte, Institute for Pathology, Teutoburger Straße 50, 33604 Bielefeld, Germany.
20
Department Pathology, Morristown Memorial Hospital, Morristown, NJ 07960, USA.
21
IAS HKUST - Scripps R&D Laboratory, Institute for Advanced Study, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China; The Scripps Laboratories for tRNA Synthetase Research, The Scripps Research Institute, 10650 North Torrey Pines Road, La Jolla, CA 92037, USA; Department of Molecular Medicine, The Scripps Research Insitute, La Jolla, CA 92037, USA.
22
IAS HKUST - Scripps R&D Laboratory, Institute for Advanced Study, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China; Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
23
Department of Medicine, Columbia University, New York, NY 10032, USA; Department of Pediatrics, Columbia University, New York, NY 10032, USA. Electronic address: wkc15@cumc.columbia.edu.
24
IAS HKUST - Scripps R&D Laboratory, Institute for Advanced Study, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China; The Scripps Laboratories for tRNA Synthetase Research, The Scripps Research Institute, 10650 North Torrey Pines Road, La Jolla, CA 92037, USA; The Scripps Laboratories for tRNA Synthetase Research, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, USA. Electronic address: schimmel@scripps.edu.

Abstract

The tRNA synthetases catalyze the first step of protein synthesis and have increasingly been studied for their nuclear and extra-cellular ex-translational activities. Human genetic conditions such as Charcot-Marie-Tooth have been attributed to dominant gain-of-function mutations in some tRNA synthetases. Unlike dominantly inherited gain-of-function mutations, recessive loss-of-function mutations can potentially elucidate ex-translational activities. We present here five individuals from four families with a multi-system disease associated with bi-allelic mutations in FARSB that encodes the beta chain of the alpha2beta2 phenylalanine-tRNA synthetase (FARS). Collectively, the mutant alleles encompass a 5'-splice junction non-coding variant (SJV) and six missense variants, one of which is shared by unrelated individuals. The clinical condition is characterized by interstitial lung disease, cerebral aneurysms and brain calcifications, and cirrhosis. For the SJV, we confirmed exon skipping leading to a frameshift associated with noncatalytic activity. While the bi-allelic combination of the SJV with a p.Arg305Gln missense mutation in two individuals led to severe disease, cells from neither the asymptomatic heterozygous carriers nor the compound heterozygous affected individual had any defect in protein synthesis. These results support a disease mechanism independent of tRNA synthetase activities in protein translation and suggest that this FARS activity is essential for normal function in multiple organs.

KEYWORDS:

bi-allelic mutation; cerebral calcifications; cholesterol pneumonitis; exome sequencing; interstitial lung disease; missense mutation; multi-system disease; non-canonical function; non-coding variant; tRNA synthetase

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