{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T13:01:39Z","timestamp":1793278899996,"version":"4.5.0"},"reference-count":28,"publisher":"BMJ","issue":"12","license":[{"start":{"date-parts":[[2022,8,30]],"date-time":"2022-08-30T00:00:00Z","timestamp":1661817600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Agence National de la Recherche"},{"name":"French National Programme"},{"DOI":"10.13039\/100018433","name":"Hesperia Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100018433","id-type":"DOI","asserted-by":"crossref"}]},{"name":"the Generalitat de Catalunya, the Center for Biomedical Research","award":["ACCI14-759"],"award-info":[{"award-number":["ACCI14-759"]}]},{"name":"the Generalitat de Catalunya, the Center for Biomedical Research","award":["SLT002\/16\/00174"],"award-info":[{"award-number":["SLT002\/16\/00174"]}]},{"name":"Laboratory of Excellence"},{"name":"ANR"},{"name":"CNRS"},{"DOI":"10.13039\/501100003768","name":"University of Strasbourg","doi-asserted-by":"crossref","award":["ANR-10-IDEX-0002-02"],"award-info":[{"award-number":["ANR-10-IDEX-0002-02"]}],"id":[{"id":"10.13039\/501100003768","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100008530","name":"Fondo Europeo de Desarrollo Regional","doi-asserted-by":"crossref","award":["202006-30"],"award-info":[{"award-number":["202006-30"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100008530","name":"Fondo Europeo de Desarrollo Regional","doi-asserted-by":"crossref","award":["PI20\/00758"],"award-info":[{"award-number":["PI20\/00758"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["CD19\/00221"],"award-info":[{"award-number":["CD19\/00221"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"name":"CERCA Program\/Generalitat de Catalunya"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2022,7,25]]},"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Aminoacyl-tRNA synthetases (ARS) are key enzymes catalysing the first reactions in protein synthesis, with increasingly recognised pleiotropic roles in tumourgenesis, angiogenesis, immune response and lifespan. Germline mutations in several ARS genes have been associated with both recessive and dominant neurological diseases. Recently, patients affected with microcephaly, intellectual disability and ataxia harbouring biallelic variants in the seryl-tRNA synthetase encoded by seryl-tRNA synthetase 1 (<jats:italic>SARS1<\/jats:italic>) were reported.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We used exome sequencing to identify the causal variant in a patient affected by complex spastic paraplegia with ataxia, intellectual disability, developmental delay and seizures, but without microcephaly. Complementation and serylation assays using patient\u2019s fibroblasts and an <jats:italic>Saccharomyces cerevisiae<\/jats:italic> model were performed to examine this variant\u2019s pathogenicity.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>A <jats:italic>de novo<\/jats:italic> splice site deletion in <jats:italic>SARS1<\/jats:italic> was identified in our patient, resulting in a 5-amino acid in-frame insertion near its active site. Complementation assays in <jats:italic>S. cerevisiae<\/jats:italic> and serylation assays in both yeast strains and patient fibroblasts proved a loss-of-function, dominant negative effect. Fibroblasts showed an abnormal cell shape, arrested division and increased beta-galactosidase staining along with a senescence-associated secretory phenotype (raised interleukin-6, p21, p16 and p53 levels).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>We refine the phenotypic spectrum and modes of inheritance of a newly described, ultrarare neurodevelopmental disorder, while unveiling the role of SARS1 as a regulator of cell growth, division and senescence.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmg-2022-108529","type":"journal-article","created":{"date-parts":[[2022,8,30]],"date-time":"2022-08-30T13:20:28Z","timestamp":1661865628000},"page":"1227-1233","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":11,"title":["Loss of seryl-tRNA synthetase (<i>SARS1<\/i>) causes complex spastic paraplegia and cellular 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