Bögershausen N1, Krawczyk HE1, Jamra RA2, Lin SJ3, Yigit G1, Hüning I4, Polo AM5, Vona B1 6, Huang K3, Schmidt J1, Altmüller J7 8 9, Luppe J2, Platzer K2, Dörgeloh BB10, Busche A11, Biskup S12, Mendes MI13, Smith DEC13, Salomons GS13, Zibat A1, Bültmann E14, Nürnberg P7 15, Spielmann M4, Lemke JR2, Li Y1, Zenker M16, Varshney GK3, Hillen HS17 18 19, Kratz CP10, Wollnik B1 19 20
Aminoacylation of transfer RNA (tRNA) is a key step in protein biosynthesis, carried out by highly specific aminoacyl-tRNA synthetases (ARSs). ARSs have been implicated in autosomal dominant and autosomal recessive human disorders. Autosomal dominant variants in tryptophanyl-tRNA synthetase 1 (WARS1) are known to cause distal hereditary motor neuropathy and Charcot-Marie-Tooth disease, but a recessively inherited phenotype is yet to be clearly defined. Seryl-tRNA synthetase 1 (SARS1) has rarely been implicated in an autosomal recessive developmental disorder. Here, we report five individuals with biallelic missense variants in WARS1 or SARS1, who presented with an overlapping phenotype of microcephaly, developmental delay, intellectual disability, and brain anomalies. Structural mapping showed that the SARS1 variant is located directly within the enzyme’s active site, most likely diminishing activity, while the WARS1 variant is located in the N-terminal domain. We further characterize the identified WARS1 variant by showing that it negatively impacts protein abundance and is unable to rescue the phenotype of a CRISPR/Cas9 wars1 knockout zebrafish model. In summary, we describe two overlapping autosomal recessive syndromes caused by variants in WARS1 and SARS1, present functional insights into the pathogenesis of the WARS1-related syndrome and define an emerging disease spectrum: ARS-related developmental disorders with or without microcephaly.
Keywords: ARS; CRISPR/Cas9; SARS1; WARS1; aminoacyl-tRNA synthetase; aminoacylation; intellectual disability; microcephaly; tRNA; zebrafish.
- Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany.
- Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
- Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
- Institut für Humangenetik, Universitätsklinikum Schleswig-Holstein, Lübeck, Germany.
- MVZ Labor Krone, Filialpraxis für Humangenetik, Bielefeld, Germany.
- Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany.
- Cologne Center for Genomics (CCG), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
- Core Facility Genomics, Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany.
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
- Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
- Institut für Humangenetik, Westfälische Wilhelms-Universität Münster, Münster, Germany.
- CeGaT GmbH, Center for Genomics and Transcriptomics, Tübingen, Germany.
- Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology and Metabolism, Amsterdam Neuroscience, Amsterdam UMC, Amsterdam, Netherlands.
- Institute of Diagnostic and Interventional Neuroradiology, Hannover Medical School, Hannover, Germany.
- Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
- Institute of Human Genetics, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
- Research Group Structure and Function of Molecular Machines, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.
- Department of Cellular Biochemistry, University Medical Center Göttingen, Göttingen, Germany.
- Cluster of Excellence “Multiscale Bioimaging: From Molecular Machines to Networks of Excitable cells” (MBExC), University of Göttingen, Göttingen, Germany.
- DZHK (German Centre for Cardiovascular Research), Partner Site Göttingen, Göttingen, Germany.