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

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 synthet...

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Published in:	American journal of human genetics Vol. 103; no. 1; pp. 100 - 114
Main Authors:	Xu, Zhiwen, Lo, Wing-Sze, Beck, David B., Schuch, Luise A., Oláhová, Monika, Kopajtich, Robert, Chong, Yeeting E., Alston, Charlotte L., Seidl, Elias, Zhai, Liting, Lau, Ching-Fun, Timchak, Donna, LeDuc, Charles A., Borczuk, Alain C., Teich, Andrew F., Juusola, Jane, Sofeso, Christina, Müller, Christoph, Pierre, Germaine, Hilliard, Tom, Turnpenny, Peter D., Wagner, Matias, Kappler, Matthias, Brasch, Frank, Bouffard, John Paul, Nangle, Leslie A., Yang, Xiang-Lei, Zhang, Mingjie, Taylor, Robert W., Prokisch, Holger, Griese, Matthias, Chung, Wendy K., Schimmel, Paul
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 05-07-2018 Elsevier
Subjects:	Adolescent Alleles Amino Acyl-tRNA Synthetases - genetics bi-allelic mutation cerebral calcifications Charcot-Marie-Tooth Disease - genetics Child, Preschool cholesterol pneumonitis exome sequencing Female Genes, Recessive - genetics Heterozygote Humans Infant interstitial lung disease Lung Diseases - genetics Male missense mutation multi-system disease Mutation - genetics non-canonical function non-coding variant Protein Biosynthesis - genetics tRNA synthetase cerebral calcifications exome sequencing bi-allelic mutation cholesterol pneumonitis interstitial lung disease non-coding variant tRNA synthetase missense mutation multi-system disease non-canonical function
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work
ISSN:	0002-9297 1537-6605
DOI:	10.1016/j.ajhg.2018.06.006