Mutation in a primate-conserved retrotransposon reveals a noncoding RNA as a mediator of infantile encephalopathy

Proc Natl Acad Sci U S A. 2012 Mar 27;109(13):4980-5. doi: 10.1073/pnas.1111596109. Epub 2012 Mar 12.


The human genome is densely populated with transposons and transposon-like repetitive elements. Although the impact of these transposons and elements on human genome evolution is recognized, the significance of subtle variations in their sequence remains mostly unexplored. Here we report homozygosity mapping of an infantile neurodegenerative disease locus in a genetic isolate. Complete DNA sequencing of the 400-kb linkage locus revealed a point mutation in a primate-specific retrotransposon that was transcribed as part of a unique noncoding RNA, which was expressed in the brain. In vitro knockdown of this RNA increased neuronal apoptosis, consistent with the inappropriate dosage of this RNA in vivo and with the phenotype. Moreover, structural analysis of the sequence revealed a small RNA-like hairpin that was consistent with the putative gain of a functional site when mutated. We show here that a mutation in a unique transposable element-containing RNA is associated with lethal encephalopathy, and we suggest that RNAs that harbor evolutionarily recent repetitive elements may play important roles in human brain development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anorexia / complications
  • Anorexia / genetics
  • Base Sequence
  • Brain Diseases / complications
  • Brain Diseases / genetics*
  • Brain Diseases / pathology
  • Chromosome Mapping
  • Chromosome Segregation / genetics
  • Chromosomes, Human, Pair 8 / genetics
  • Conserved Sequence / genetics*
  • Disease Progression
  • Genes, Recessive / genetics
  • Genetic Loci
  • Geography
  • Humans
  • Indian Ocean
  • Infant
  • Introns / genetics
  • Magnetic Resonance Imaging
  • Molecular Sequence Data
  • Mutation / genetics*
  • Nucleic Acid Conformation
  • Nucleotides / genetics
  • Phenotype
  • Primates / genetics*
  • RNA, Untranslated / chemistry
  • RNA, Untranslated / genetics*
  • Retroelements / genetics*
  • Young Adult


  • Nucleotides
  • RNA, Untranslated
  • Retroelements