Homozygosity for a mutation affecting the catalytic domain of tyrosyl-tRNA synthetase (YARS) causes multisystem disease

Title

Homozygosity for a mutation affecting the catalytic domain of tyrosyl-tRNA synthetase (YARS) causes multisystem disease

Creator

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

Publisher

Human Molecular Genetics

Date

2019
1905-7

Description

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.

Subject

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

Identifier

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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

Citation

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, “Homozygosity for a mutation affecting the catalytic domain of tyrosyl-tRNA synthetase (YARS) causes multisystem disease,” NEOMED Bibliography Database, accessed January 24, 2021, https://neomed.omeka.net/items/show/6511.

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