Format

Send to

Choose Destination
Am J Hum Genet. 2019 Mar 7;104(3):520-529. doi: 10.1016/j.ajhg.2019.01.006. Epub 2019 Feb 26.

Cysteinyl-tRNA Synthetase Mutations Cause a Multi-System, Recessive Disease That Includes Microcephaly, Developmental Delay, and Brittle Hair and Nails.

Author information

1
Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Medical Scientist Training Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
2
Department of Molecular Genetics, Oncode Institute, Erasmus Medical Center, University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 CN Rotterdam, the Netherlands.
3
Department of Clinical Genetics, Erasmus Medical Center, University Medical Center, 3015 GD Rotterdam, the Netherlands.
4
Undiagnosed Diseases Program and Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
5
Department of Biochemistry and Molecular Biochemistry, Thomas Jefferson University, Philadelphia, PA 19107, USA.
6
Metabolic Unit, Department of Clinical Chemistry, Amsterdam University Medical Center and Amsterdam Gastroenterology and Metabolism, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, 1081 HZ Amsterdam, the Netherlands.
7
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
8
Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Neurology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: antonell@umich.edu.
9
Metabolic Unit, Department of Clinical Chemistry, Amsterdam University Medical Center and Amsterdam Gastroenterology and Metabolism, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, 1081 HZ Amsterdam, the Netherlands; Genetic Metabolic Diseases, Amsterdam University Medical Center, University of Amsterdam, 1081 HZ Amsterdam, the Netherlands. Electronic address: g.salomons@vumc.nl.

Abstract

Aminoacyl-tRNA synthetases (ARSs) are essential enzymes responsible for charging tRNA molecules with cognate amino acids. Consistent with the essential function and ubiquitous expression of ARSs, mutations in 32 of the 37 ARS-encoding loci cause severe, early-onset recessive phenotypes. Previous genetic and functional data suggest a loss-of-function mechanism; however, our understanding of the allelic and locus heterogeneity of ARS-related disease is incomplete. Cysteinyl-tRNA synthetase (CARS) encodes the enzyme that charges tRNACys with cysteine in the cytoplasm. To date, CARS variants have not been implicated in any human disease phenotype. Here, we report on four subjects from three families with complex syndromes that include microcephaly, developmental delay, and brittle hair and nails. Each affected person carries bi-allelic CARS variants: one individual is compound heterozygous for c.1138C>T (p.Gln380) and c.1022G>A (p.Arg341His), two related individuals are compound heterozygous for c.1076C>T (p.Ser359Leu) and c.1199T>A (p.Leu400Gln), and one individual is homozygous for c.2061dup (p.Ser688Glnfs2). Measurement of protein abundance, yeast complementation assays, and assessments of tRNA charging indicate that each CARS variant causes a loss-of-function effect. Compared to subjects with previously reported ARS-related diseases, individuals with bi-allelic CARS variants are unique in presenting with a brittle-hair-and-nail phenotype, which most likely reflects the high cysteine content in human keratins. In sum, our efforts implicate CARS variants in human inherited disease, expand the locus and clinical heterogeneity of ARS-related clinical phenotypes, and further support impaired tRNA charging as the primary mechanism of recessive ARS-related disease.

KEYWORDS:

aminoacyl-tRNA synthetase; cysteinyl-tRNA synthetase; developmental delay; microcephaly; peripheral neuropathy; recessive disease

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center