Your browser doesn't support javascript.
loading
Dominant NARS1 mutations causing axonal Charcot-Marie-Tooth disease expand NARS1-associated diseases.
Beijer, Danique; Marte, Sheila; Li, Jiaxin C; De Ridder, Willem; Chen, Jessie Z; Tadenev, Abigail L D; Miers, Kathy E; Deconinck, Tine; Macdonell, Richard; Marques, Wilson; De Jonghe, Peter; Pratt, Samia L; Meyer-Schuman, Rebecca; Züchner, Stephan; Antonellis, Anthony; Burgess, Robert W; Baets, Jonathan.
Afiliación
  • Beijer D; Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, B-2610, Belgium.
  • Marte S; Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Wilrijk, B-2610, Belgium.
  • Li JC; Department for Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL 33136, USA.
  • De Ridder W; Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Chen JZ; The Jackson Laboratory, Bar Harbor, ME 04609, USA.
  • Tadenev ALD; Genetics Program, Graduate School of Biomedical Sciences, Tufts University, Boston, MA 02111, USA.
  • Miers KE; Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, B-2610, Belgium.
  • Deconinck T; Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Wilrijk, B-2610, Belgium.
  • Macdonell R; Neuromuscular Reference Centre, Department of Neurology, Antwerp University Hospital, Wilrijk, B-2610, Belgium.
  • Marques W; Department of Neurology, Austin Health, Melbourne, VIC 3084, Australia.
  • De Jonghe P; The Jackson Laboratory, Bar Harbor, ME 04609, USA.
  • Pratt SL; The Jackson Laboratory, Bar Harbor, ME 04609, USA.
  • Meyer-Schuman R; Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, B-2610, Belgium.
  • Züchner S; Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Edegem, B-2650, Belgium.
  • Antonellis A; Department of Neurology, Austin Health, Melbourne, VIC 3084, Australia.
  • Burgess RW; Department of Neurosciences and Behavior Sciences, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, SP, 14051-140, Brazil.
  • Baets J; Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, B-2610, Belgium.
Brain Commun ; 6(2): fcae070, 2024.
Article en En | MEDLINE | ID: mdl-38495304
ABSTRACT
Pathogenic variants in six aminoacyl-tRNA synthetase (ARS) genes are implicated in neurological disorders, most notably inherited peripheral neuropathies. ARSs are enzymes that charge tRNA molecules with cognate amino acids. Pathogenic variants in asparaginyl-tRNA synthetase (NARS1) cause a neurological phenotype combining developmental delay, ataxia and demyelinating peripheral neuropathy. NARS1 has not yet been linked to axonal Charcot-Marie-Tooth disease. Exome sequencing of patients with inherited peripheral neuropathies revealed three previously unreported heterozygous NARS1 variants in three families. Clinical and electrophysiological details were assessed. We further characterized all three variants in a yeast complementation model and used a knock-in mouse model to study variant p.Ser461Phe. All three variants (p.Met236del, p.Cys342Tyr and p.Ser461Phe) co-segregate with the sensorimotor axonal neuropathy phenotype. Yeast complementation assays show that none of the three NARS1 variants support wild-type yeast growth when tested in isolation (i.e. in the absence of a wild-type copy of NARS1), consistent with a loss-of-function effect. Similarly, the homozygous knock-in mouse model (p.Ser461Phe/Ser472Phe in mouse) also demonstrated loss-of-function characteristics. We present three previously unreported NARS1 variants segregating with a sensorimotor neuropathy phenotype in three families. Functional studies in yeast and mouse support variant pathogenicity. Thus, NARS1 is the seventh ARS implicated in dominant axonal Charcot-Marie-Tooth disease, further stressing that all dimeric ARSs should be evaluated for Charcot-Marie-Tooth disease.
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Brain Commun Año: 2024 Tipo del documento: Article País de afiliación: Bélgica Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Brain Commun Año: 2024 Tipo del documento: Article País de afiliación: Bélgica Pais de publicación: Reino Unido