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


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.

DOI: 10.1073/pnas.1111596109

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@article{Cartault2012MutationIA, title={Mutation in a primate-conserved retrotransposon reveals a noncoding RNA as a mediator of infantile encephalopathy.}, author={François Cartault and Patrick Munier and Edgar Benko and Isabelle Desguerre and Sylvain Hanein and Nathalie Boddaert and Simonetta Bandiera and Jeanine Vellayoudom and Pascale Krejbich-Trotot and M. Bintner and Jean-Jacques Hoarau and Muriel Girard and Emmanuelle G{\'e}nin and Pascale de Lonlay and Alain Fourmaintraux and Magali Naville and Diana L Rodriguez and Josu{\'e} Feingold and Michel Renouil and Arnold Munnich and Eric Westhof and Michael F{\"a}hling and Stanislas Lyonnet and Alexandra Henrion-Caude}, journal={Proceedings of the National Academy of Sciences of the United States of America}, year={2012}, volume={109 13}, pages={4980-5} }