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Open Access Highly Accessed Research article

Rare recessive loss-of-function methionyl-tRNA synthetase mutations presenting as a multi-organ phenotype

Eline van Meel1, Daniel J Wegner2, Paul Cliften3, Marcia C Willing4, Frances V White5, Stuart Kornfeld1 and F Sessions Cole2*

Author Affiliations

1 Division of Hematology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA

2 Division of Newborn Medicine, Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA

3 Genome Technology Access Center, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA

4 Division of Genetics & Genomics Medicine, Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA

5 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA

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BMC Medical Genetics 2013, 14:106  doi:10.1186/1471-2350-14-106

Published: 8 October 2013

Abstract

Background

Methionyl-tRNA synthetase (MARS) catalyzes the ligation of methionine to its cognate transfer RNA and therefore plays an essential role in protein biosynthesis.

Methods

We used exome sequencing, aminoacylation assays, homology modeling, and immuno-isolation of transfected MARS to identify and characterize mutations in the methionyl-tRNA synthetase gene (MARS) in an infant with an unexplained multi-organ phenotype.

Results

We identified compound heterozygous mutations (F370L and I523T) in highly conserved regions of MARS. The parents were each heterozygous for one of the mutations. Aminoacylation assays documented that the F370L and I523T MARS mutants had 18 ± 6% and 16 ± 6%, respectively, of wild-type activity. Homology modeling of the human MARS sequence with the structure of E. coli MARS showed that the F370L and I523T mutations are in close proximity to each other, with residue I523 located in the methionine binding pocket. We found that the F370L and I523T mutations did not affect the association of MARS with the multisynthetase complex.

Conclusion

This infant expands the catalogue of inherited human diseases caused by mutations in aminoacyl-tRNA synthetase genes.

Keywords:
Methionyl-tRNA synthetase; Loss-of-function mutations; Aminoacylation