Impairment of the tRNA-splicing endonuclease subunit 54 (tsen54) gene causes neurological abnormalities and larval death in zebrafish models of pontocerebellar hypoplasia

• DOI: 10.1093/hmg/ddr034
• Publication Date: 2011-01-28T03:24:24Z
• Authors: Paul R. Kasher; Yasmin Namavar; Paula van Tijn; Kees Fluiter; Aleksander Sizarov; Maarten Kamermans; Andrew J. Grierson; Danica Zivkovic; Frank Baas
• Keywords: Morpholino

Pontocerebellar hypoplasia (PCH) represents a group (PCH1–6) of neurodegenerative autosomal recessive disorders characterized by and/or atrophy the cerebellum, ventral pons, progressive microcephaly and variable neocortical atrophy. The majority PCH2 PCH4 cases are caused mutations in TSEN54 gene; one four subunits comprising tRNA-splicing endonuclease (TSEN) complex. We hypothesized that act through loss function mechanism. At 8 weeks gestation, human is expressed ubiquitously brain, yet strong expression seen within telencephalon metencephalon. Comparable patterns for tsen54 observed zebrafish embryos. Morpholino (MO) knockdown embryos results structural definition brain. This phenotype was partially rescued co-injecting MO with mRNA. A developmental patterning defect not associated knockdown; however, an increase cell death brain observed, thus bearing resemblance to PCH pathophysiology. Additionally, N-methyl-N-nitrosourea mutant homozygous premature stop-codon mutation die 9 days post-fertilization. To determine whether common disease pathway exists between other PCH-related genes, we also monitored effects mitochondrial arginyl-tRNA synthetase (rars2; PCH1 PCH6) zebrafish. phenotypes were following inhibition both genes. These data strongly support hypothesis cause Also suggest may exist TSEN54- RARS2-related PCH, which involve tRNA processing-related