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

François Cartault 1 Patrick Munier 1 Edgar Benko Isabelle Desguerre 2 Sylvain Hanein 3 Nathalie Boddaert 3 Simonetta Bandiera 3 Jeanine Vellayoudom 1 Pascale Krejbich-Trotot 4 Marc Bintner 5 Jean-Jacques Hoarau 4 Muriel Girard 6 Emmanuelle Génin 7 Pascale Lonlay 3 Alain Fourmaintraux 8, 9 Magali Naville 10 Diana Rodriguez 11, 12, 13 Josué Feingold 14 Michel Renouil 5 Arnold Munnich 3 Eric Westhof 15 Michael Fähling Stanislas Lyonnet 14 Alexandra Henrion-Caude 3
1 Service de génétique
2 Service de Neuropédiatrie
3 Inserm U781 - Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement
4 GRI - Groupe de Recherche en Immunopathologies et maladies infectueuses
5 CHU La Réunion - Centre Hospitalier Universitaire de La Réunion
6 CITERES - Cités, Territoires, Environnement et Sociétés
7 Variabilité Génétique et Maladies Humaines
8 GHSR - Groupe Hospitalier Sud Réunion
9 CHR La réunion
10 IGM - Institut de génétique et microbiologie [Orsay]
11 Centre de Référence Maladies Rares " malformations et maladies congénitales du cervelet "
12 Physiopathologie, conséquences fonctionnelles et neuroprotection des atteintes du cerveau en développement
13 CHU Trousseau [APHP]
14 Service de Génétique Médicale [CHU Necker]
15 ARN - Architecture et Réactivité de l'ARN
Abstract : 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.
Keywords : pediatrics medulla oblongata genetic disease long interspersed element 1 long noncoding RNA
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François Cartault, Patrick Munier, Edgar Benko, Isabelle Desguerre, Sylvain Hanein, et al.. Mutation in a primate-conserved retrotransposon reveals a noncoding RNA as a mediator of infantile encephalopathy. Proceedings of the National Academy of Sciences of the United States of America , National Academy of Sciences, 2012, 109 (13), pp.4980-4985. ⟨10.1073/pnas.1111596109⟩. ⟨hal-01285444⟩

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