1
40
1
-
Text
A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text.
URL Address
<a href="http://doi.org/10.1093/hmg/ddy344" target="_blank" rel="noreferrer noopener">http://doi.org/10.1093/hmg/ddy344</a>
Rights
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Pages
525-538
Issue
4
Volume
28
Search for Full-text
Locate full-text within NEOMED Library's e-journal collections
<p>Users with a NEOMED Library login can search for full-text journal articles at the following url: <a href="https://libraryguides.neomed.edu/home">https://libraryguides.neomed.edu/home</a></p>
Dublin Core
The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/.
Title
A name given to the resource
Homozygosity for a mutation affecting the catalytic domain of tyrosyl-tRNA synthetase (YARS) causes multisystem disease
Publisher
An entity responsible for making the resource available
Human Molecular Genetics
Date
A point or period of time associated with an event in the lifecycle of the resource
2019
1905-7
Subject
The topic of the resource
Adult; Biochemistry & Molecular Biology; Catalytic Domain; Child; Female; gene; Genetic Diseases; Genetic Predisposition to Disease; Genetics & Heredity; Hearing Loss; Heterozygote; Homozygote; Humans; impairment; Inborn; Infant; lactic-acidosis; Loss of Function Mutation; Male; mechanisms; Mutation; myopathy; Newborn; onset; Pedigree; Phenotype; phenotypic variability; Preschool; recessive mutations; Sensorineural; Severity of Illness Index; swiss-model; Tyrosine-tRNA Ligase; variant; Whole Exome Sequencing; Yeasts
Creator
An entity primarily responsible for making the resource
Williams Katie B; Brigatti Karlla W; Puffenberger Erik G; Gonzaga-Jauregui Claudia; Griffin Laurie B; Martinez Erick D; Wenger Olivia K; Yoder Mark A; Kandula Vinay V R; Fox Michael D; Demczko Matthew M; Poskitt Laura; Furuya Katryn N; Reid Jeffrey G; Overton John D; Baras Aris; Miles Lili; Radhakrishnan Kadakkal; Carson Vincent J; Antonellis Anthony; Jinks Robert N; Strauss Kevin A
Description
An account of the resource
Aminoacyl-tRNA synthetases (ARSs) are critical for protein translation. Pathogenic variants of ARSs have been previously associated with peripheral neuropathy and multisystem disease in heterozygotes and homozygotes, respectively. We report seven related children homozygous for a novel mutation in tyrosyl-tRNA synthetase (YARS, c.499C > A, p.Pro167Thr) identified by whole exome sequencing. This variant lies within a highly conserved interface required for protein homodimerization, an essential step in YARS catalytic function. Affected children expressed a more severe phenotype than previously reported, including poor growth, developmental delay, brain dysmyelination, sensorineural hearing loss, nystagmus, progressive cholestatic liver disease, pancreatic insufficiency, hypoglycemia, anemia, intermittent proteinuria, recurrent bloodstream infections and chronic pulmonary disease. Related adults heterozygous for YARS p.Pro167Thr showed no evidence of peripheral neuropathy on electromyography, in contrast to previous reports for other YARS variants. Analysis of YARS p.Pro167Thr in yeast complementation assays revealed a loss-of-function, hypomorphic allele that significantly impaired growth. Recombinant YARS p.Pro167Thr demonstrated normal subcellular localization, but greatly diminished ability to homodimerize in human embryonic kidney cells. This work adds to a rapidly growing body of research emphasizing the importance of ARSs in multisystem disease and significantly expands the allelic and clinical heterogeneity of YARS-associated human disease. A deeper understanding of the role of YARS in human disease may inspire innovative therapies and improve care of affected patients.
Identifier
An unambiguous reference to the resource within a given context
<a href="http://doi.org/10.1093/hmg/ddy344" target="_blank" rel="noreferrer noopener">10.1093/hmg/ddy344</a>
2019
Adult
Antonellis Anthony
Baras Aris
Biochemistry & Molecular Biology
Brigatti Karlla W
Carson Vincent J
Catalytic Domain
Child
Demczko Matthew M
Female
Fox Michael D
Furuya Katryn N
gene
Genetic Diseases
Genetic Predisposition to Disease
Genetics & Heredity
Gonzaga-Jauregui Claudia
Griffin Laurie B
Hearing Loss
Heterozygote
Homozygote
Human molecular genetics
Humans
impairment
Inborn
Infant
Jinks Robert N
Kandula Vinay V R
lactic-acidosis
Loss of Function Mutation
Male
Martinez Erick D
mechanisms
Miles Lili
Mutation
myopathy
NEOMED College of Medicine Student
NEOMED Student Publications
Newborn
onset
Overton John D
Pedigree
Phenotype
phenotypic variability
Poskitt Laura
Preschool
Puffenberger Erik G
Radhakrishnan Kadakkal
recessive mutations
Reid Jeffrey G
Sensorineural
September 2019 Update
Severity of Illness Index
Strauss Kevin A
swiss-model
Tyrosine-tRNA Ligase
variant
Wenger Olivia K
Whole Exome Sequencing
Williams Katie B
Yeasts
Yoder Mark A