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

Autor: Grazia M.S. Mancini, Wim Vermeulen, Rebecca Meyer-Schuman, Marjon van Slegtenhorst, Marisa I. Mendes, Catherine Groden, Shino Shimada, Thomas Christian, Anja Raams, Desirée E.C. Smith, Ya-Ming Hou, L.M. Hussaarts-Odijk, Gajja S. Salomons, May Christine V. Malicdan, Martina Wilke, Molly E. Kuo, Eric van der Meijden, Anthony Antonellis, Arjan F. Theil, William A. Gahl, Frans W. Verheijen, Anneke Kievit, Wendy J. Introne
Přispěvatelé: AGEM - Inborn errors of metabolism, AGEM - Endocrinology, metabolism and nutrition, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Clinical chemistry, Amsterdam Reproduction & Development (AR&D), Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology Endocrinology Metabolism, Molecular Genetics, Clinical Genetics
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: Kuo, M E, Theil, A F, Kievit, A, Malicdan, M C, Introne, W J, Christian, T, Verheijen, F W, Smith, D E C, Mendes, M I, Hussaarts-Odijk, L, van der Meijden, E, van Slegtenhorst, M, Wilke, M, Vermeulen, W, Raams, A, Groden, C, Shimada, S, Meyer-Schuman, R, Hou, Y M, Gahl, W A, Antonellis, A, Salomons, G S & Mancini, G M S 2019, ' Cysteinyl-tRNA Synthetase Mutations Cause a Multi-System, Recessive Disease That Includes Microcephaly, Developmental Delay, and Brittle Hair and Nails ', American journal of human genetics, vol. 104, no. 3, pp. 520-529 . https://doi.org/10.1016/j.ajhg.2019.01.006
American journal of human genetics, 104(3), 520-529. Cell Press
American Journal of Human Genetics, 104(3), 520-529. Cell Press
ISSN: 0002-9297
DOI: 10.1016/j.ajhg.2019.01.006
Popis: 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 tRNA Cys 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.Ser688Glnfs ∗ 2). 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.
Databáze: OpenAIRE
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