Variants in PUS7 cause intellectual disability with speech delay, microcephaly, short stature, and aggressive behavior
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA496017 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8041720.fastq.gz | Fastqsanger.gz | |||
| SRR8041721.fastq.gz | Fastqsanger.gz | |||
| SRR8041712.fastq.gz | Fastqsanger.gz | |||
| SRR8041722.fastq.gz | Fastqsanger.gz | |||
| SRR8041713.fastq.gz | Fastqsanger.gz |
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Project description:We describe six patients from three families with three homozygous protein truncating variants in PUS7: c.89_90del, p.(Thr30Lysfs20*); c.1348C>T, p.(Arg450*); and a deletion of the penultimate exon 15. All patients have intellectual disability with speech delay, short stature, microcephaly, and aggressive behavior. PUS7 encodes the RNA-independent pseudouridylate synthase 7. Pseudouridylation is the most abundant post-transcriptional modification in RNA, which is primarily thought to stabilize secondary structures of RNA. We show that the disease-related variants lead to abolishment of PUS7 activity on both tRNA and mRNA substrates. Moreover, Pus7 knockout in Drosophila melanogaster results in a number of behavioral defects, including increased activity with slower walking speed and disorientation supporting that neurological defects are caused by PUS7 variants. Our findings demonstrate that RNA pseudouridylation by PUS7 is essential for proper neuronal development and function.
2018-10-13 | GSE121177 | GEO
Project description:We describe six persons from three families with three homozygous protein truncating variants in PUS7: c.89_90del (p.Thr30Lysfs∗20), c.1348C>T (p.Arg450∗), and a deletion of the penultimate exon 15. All these individuals have intellectual disability with speech delay, short stature, microcephaly, and aggressive behavior. PUS7 encodes the RNA-independent pseudouridylate synthase 7. Pseudouridylation is the most abundant post-transcriptional modification in RNA, which is primarily thought to stabilize secondary structures of RNA. We show that the disease-related variants lead to abolishment of PUS7 activity on both tRNA and mRNA substrates. Moreover, pus7 knockout in Drosophila melanogaster results in a number of behavioral defects, including increased activity, disorientation, and aggressiveness supporting that neurological defects are caused by PUS7 variants. Our findings demonstrate that RNA pseudouridylation by PUS7 is essential for proper neuronal development and function.
| S-EPMC6288278 | biostudies-literature
Project description:Pseudouridylation is the most common post-transcriptional modification, wherein uridine is isomerized into 5-ribosyluracil (pseudouridine, Ψ). The resulting increase in base stacking and creation of additional hydrogen bonds are thought to enhance RNA stability. Pseudouridine synthases are encoded in humans by 13 genes, two of which are linked to Mendelian diseases: PUS1 and PUS3. Very recently, PUS7 mutations were reported to cause intellectual disability with growth retardation. We describe two families in which two different homozygous PUS7 mutations (missense and frameshift deletion) segregate with a phenotype comprising intellectual disability and progressive microcephaly. Short stature and hearing loss were variable in these patients. Functional characterization of the two mutations confirmed that both result in decreased levels of Ψ13 in tRNAs. Furthermore, the missense variant of the S. cerevisiae ortholog failed to complement the growth defect of S. cerevisiae pus7Δ trm8Δ mutants. Our results confirm that PUS7 is a bona fide Mendelian disease gene and expand the list of human diseases caused by impaired pseudouridylation.
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Project description:CNV are known to be a frequent cause of the autism spectrum disorders (ASD) and intellectual disabilities (ID). However, the clinical heterogeneity of both disorders causes the diagnostic efficacy of CNV analysis to be modest. We conclude that comorbidities such as microcephaly, facial dysmorphia and epilepsy increase the risk of the pathogenic CNV finding in patients with ID and ASD. However, the significance of these comorbidities differs between both groups and shows dependency on whether the patients were primarily classified as ID or ASD. We suggest that stratification of the patients according to their comorbidities before testing can increase the yield of the detection rate of pathogenic CNV in both groups. The likelihood of pathogenic CNV detection in ASD patients without any comorbidities is low. Therefore, the effectivity of CNV analysis in these cases is modest
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Project description:BackgroundPathogenic variants in the centrosome protein (CEP) family have been implicated in primary microcephaly, Seckel syndrome, and classical ciliopathies. However, most CEP genes remain unlinked to specific Mendelian genetic diseases in humans. We sought to explore the roles of CEP295 in human pathology.MethodsWhole-exome sequencing was performed to screen for pathogenic variants in patients with severe microcephaly. Patient-derived fibroblasts and CEP295-depleted U2OS and RPE1 cells were used to clarify the underlying pathomechanisms, including centriole/centrosome development, cell cycle and proliferation changes, and ciliogenesis. Complementary experiments using CEP295 mRNA were performed to determine the pathogenicity of the identified missense variant.FindingsHere, we report bi-allelic variants of CEP295 in four children from two unrelated families, characterized by severe primary microcephaly, short stature, developmental delay, intellectual disability, facial deformities, and abnormalities of fingers and toes, suggesting a Seckel-like syndrome. Mechanistically, depletion of CEP295 resulted in a decrease in the numbers of centrioles and centrosomes and triggered p53-dependent G1 cell cycle arrest. Moreover, loss of CEP295 causes extensive primary ciliary defects in both patient-derived fibroblasts and RPE1 cells. The results from complementary experiments revealed that the wild-type CEP295, but not the mutant protein, can correct the developmental defects of the centrosome/centriole and cilia in the patient-derived skin fibroblasts.InterpretationThis study reports CEP295 as a causative gene of the syndromic microcephaly phenotype in humans. Our study also demonstrates that defects in CEP295 result in primary ciliary defects.FundingA full list of funding bodies that contributed to this study can be found under "Acknowledgments."
| S-EPMC10784679 | biostudies-literature
Project description:We report two consanguineous families with probands that exhibit intellectual disability, developmental delay, short stature, aphasia, and hypotonia in which homozygous non-synonymous variants were identified in IQSEC1 (GenBank: NM_001134382.3). In a Pakistani family, the IQSEC1 segregating variant is c.1028C>T (p.Thr343Met), while in a Saudi Arabian family the variant is c.962G>A (p.Arg321Gln). IQSEC1-3 encode guanine nucleotide exchange factors for the small GTPase ARF6 and their loss affects a variety of actin-dependent cellular processes, including AMPA receptor trafficking at synapses. The ortholog of IQSECs in the fly is schizo and its loss affects growth cone guidance at the midline in the CNS, also an actin-dependent process. Overexpression of the reference IQSEC1 cDNA in wild-type flies is lethal, but overexpression of the two variant IQSEC1 cDNAs did not affect viability. Loss of schizo caused embryonic lethality that could be rescued to 2nd instar larvae by moderate expression of the human reference cDNA. However, the p.Arg321Gln and p.Thr343Met variants failed to rescue embryonic lethality. These data indicate that the variants behave as loss-of-function mutations. We also show that schizo in photoreceptors is required for phototransduction. Finally, mice with a conditional Iqsec1 deletion in cortical neurons exhibited an increased density of dendritic spines with an immature morphology. The phenotypic similarity of the affecteds and the functional experiments in flies and mice indicate that IQSEC1 variants are the cause of a recessive disease with intellectual disability, developmental delay, and short stature, and that axonal guidance and dendritic projection defects as well as dendritic spine dysgenesis may underlie disease pathogenesis.
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Project description:An increasing number of genes involved in chromatin structure and epigenetic regulation has been implicated in a variety of developmental disorders, often including intellectual disability. By trio exome sequencing and subsequent mutational screening we now identified two de novo frameshift mutations and one de novo missense mutation in the CTCF gene in individuals with intellectual disability, microcephaly and growth retardation. Furthermore, a patient with a larger deletion including CTCF was identified. CTCF (CCCTC-binding factor) is one of the most important chromatin organizers in vertebrates and is involved in various chromatin regulation processes such as higher order of chromatin organization, enhancer function, and maintenance of three-dimensional chromatin structure. Transcriptome analyses in all three patients with point mutations revealed deregulation of genes involved in signal transduction and emphasized the role of CTCF in enhancer-driven expression of genes. Our findings indicate that haploinsufficiency of CTCF affects genomic interaction of enhancers and their regulated gene promoters that drive developmental processes and cognition. Comparison of lymphocyte gene expression between 3 de novo CTCF mutation patients and 8 controls (4 technical replicates each, no biological replicates).
2013-06-01 | E-GEOD-46831 | biostudies-arrayexpress
Project description:An increasing number of genes involved in chromatin structure and epigenetic regulation has been implicated in a variety of developmental disorders, often including intellectual disability. By trio exome sequencing and subsequent mutational screening we now identified two de novo frameshift mutations and one de novo missense mutation in the CTCF gene in individuals with intellectual disability, microcephaly and growth retardation. Furthermore, a patient with a larger deletion including CTCF was identified. CTCF (CCCTC-binding factor) is one of the most important chromatin organizers in vertebrates and is involved in various chromatin regulation processes such as higher order of chromatin organization, enhancer function, and maintenance of three-dimensional chromatin structure. Transcriptome analyses in all three patients with point mutations revealed deregulation of genes involved in signal transduction and emphasized the role of CTCF in enhancer-driven expression of genes. Our findings indicate that haploinsufficiency of CTCF affects genomic interaction of enhancers and their regulated gene promoters that drive developmental processes and cognition. ChIP-seq analysis of CTCF genomic binding sites in lymphocytes of a control individual (no replicates).
2013-06-01 | E-GEOD-46832 | biostudies-arrayexpress
Project description:Microtubule associated proteins (MAPs) are widely expressed in the central nervous system, and have established roles in cell proliferation, myelination, neurite formation, axon specification, outgrowth, dendrite, and synapse formation. We report eleven individuals from seven families harboring predicted pathogenic biallelic, de novo, and heterozygous variants in the NAV3 gene, which encodes the microtubule positive tip protein neuron navigator 3 (NAV3). All affected individuals have intellectual disability (ID), microcephaly, skeletal deformities, ocular anomalies, and behavioral issues. In mouse brain, Nav3 is expressed throughout the nervous system, with more prominent signatures in postmitotic, excitatory, inhibiting, and sensory neurons. When overexpressed in HEK293T and COS7 cells, pathogenic variants impaired NAV3 ability to stabilize microtubules. Further, knocking-down nav3 in zebrafish led to severe morphological defects, microcephaly, impaired neuronal growth, and behavioral impairment, which were rescued with co-injection of WT NAV3 mRNA and not by transcripts encoding the pathogenic variants. Our findings establish the role of NAV3 in neurodevelopmental disorders, and reveal its involvement in neuronal morphogenesis, and neuromuscular responses.
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Project description:Pseudouridine is the first discovered and the most frequent modification in RNA. However, its biological functions in physiology and human diseases are largely unknown. Here, we show that pseudouridine synthase PUS7 is differentially expressed in glioblastoma patient tissues verse non-tumor brain tissues, and highly expressed in patient brain-derived cancer stem cells, compared to normal brain-derived neural stem cells. Upregulated expression of PUS7 predicts worse survival in glioblastoma patients in multiple databases. Indeed, we show that PUS7 plays an important role in regulating the self-renewal and tumorigenesis of glioblastoma stem cells. Overexpression of the wild type but not the catalytically inactive PUS7 increases the growth and self-renewal of GSCs. In contrast, knockdown of PUS7 dramatically suppresses GSC growth, self-renewal and tumorigenesis. Mechanistically, knockdown of PUS7 activates interferon pathway through translational control of TYK2 via PUS7-regulated tRNAs. Moreover, we have identified chemical inhibitors for PUS7 in this study. These chemical compounds target pseudouridine modification and suppress GSC growth and tumorigenesis, providing a potential therapeutic tool for GBM treatment.
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