title: Mutation in a primate-conserved retrotransposon reveals a noncoding RNA as a mediator of infantile encephalopathy.
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.
authors.affiliation: Département de Génétique and Groupe de Recherche Immunopathologies et Maladies Infectieuses, Université de La Réunion, Centre Hospitalier Régional de La Réunion, 97405 Saint-Denis, La Réunion, France. francois.cartault@chr-reunion.fr
authors.forename: François
authors.initials: F
authors.lastname: Cartault
authors.forename: Patrick
authors.initials: P
authors.lastname: Munier
authors.forename: Edgar
authors.initials: E
authors.lastname: Benko
authors.forename: Isabelle
authors.initials: I
authors.lastname: Desguerre
authors.forename: Sylvain
authors.initials: S
authors.lastname: Hanein
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boddaert
authors.forename: Simonetta
authors.initials: S
authors.lastname: Bandiera
authors.forename: Jeanine
authors.initials: J
authors.lastname: Vellayoudom
authors.forename: Pascale
authors.initials: P
authors.lastname: Krejbich-Trotot
authors.forename: Marc
authors.initials: M
authors.lastname: Bintner
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Hoarau
authors.forename: Muriel
authors.initials: M
authors.lastname: Girard
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Génin
authors.forename: Pascale
authors.initials: P
authors.lastname: de Lonlay
authors.forename: Alain
authors.initials: A
authors.lastname: Fourmaintraux
authors.forename: Magali
authors.initials: M
authors.lastname: Naville
authors.forename: Diana
authors.initials: D
authors.lastname: Rodriguez
authors.forename: Josué
authors.initials: J
authors.lastname: Feingold
authors.forename: Michel
authors.initials: M
authors.lastname: Renouil
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Eric
authors.initials: E
authors.lastname: Westhof
authors.forename: Michael
authors.initials: M
authors.lastname: Fähling
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
authors.forename: Alexandra
authors.initials: A
authors.lastname: Henrion-Caude
mesh_terms: D000818:Animals; D000855:Anorexia / Q000150:complications / Q000235:genetics; D001483:Base Sequence; D001927:Brain Diseases / Q000150:complications / Q000235:genetics* / Q000473:pathology; D002874:Chromosome Mapping; D020090:Chromosome Segregation / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D017124:Conserved Sequence / Q000235:genetics*; D018450:Disease Progression; D005808:Genes, Recessive / Q000235:genetics; D056426:Genetic Loci; D005843:Geography; D006801:Humans; D019156:Indian Ocean; D007223:Infant; D007438:Introns / Q000235:genetics; D008279:Magnetic Resonance Imaging; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009690:Nucleic Acid Conformation; D009711:Nucleotides / Q000235:genetics; D010641:Phenotype; D011323:Primates / Q000235:genetics*; D022661:RNA, Untranslated / Q000737:chemistry / Q000235:genetics*; D018626:Retroelements / Q000235:genetics*; D055815:Young Adult
chemical_list: D009711:Nucleotides; D022661:RNA, Untranslated; D018626:Retroelements