PUBLICATION

Biallelic variants in KARS1 are associated with neurodevelopmental disorders and hearing loss recapitulated by the knockout zebrafish

Authors
Lin, S.J., Vona, B., Barbalho, P.G., Kaiyrzhanov, R., Maroofian, R., Petree, C., Severino, M., Stanley, V., Varshney, P., Bahena, P., Alzahrani, F., Alhashem, A., Pagnamenta, A.T., Aubertin, G., Estrada-Veras, J.I., Hernández, H.A.D., Mazaheri, N., Oza, A., Thies, J., Renaud, D.L., Dugad, S., McEvoy, J., Sultan, T., Pais, L.S., Tabarki, B., Villalobos-Ramirez, D., Rad, A., Genomics England Research Consortium, Galehdari, H., Ashrafzadeh, F., Sahebzamani, A., Saeidi, K., Torti, E., Elloumi, H.Z., Mora, S., Palculict, T.B., Yang, H., Wren, J.D., Ben Fowler, ., Joshi, M., Behra, M., Burgess, S.M., Nath, S.K., Hanna, M.G., Kenna, M., Merritt, J.L., Houlden, H., Karimiani, E.G., Zaki, M.S., Haaf, T., Alkuraya, F.S., Gleeson, J.G., Varshney, G.K.
ID
ZDB-PUB-210629-14
Date
2021
Source
Genetics in medicine : official journal of the American College of Medical Genetics   23(10): 1933-1943 (Journal)
Registered Authors
Lin, Sheng-Jia, Varshney, Gaurav
Keywords
none
MeSH Terms
  • Alleles
  • Animals
  • Disease Models, Animal
  • Hearing Loss*/genetics
  • Humans
  • Lysine-tRNA Ligase/genetics*
  • Neurodevelopmental Disorders*/genetics
  • Phenotype
  • Zebrafish/genetics
PubMed
34172899 Full text @ Genet. Med.
Abstract
Pathogenic variants in Lysyl-tRNA synthetase 1 (KARS1) have increasingly been recognized as a cause of early-onset complex neurological phenotypes. To advance the timely diagnosis of KARS1-related disorders, we sought to delineate its phenotype and generate a disease model to understand its function in vivo.
Through international collaboration, we identified 22 affected individuals from 16 unrelated families harboring biallelic likely pathogenic or pathogenic in KARS1 variants. Sequencing approaches ranged from disease-specific panels to genome sequencing. We generated loss-of-function alleles in zebrafish.
We identify ten new and four known biallelic missense variants in KARS1 presenting with a moderate-to-severe developmental delay, progressive neurological and neurosensory abnormalities, and variable white matter involvement. We describe novel KARS1-associated signs such as autism, hyperactive behavior, pontine hypoplasia, and cerebellar atrophy with prevalent vermian involvement. Loss of kars1 leads to upregulation of p53, tissue-specific apoptosis, and downregulation of neurodevelopmental related genes, recapitulating key tissue-specific disease phenotypes of patients. Inhibition of p53 rescued several defects of kars1-/- knockouts.
Our work delineates the clinical spectrum associated with KARS1 defects and provides a novel animal model for KARS1-related human diseases revealing p53 signaling components as potential therapeutic targets.
Genes / Markers
Figures
Show all Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping