Mutations in DCPS and EDC3 in autosomal recessive intellectual disability indicate a crucial role for mRNA decapping in neurodevelopment

Ahmed, Iltaf; Buchert, Rebecca; Zhou, Mi; Jiao, Xuan; Mittal, Kirti; Sheikh, Taimoor I.; Scheller, Ute; Vasli, Nasim; Rafiq, Muhammad; Brohi, Muhammad Qasim; Mikhailov, Anna; Ayaz, Muhammad; Bhatti, Attya; Sticht, Heinrich; Nasr, Tanveer; Carter, Melissa T.; Uebe, Steffen; Reis, André; Ayub, Muhammad; John, Peter; Kiledjian, Megerditch; Vincent, John B.; Jamra, Rami Abou

doi:10.1093/hmg/ddv069

Cited by 50 publications

(64 citation statements)

References 42 publications

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“…However, it is evident that DcpS fulfills both a decapping-dependent and -independent function. The recent identification of individuals with homozygous mutations disrupting DcpS decapping activity as the underlying cause of intellectual disability (Ahmed et al 2015;Ng et al 2015) demonstrates the importance of DcpS decapping in normal cognition. Nevertheless, the viability of the affected individuals with DcpS decapping null mutations in contrast to the embryonic lethality of mice lacking DcpS expression demonstrates a distinct decappingindependent function for DcpS in embryogenesis and a decapping-dependent role for DcpS in normal neural function.…”

Section: Discussionmentioning

confidence: 99%

DcpS is a transcript-specific modulator of RNA in mammalian cells

Zhou

Bail

Plasterer

et al. 2015

RNA

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The scavenger decapping enzyme DcpS is a multifunctional protein initially identified by its property to hydrolyze the resulting cap structure following 3 ′ end mRNA decay. In Saccharomyces cerevisiae, the DcpS homolog Dcs1 is an obligate cofactor for the 5 ′ -3 ′ exoribonuclease Xrn1 while the Caenorhabditis elegans homolog Dcs-1, facilitates Xrn1 mediated microRNA turnover. In both cases, this function is independent of the decapping activity. Whether DcpS and its decapping activity can affect mRNA steady state or stability in mammalian cells remains unknown. We sought to determine DcpS target genes in mammalian cells using a cell-permeable DcpS inhibitor compound, RG3039 initially developed for therapeutic treatment of spinal muscular atrophy. Global mRNA levels were examined following DcpS decapping inhibition with RG3039. The steady-state levels of 222 RNAs were altered upon RG3039 treatment. Of a subset selected for validation, two transcripts that appear to be long noncoding RNAs HS370762 and BC011766, were dependent on DcpS and its scavenger decapping catalytic activity and referred to as DcpS-responsive noncoding transcripts (DRNT) 1 and 2, respectively. Interestingly, only the increase in DRNT1 transcript was accompanied with an increase of its RNA stability and this increase was dependent on both DcpS and Xrn1. Importantly, unlike in yeast where the DcpS homolog is an obligate cofactor for Xrn1, stability of additional Xrn1 dependent RNAs were not altered by a reduction in DcpS levels. Collectively, our data demonstrate that DcpS in conjunction with Xrn1 has the potential to regulate RNA stability in a transcript-selective manner in mammalian cells.

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Section: Discussionmentioning

confidence: 99%

DcpS is a transcript-specific modulator of RNA in mammalian cells

Zhou

Bail

Plasterer

et al. 2015

RNA

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“…38 More recently, mutations in DCPS, encoding an mRNA decapping enzyme (MIM: 610534), and EDC3, encoding enhancer of mRNA decapping 3 (MIM: 609842), have been implicated in ID. 39,40 All human cells require mRNA export for efficient protein synthesis, yet tissue-specific defects due to mutations in general mRNA-export factors have been observed. 33 In mice, Thoc5 depletion interferes with the maintenance of hematopoiesis, 41,42 and Thoc1 deficiency interferes with Fibroblasts seeded on coverslips precoated with BD BioCoat were fixed with 4% paraformaldehyde for 10 min at room temperature and permeabilized with 0.2% Triton X-100 for 10 min at room temperature.…”

Section: Dysmorphismsmentioning

confidence: 99%

THOC2 Mutations Implicate mRNA-Export Pathway in X-Linked Intellectual Disability

Kumar

Corbett

Bon

et al. 2015

The American Journal of Human Genetics

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Export of mRNA from the cell nucleus to the cytoplasm is essential for protein synthesis, a process vital to all living eukaryotic cells. mRNA export is highly conserved and ubiquitous. Mutations affecting mRNA and mRNA processing or export factors, which cause aberrant retention of mRNAs in the nucleus, are thus emerging as contributors to an important class of human genetic disorders. Here, we report that variants in THOC2, which encodes a subunit of the highly conserved TREX mRNA-export complex, cause syndromic intellectual disability (ID). Affected individuals presented with variable degrees of ID and commonly observed features included speech delay, elevated BMI, short stature, seizure disorders, gait disturbance, and tremors. X chromosome exome sequencing revealed four missense variants in THOC2 in four families, including family MRX12, first ascertained in 1971. We show that two variants lead to decreased stability of THOC2 and its TREX-complex partners in cells derived from the affected individuals. Protein structural modeling showed that the altered amino acids are located in the RNA-binding domains of two complex THOC2 structures, potentially representing two different intermediate RNA-binding states of THOC2 during RNA transport. Our results show that disturbance of the canonical molecular pathway of mRNA export is compatible with life but results in altered neuronal development with other comorbidities.

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“…At the iN stage, a number of genes were identified as differentially expressed that have been previously implicated in neuropsychiatric disorders associated with the 15q13.3 microdeletion. These genes include VIPR2, PRODH, and DGCR6 for schizophrenia [33][34][35]; CACNG3, SCN8A, SPATA5, and KCNA2 for epilepsy [36][37][38][39]; and LINS1 and DCPS for intellectual disability [40][41][42].…”

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confidence: 99%

Network effects of the neuropsychiatric 15q13.3 microdeletion on the transcriptome and epigenome in human induced neurons

Zhang

et al. 2019

Preprint

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Heterozygous deletions in the 15q13.3 region are associated with several neuropsychiatric disorders including autism, schizophrenia, and attention deficit hyperactivity disorder. Several genes within the 15q13.3 deletion region may play a role in neuronal dysfunction, based on association studies in humans and functional studies in mice, but the intermediate molecular mechanisms remain unknown.We analyzed the genome-wide effects of the 15q13.3 microdeletion on the transcriptome and epigenome. Induced pluripotent stem cell (iPSC) lines from three patients with the typical heterozygous 15q13.3 microdeletion and three sex-matched controls were generated and converted into induced neurons (iNs) using the neurogenin-2 induction method. We analyzed genome-wide gene expression using RNA-Seq, genome-wide DNA methylation using SeqCap-Epi, and genome-wide chromatin accessibility using ATAC-Seq, in both iPSCs and iNs. In both cell types, gene copy number change within the 15q13.3 microdeletion was accompanied by significantly decreased gene expression and no compensatory changes in DNA methylation or chromatin accessibility, supporting the model that haploinsufficiency of genes within the deleted region drives the disorder. Further, we observed global effects of the deletion on the transcriptome and epigenome, with the effects being cell type specific and occurring at discrete loci. Several genes and pathways associated with neuropsychiatric disorders and neuronal development were significantly altered, including Wnt signaling, ribosome biogenesis, DNA binding, and clustered protocadherins. This molecular systems analysis of a large neuropsychiatric microdeletion can also be applied to other brain relevant chromosomal aberrations to further our etiological understanding of neuropsychiatric disorders. IntroductionThe neuropsychiatric 15q13.3 microdeletion (OMIM 612001) is a heterozygous deletion of approximately 1.5-2 Mb at coordinates 30.5 Mb to 32.5 Mb on chromosome 15 (hg19) [1]. The deletion breakpoints lie within two regions of segmental duplications, which likely mediate the creation of the recurrent microdeletion via non-allelic homologous recombination [2]. The 15q13.3 microdeletion has an estimated prevalence of 1 in 40,000 individuals, and was first reported in 2008, in nine individuals with mental retardation, seizures, and mild facial dysmorphism [3]. Since then, several other phenotypes have been associated with this copy number variant (CNV), including autism spectrum disorder, schizophrenia, mood disorders, attention deficit hyperactivity disorder, hypotonia, and cardiac defects [1,4,5].The most common form of the 15q13.3 microdeletion, which is the subject of our study, results in the heterozygous loss of seven protein-coding genes (CHRNA7, FAN1, TRPM1, KLF13, OTUD7A, MTMR10, ARHGAP11B) and one microRNA (MIR211) [4]. Several of these genes have previously been investigated as candidates for having a role in the neuropsychiatric symptoms associated with the CNV. The most frequently proposed candidate gene is C...

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Mutations in DCPS and EDC3 in autosomal recessive intellectual disability indicate a crucial role for mRNA decapping in neurodevelopment

Cited by 50 publications

References 42 publications

DcpS is a transcript-specific modulator of RNA in mammalian cells

DcpS is a transcript-specific modulator of RNA in mammalian cells

THOC2 Mutations Implicate mRNA-Export Pathway in X-Linked Intellectual Disability

Network effects of the neuropsychiatric 15q13.3 microdeletion on the transcriptome and epigenome in human induced neurons

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