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

Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function

“…Many ARS encoding genes such as GARS1 , HARS, VARS1 , KARS1 have been studied in zebrafish to understand their function (Lin et al, 2021; Malissovas et al, 2016; Siekierska et al, 2019; Waldron et al, 2019). Recently, a zebrafish model for bifunctional tRNA synthetase, Kars1 has been shown to recapitulate key clinical symptoms, and kars1 knockout animals showed increased expression of genes related to p53 signaling and apoptosis that leads to downregulation of key myelin‐related genes (Lin et al, 2021). Similarly, a knockout model for vars1 recapitulates microcephaly, and developmental encephalopathy caused by biallelic variants in VARS (Siekierska et al, 2019).…”

“…The single guide RNAs (sgRNAs) were synthesized as described previously (Varshney et al, 2016). A mixture containing 1 μl of 40 μM Cas9‐NLS protein (UC Berkeley QB3 Macrolab), 500 ng of each sgRNA (in 3 μl), and 2 μl of 1 M potassium chloride was injected into one‐cell‐stage wild‐type NHGRI‐1 genetic background or transgenic line Tg(pou4f3:GAP‐GFP) (Xiao et al, 2005) embryos as described previously (LaFave et al, 2014; Lin et al, 2021).…”

“…The head and eye sizes were measured directly from scale‐calibrated images using ImageJ software and the size measurements were calculated in percentage of mean value of uninjected embryos. HC stereocilia of the inner ear and muscle fibers were stained for F‐actin with fluorescently labeled (FITC) phalloidin dye at 5 and 8 dpf, respectively, as described earlier (Lin et al, 2021). Whole‐mount FM1‐43 (Invitrogen) staining was used to investigate the function of HCs in sensory lateral line neuromasts.…”

WARS1 and SARS1 : Two tRNA synthetases implicated in autosomal recessive microcephaly

“…Knock‐down efficiency was confirmed by Quantitative reverse transcription polymerase chain reaction (RT‐qPCR) (Supporting Information: Figure ). Phenotyping was performed as described in previous methods (Lin et al, 2021). For size measurements, the mean values of head size and eye size of uninjected embryos were set as 100% and then comparative percentages were calculated for each other group ( wars1 F0, F0 + WT, and F0 + Arg133Cys).…”

Aminoacyl-tRNA synthetases of the multi-tRNA synthetase complex and their role in tumorigenesis

“…The KARS1 P200L mutation site is close to Ser207, the residue that when phosphorylated causes release from MSC, consistent with a role of local structure in MSC retention. Other neurological disease-causing KARS1 mutations including Phe127Leu and Pro297Ala, reduce dimerization; as KARS1 is present as a dimer in the MSC, reduced dimerization might influence its localization [176] . Mutations in AIMPs 1 and 2 have been observed in neurodegenerative diseases, whereas multiple point mutations in AIMP3 (Thr35/Ser40, Thr76, Thr80, Ser87, Val106 and Arg144) are seen in chronic myeloid leukemia patients.…”