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

Germaine Pierre,Leslie A Nangle,John Paul Bouffard,Holger Prokisch,Christina Sofeso,Robert W Taylor,Frank Brasch,Tom Hilliard,Matthias Kappler,Matthias Griese,Charles A Leduc,Paul Schimmel,Woo-Kuen Lo ,Donna M Timchak ,Xiang‐Lei Yang ,Lu Zhai ,Alain C Borczuk,Matias Wagner,Luise A Schuch,Robert Kopajtich,Christoph Müller,David B Beck,Ching-Fun Lau,Monika Oláhová,Charlotte L Alston,Elias Seidl,Peter D Turnpenny,Mingjie Zhang,Andrew F Teich,Yeeting E Chong,Jane Juusola,Zhiwen Xu,Wendy K Chung

doi:10.1016/j.ajhg.2018.06.006

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.

Highlights

The universal aminoacyl tRNA synthetase family of enzymes is necessary for protein synthesis and is increasingly implicated in key signaling pathways outside of protein synthesis
We describe a novel genetic disorder with an unusual multi-organ phenotype of interstitial lung disease with cholesterol pneumonitis, intracranial aneurysms, cerebral calcifications, hypotonia, and liver cirrhosis caused by biallelic mutations in FARSB
The most consistent and life-limiting feature so far has been pulmonary disease participants were not systematically investigated for all the features observed across all individuals, and were evaluated at different ages

Summary

Introduction

The universal aminoacyl tRNA synthetase (aaRS) family of enzymes is necessary for protein synthesis and is increasingly implicated in key signaling pathways outside of protein synthesis In that connection, they have been associated with previously unrecognized human diseases and functions.[1,2,3,4,5] aaRSs have nuclear and extra-cellular activities that in some cases integrate translation with cell signaling pathways as well as functions independent of protein translation.

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