A novel mutation in the promoter of RARS2 causes pontocerebellar hypoplasia in two siblings

J Hum Genet. 2015 Jul;60(7):363-9. doi: 10.1038/jhg.2015.31. Epub 2015 Mar 26.


Pontocerebellar hypoplasia (PCH) is characterized by hypoplasia and atrophy of the cerebellum, variable pontine atrophy, microcephaly, severe mental and motor impairments and seizures. Mutations in 11 genes have been reported in 8 out of 10 forms of PCH. Recessive mutations in the mitochondrial arginyl-transfer RNA synthetase gene (RARS2) have been recently associated with PCH type 6, which is characterized by early-onset encephalopathy with signs of oxidative phosphorylation defect. Here we describe the clinical presentation, neuroimaging findings and molecular characterizations of two siblings with a clinical diagnosis of PCH who displayed a novel variant (c.-2A>G) in the 5'-UTR of the RARS2 gene in the homozygous state. This variant was identified through next-generation sequencing testing of a panel of nine genes known to be involved in PCH. Gene expression and functional studies demonstrated that the c.-2A>G sequence change directly leads to a reduced RARS2 messenger RNA expression in the patients by decreasing RARS2 promoter activity, thus providing evidence that mutations in the RARS2 promoter are likely to represent a new causal mechanism of PCH6.

Publication types

  • Case Reports

MeSH terms

  • Arginine-tRNA Ligase / genetics*
  • Base Sequence
  • Cerebellar Diseases / diagnosis
  • Cerebellar Diseases / genetics
  • Child, Preschool
  • DNA Mutational Analysis
  • Female
  • Genetic Association Studies
  • Humans
  • Infant
  • Male
  • Molecular Sequence Data
  • Mutation, Missense
  • Point Mutation
  • Promoter Regions, Genetic*


  • Arginine-tRNA Ligase
  • RARS2 protein, human

Supplementary concepts

  • Pontocerebellar Hypoplasia