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.genetic disease | long noncoding RNA | long interspersed element 1 | medulla oblongata | pediatrics

Long Non-coding RNAs: Novel Targets for Nervous System Disease Diagnosis and Therapy

“…Two lncRNAs, SLC7A2-IT1A and SLC7A2-IT1B, are transcribed from this locus and expressed in brain. In vitro knock down of these lncRNAs leads to neuronal apoptosis, consistent with the human neuropathological findings [77].…”

The RIDL hypothesis: transposable elements as functional domains of long noncoding RNAs

“…Further attesting to the significance of TE-derived lncRNA comes from an intriguing recent study on a rare neurodegenerative condition, infantile encephalopathy, which is restricted to a small population from the island of Reunion (Cartault et al 2012). By genetic mapping, a single-nucleotide disease-causing mutation was discovered in a L1PA8 element embedded within a novel intergenic lncRNA locus with brain specific expression, SLC7A2-IT1.…”

Epigenetic Mechanisms Underlying the Pathogenesis of Neurogenetic Diseases

“…Disruption of the LINC00299 lncRNA gene also produces a form of IDD [22]. Similarly, a point mutation in the SLC7A2-IT1 lncRNA gene is responsible for progressive encephalopathy with severe infantile anorexia (Ravine encephalopathy) [23].…”

“…Point mutation in a primate-specific repeat (L1PA8) within an Alu element, which is embedded in a brain expressed lncRNA, mediates disease [23] Rett syndrome MeCP2 represses L1 retrotransposition in neuronal cells and, in reprogrammed cells from Rett syndrome patient tissues, L1 activity is increased [47] Schizophrenia L1 copy number is increased in neurons from patient-derived prefrontal cortex specimens, and brain-specific L1 insertions seem to preferentially target genes involved in synaptic function or linked to schizophrenia [46] ATM = ataxia telangiectasia mutated; SVA = SINE-VNTR-Alu; 3′-UTR = 3′-untranslated region; lncRNA = long noncoding RNA; MeCP2 = methylCpG-binding protein 2; L1 = long interspersed element 1 during development and aging [89][90][91][92][93][94]. Moreover, it is notable that methylation marks measured in easily accessible peripheral tissues, such as blood, can serve as reliable surrogates for those present in brain for certain subsets of genes [89].…”