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Intellectual disability (ID) and autism spectrum disorder (ASD) are the most common neurodevelopmental disorders and are characterized by substantial impairment in intellectual and adaptive functioning, with their genetic and molecular basis remaining largely unknown. Here, we identify biallelic variants in the gene encoding one of the Elongator complex subunits, ELP2, in patients with ID and ASD. Modelling the variants in mice recapitulates the patient features, with brain imaging and tractography analysis revealing microcephaly, loss of white matter tract integrity and an aberrant functional connectome. We show that the Elp2 mutations negatively impact the activity of the complex and its function in translation via tRNA modification. Further, we elucidate that the mutations perturb protein homeostasis leading to impaired neurogenesis, myelin loss and neurodegeneration. Collectively, our data demonstrate an unexpected role for tRNA modification in the pathogenesis of monogenic ID and ASD and define Elp2 as a key regulator of brain development.
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http://dx.doi.org/10.1038/s41467-021-22888-5 | DOI Listing |
J Hum Genet
July 2023
Frazer Institute, The University of Queensland, Woolloongabba, QLD, 4102, Australia.
Background: Neurodevelopmental disorders (NDDs) are heterogeneous, debilitating conditions that include motor and cognitive disability and social deficits. The genetic factors underlying the complex phenotype of NDDs remain to be elucidated. Accumulating evidence suggest that the Elongator complex plays a role in NDDs, given that patient-derived mutations in its ELP2, ELP3, ELP4 and ELP6 subunits have been associated with these disorders.
View Article and Find Full Text PDFCancer Res
June 2022
Department of Epidemiology and Biostatistics, School of Public Health, Wuhan University, Wuhan, Hubei, China.
Unlabelled: Understanding the genetic variation underlying transcript splicing is essential for fully dissecting the molecular mechanisms of common diseases. The available evidence from splicing quantitative trait locus (sQTL) studies using pancreatic ductal adenocarcinoma (PDAC) tissues have been limited to small sample sizes. Here we present a genome-wide sQTL analysis to identify SNP that control mRNA splicing in 176 PDAC samples from TCGA.
View Article and Find Full Text PDFEur J Med Genet
December 2021
Department of Medical Sciences Pediatric Section, University of Ferrara, Italy; Robert Hollman Foundation, Padova, Italy.
The elongator complex is a highly conserved macromolecular assembly composed by 6 individual proteins (Elp 1-6) and it is essential for many cellular functions such as transcription elongation, histone acetylation and tRNA modification. ELP2 is the second major subunit and with Elp1 and Elp3 it shapes the catalytic core of this essential complex. ELP2 gene pathogenic variants have been reported to be associated with several neurodevelopmental disorders, such as intellectual disability, severe motor development delay with truncal hypotonia, spastic diplegia, choreoathetosis, short stature and neuropsychiatric problems.
View Article and Find Full Text PDFNat Commun
May 2021
The University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD, Australia.
Intellectual disability (ID) and autism spectrum disorder (ASD) are the most common neurodevelopmental disorders and are characterized by substantial impairment in intellectual and adaptive functioning, with their genetic and molecular basis remaining largely unknown. Here, we identify biallelic variants in the gene encoding one of the Elongator complex subunits, ELP2, in patients with ID and ASD. Modelling the variants in mice recapitulates the patient features, with brain imaging and tractography analysis revealing microcephaly, loss of white matter tract integrity and an aberrant functional connectome.
View Article and Find Full Text PDFActa Neurol Belg
April 2022
Department of Pediatric Neurology, Umraniye Training and Research Hospital, Istanbul, Turkey.
Hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of conditions that are characterized by lower limb spasticity and weakness. Considering the clinical overlap between metabolic causes, genetic diseases, and autosomal recessive HSP, differentiation between these types can be difficult based solely on their clinical characteristics. This study aimed to investigate the genetic etiology of patients with clinically suspected HSP.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!