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Eur J Med Genet. 2018 Oct;61(10):616-620. doi: 10.1016/j.ejmg.2018.04.005. Epub 2018 Apr 12.

MARS variant associated with both recessive interstitial lung and liver disease and dominant Charcot-Marie-Tooth disease.

Author information

1
Department of Pediatrics, Hadassah Ein-Kerem Medical Center, Jerusalem, Israel.
2
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, United States.
3
Pediatric Pulmonology Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
4
Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
5
Pediatric Hematology, Shaare Zedek Medical Center, Hebrew University, Jerusalem, Israel.
6
Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. Electronic address: elpeleg@hadassah.org.il.
7
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, United States; Department of Neurology, University of Michigan Medical School, Ann Arbor, MI, United States.
8
Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. Electronic address: tamarhe@hadassah.org.il.

Abstract

Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes responsible for charging tRNA with cognate amino acids during protein translation. Non-canonical functions are increasingly recognized, and include transcription and translation control and extracellular signaling. Monoallelic mutations in genes encoding several ARSs have been identified in axonal Charcot-Marie-Tooth (CMT2) disease, whereas biallelic mutations in ARS loci have been associated with multi-tissue syndromes, variably involving the central nervous system, lung, and liver. We report a male infant of non-consanguineous origin, presenting with successive onset of transfusion-dependent anemia, hypothyroidism, cholestasis, interstitial lung disease, and developmental delay. Whole-exome sequencing (WES) revealed compound heterozygosity for two variants (p.Tyr307Cys and p.Arg618Cys) in MARS, encoding methionyl-tRNA synthetase. Biallelic MARS mutations are associated with interstitial lung and liver disease (ILLD). Interestingly, the p.Arg618Cys variant, inherited from an unaffected father, was previously reported in a family with autosomal dominant late-onset CMT2. Yeast complementation assays confirmed pathogenicity of p.Arg618Cys, yet suggested retained function of p.Tyr307Cys. Our findings underscore the phenotypic variability associated with ARS mutations, and suggest genetic or environmental modifying factors in the onset of monoallelic MARS-associated CMT2.

KEYWORDS:

Aminoacyl-tRNA synthetases; Interstitial lung and liver disease; MARS; Whole exome sequencing

PMID:
29655802
PMCID:
PMC6133759
[Available on 2019-10-01]
DOI:
10.1016/j.ejmg.2018.04.005
[Indexed for MEDLINE]

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