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

2.50
Hdl Handle:
http://hdl.handle.net/11287/620764
Title:
Bi-allelic Mutations in Phe-tRNA Synthetase Associated with a Multi-system Pulmonary Disease Support Non-translational Function.
Authors:
Xu, Z.[et al]; Turnpenny, Peter D.
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.
Citation:
Bi-allelic Mutations in Phe-tRNA Synthetase Associated with a Multi-system Pulmonary Disease Support Non-translational Function. 2018, 103 (1):100-114 Am. J. Hum. Genet.
Publisher:
Cell Press
Journal:
American journal of human genetics
Issue Date:
5-Jul-2018
URI:
http://hdl.handle.net/11287/620764
DOI:
10.1016/j.ajhg.2018.06.006
PubMed ID:
29979980
Type:
Journal Article
Language:
en
ISSN:
1537-6605
Appears in Collections:
Clinical Genetics (Peninsula Genetics); 2018 RD&E publications

Full metadata record

DC FieldValue Language
dc.contributor.authorXu, Z.[et al]en
dc.contributor.authorTurnpenny, Peter D.en
dc.date.accessioned2018-07-11T13:53:40Z-
dc.date.available2018-07-11T13:53:40Z-
dc.date.issued2018-07-05-
dc.identifier.citationBi-allelic Mutations in Phe-tRNA Synthetase Associated with a Multi-system Pulmonary Disease Support Non-translational Function. 2018, 103 (1):100-114 Am. J. Hum. Genet.en
dc.identifier.issn1537-6605-
dc.identifier.pmid29979980-
dc.identifier.doi10.1016/j.ajhg.2018.06.006-
dc.identifier.urihttp://hdl.handle.net/11287/620764-
dc.description.abstractThe 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.en
dc.language.isoenen
dc.publisherCell Pressen
dc.rightsArchived with thanks to American journal of human geneticsen
dc.subjectWessex Classification Subject Headings::Oncology. Pathology.::Geneticsen
dc.titleBi-allelic Mutations in Phe-tRNA Synthetase Associated with a Multi-system Pulmonary Disease Support Non-translational Function.en
dc.typeJournal Articleen
dc.identifier.journalAmerican journal of human geneticsen
dc.type.versionPublisheden

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