Loss of seryl-tRNA synthetase (SARS1) causes complex spastic paraplegia and cellular senescence
Verdura, Edgard (Instituto de Salud Carlos III)
Senger, Bruno (Université de Strasbourg 1)
Raspall-Chaure, Miquel (Hospital Universitari Vall d'Hebron)
Schlüter, Agatha (Instituto de Salud Carlos III)
Launay, Nathalie (Instituto de Salud Carlos III)
Ruiz, Montserrat (Instituto de Salud Carlos III)
Casasnovas, Carlos (Hospital Universitari de Bellvitge)
Rodriguez-Palmero, Agustí (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Macaya Ruiz, Alfons (Universitat Autònoma de Barcelona. Institut de Neurociències)
Becker, Hubert Dominique (Université de Strasbourg 1)
Pujol, Aurora 1968- (Institució Catalana de Recerca i Estudis Avançats)

Fecha:	2022
Resumen:	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 (SARS1) were reported. 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's fibroblasts and an Saccharomyces cerevisiae model were performed to examine this variant's pathogenicity. A de novo splice site deletion in SARS1 was identified in our patient, resulting in a 5-amino acid in-frame insertion near its active site. Complementation assays in S. cerevisiae 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). 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.
Ayudas:	Instituto de Salud Carlos III PI20/00758 Ministerio de Economía y Competitividad FJCI-2016-28811
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Sequence analysis, RNA ; Pediatrics ; Neurology ; Nervous system diseases ; Genetic research
Publicado en:	Journal of medical genetics, Vol. 59 (august 2022) , p. 1227-1233, ISSN 1468-6244

DOI: 10.1136/jmg-2022-108529
PMID: 36041817

7 p, 691.7 KB

El registro aparece en las colecciones:
Artículos > Artículos de investigación
Artículos > Artículos publicados