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Hum Mol Genet. 2018 Oct 9. doi: 10.1093/hmg/ddy344. [Epub ahead of print]

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

Author information

1
Clinic for Special Children, Strasburg, PA, USA.
2
Regeneron Genetics Center, Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA.
3
Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI, USA.
4
Medical Scientist Training Program, University of Michigan, Ann Arbor, MI, USA.
5
Department of Biology, Biological Foundations of Behavior Program, Franklin & Marshall College, Lancaster, PA, USA.
6
New Leaf Center, Mount Eaton, OH, USA.
7
Department of Pediatrics, Akron Children's Hospital, Akron, OH, USA.
8
Northeast Ohio Medical University, Rootstown, OH, USA.
9
Department of Medical Imaging, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA.
10
Department of Pediatrics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA.
11
Department of Pediatrics, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, USA.
12
Division of Pediatric Gastroenterology, Department of Pediatrics, Mayo Clinic, Rochester, MN, USA.
13
Division of Pediatric Gastroenterology, Department of Pediatrics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA.
14
Department of Pathology and Laboratory Medicine, Nemours/Alfred I. duPont Hospital for Children, Orlando FL, USA.
15
Department of Gastroenterology, Children's Hospital at Cleveland Clinic, Cleveland, OH USA.
16
Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA.
17
Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.

Abstract

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.

PMID:
30304524
DOI:
10.1093/hmg/ddy344

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