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

human molecular genetics

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