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

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 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.

Aberrant induction of p19Arf-mediated cellular senescence contributes to neurodevelopmental defects

“…Among these, we identify tRNA regulation as one of the most significantly restored pathways in the absence of p19 Arf . Importantly, p19 Arf can directly block tRNA synthesis (27), while disruption of tRNA function is strongly associated with microcephaly and neurodevelopmental disorders (26,(28)(29)(30)(31)(32). Together, our findings support that VPA induction of p19 Arf -mediated senescence causes a broad repression of key developmental pathways, including tRNA function, thereby disrupting early neurodevelopmental steps.…”

Nucleolar TFIIE plays a role in ribosomal biogenesis and performance

“…We here extend this classification, and highlight a possible contribution of protein translation disturbances in the pathophysiology of TTD. Recently, mutations in aminoacyl-tRNA synthetases were identified to cause TTD (Kuo et al, 2019, Theil et al, 2019) implying that a disturbed translation process, as shown in this study, might be causal for the developmental delay and neurodegeneration observed in TTD. This assumption is based on the hypothesis that only disturbances in a common cellular signaling pathway that is affected by all genes in this genotypical heterogenous disease can explain the phenotype.…”

FARS1‐related disorders caused by bi‐allelic mutations in cytosolic phenylalanyl‐tRNA synthetase genes: Look beyond the lungs!

“…More than 60 disorders are associated with mutations in ARS genes and, depending on their individual genotype, follow both dominant or recessive inheritance patterns. [4][5][6][7][8][9][10] Cytosolic phenylalanyl-tRNA synthetase (FARS1) ranks among the most complex of the ARSs with a hetero-tetrameric structure, consisting of two FARS alpha (FARSA) and two FARS beta (FARSB) subunits. 11 The hypothesis that both genes may be associated with a similar multisystemic human disease, including features of interstitial lung disease, liver disease, neurological manifestations, and growth restriction (MIM: 619013, 613 658), needs further support.…”