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

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.

journal_name

Am J Hum Genet

journal_title

American journal of human genetics

authors

Xu Z,Lo WS,Beck DB,Schuch LA,Oláhová M,Kopajtich R,Chong YE,Alston CL,Seidl E,Zhai L,Lau CF,Timchak D,LeDuc CA,Borczuk AC,Teich AF,Juusola J,Sofeso C,Müller C,Pierre G,Hilliard T,Turnpenny PD,Wagner M,Kappler

doi

10.1016/j.ajhg.2018.06.006

subject

Has Abstract

pub_date

2018-07-05 00:00:00

pages

100-114

issue

1

eissn

0002-9297

issn

1537-6605

pii

S0002-9297(18)30199-X

journal_volume

103

pub_type

杂志文章

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