Mutation in noncoding <scp>RNA RNU12</scp> causes early onset cerebellar ataxia

Elsaid, Mahmoud F.; Chalhoub, Nader; Ben‐Omran, Tawfeg; Kumar, Pankaj; Kamel, Hussein; Ibrahim, Khalid; Mohamoud, Yasmin Ali; Al-Dous, Eman K.; Al-Azwani, Iman K.; Malek, Joel A.; Suhre, Karsten; Ross, M. Elizabeth; Abdel-Aleem, Alice

doi:10.1002/ana.24826

Cited by 77 publications

(74 citation statements)

References 30 publications

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“…Similarly, mutations in the minor spliceosome U4atac snRNA gene in humans result in splicing defects and the rare disorder microcephalic osteodysplastic primordial dwarfism type I (MOPD1) [30, 57]. Mutations in another minor spliceosome snRNA, RNU12 , result in U12-type exon retention and are associated with cerebellar ataxia[31]. Therefore, a toxic effect of the accumulation of misprocessed UsnRNAs on the spliceosome in response to INTS8 mutations is possible and could result in the differential splicing patterns that we observed in patient versus control cells.…”

Section: Discussionmentioning

confidence: 99%

“…For example, mutations in the mouse Rnu2-8 , coding for U2 snRNA, result in cerebellar degeneration [29], RNU4atac mutations in humans result in extreme microcephaly [30] and mutations in RNU12 have been found associated with early-onset cerebellar ataxia[31]. Recently, mutations in the non-canonical deadenylase TOE1 that trims the 3’ ends of pre-UsnRNA, have been linked to pontocerebellar hypoplasia[32].…”

Section: Introductionmentioning

confidence: 99%

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Human mutations in integrator complex subunits link transcriptome integrity to brain development

et al. 2017

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Integrator is an RNA polymerase II (RNAPII)-associated complex that was recently identified to have a broad role in both RNA processing and transcription regulation. Importantly, its role in human development and disease is so far largely unexplored. Here, we provide evidence that biallelic Integrator Complex Subunit 1 (INTS1) and Subunit 8 (INTS8) gene mutations are associated with rare recessive human neurodevelopmental syndromes. Three unrelated individuals of Dutch ancestry showed the same homozygous truncating INTS1 mutation. Three siblings harboured compound heterozygous INTS8 mutations. Shared features by these six individuals are severe neurodevelopmental delay and a distinctive appearance. The INTS8 family in addition presented with neuronal migration defects (periventricular nodular heterotopia). We show that the first INTS8 mutation, a nine base-pair deletion, leads to a protein that disrupts INT complex stability, while the second missense mutation introduces an alternative splice site leading to an unstable messenger. Cells from patients with INTS8 mutations show increased levels of unprocessed UsnRNA, compatible with the INT function in the 3’-end maturation of UsnRNA, and display significant disruptions in gene expression and RNA processing. Finally, the introduction of the INTS8 deletion mutation in P19 cells using genome editing alters gene expression throughout the course of retinoic acid-induced neural differentiation. Altogether, our results confirm the essential role of Integrator to transcriptome integrity and point to the requirement of the Integrator complex in human brain development.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Human mutations in integrator complex subunits link transcriptome integrity to brain development

et al. 2017

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“…There are several instances where defects in minor class splicing impact on the developing and adult central nervous system. For example, mutations in the RNU12 gene cause congenital cerebellar ataxia characterized by delayed motor milestones in development, mild learning dif-ficulties and hypotonia in infancy (Elsaid et al 2017). Interestingly, the impaired expression of the CULIN1, ATAXIN10, and SLC9A6 genes, which all contain a U12type intron, has been implicated in several cerebellar ataxia-related phenotypes.…”

Section: Relevance Of Rnpc3 Mutations To Minor Class Splicing Clinicamentioning

confidence: 99%

Early developmental arrest and impaired gastrointestinal homeostasis in U12-dependent splicing-defective Rnpc3-deficient mice

Doggett

Williams

Markmiller

et al. 2018

RNA

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Splicing is an essential step in eukaryotic gene expression. While the majority of introns is excised by the U2-dependent, or major class, spliceosome, the appropriate expression of a very small subset of genes depends on U12-dependent, or minor class, splicing. The U11/U12 65K protein (hereafter 65K), encoded by RNPC3, is one of seven proteins that are unique to the U12-dependent spliceosome, and previous studies including our own have established that it plays a role in plant and vertebrate development. To pinpoint the impact of 65K loss during mammalian development and in adulthood, we generated germline and conditional Rnpc3-deficient mice. Homozygous Rnpc3 −/− embryos died prior to blastocyst implantation, whereas Rnpc3 +/− mice were born at the expected frequency, achieved sexual maturity, and exhibited a completely normal lifespan. Systemic recombination of conditional Rnpc3 alleles in adult (Rnpc3 lox/lox ) mice caused rapid weight loss, leukopenia, and degeneration of the epithelial lining of the entire gastrointestinal tract, the latter due to increased cell death and a reduction in cell proliferation. Accompanying this, we observed a loss of both 65K and the pro-proliferative phospho-ERK1/2 proteins from the stem/progenitor cells at the base of intestinal crypts. RT-PCR analysis of RNA extracted from purified preparations of intestinal epithelial cells with recombined Rnpc3 lox alleles revealed increased frequency of U12-type intron retention in all transcripts tested. Our study, using a novel conditional mouse model of Rnpc3 deficiency, establishes that U12-dependent splicing is not only important during development but is indispensable throughout life.

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“…For instance, germline mutations in the gene RNU4ATAC, which encodes the U4atac snRNA, have been linked to the diseases microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1), Roifman syndrome and Lowry-Wood syndrome (Edery et al, 2011;Farach et al, 2018;He et al, 2011;Merico et al, 2015). Moreover, mutations in RNU12 have been associated with an early-onset form of cerebellar ataxia (Elsaid et al, 2017). Finally, mutations in RNPC3, one of the minor spliceosome-specific proteins, have been linked to isolated growth hormone deficiency (IGHD) (Argente et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…inhibition of the minor spliceosome. Transcriptomic analyses of peripheral blood mononuclear cells (PBMCs) from individuals with IGHD, cerebellar ataxia, MOPD1 and Roifman syndrome have revealed that this inhibition of the minor spliceosome results in elevated levels of retention of a subset of minor introns (Argente et al, 2014;Cologne et al, 2019;Elsaid et al, 2017;Merico et al, 2015). Despite a great degree of overlap in the MIGs that are affected in individuals with MOPD1 and Roifman syndrome, there is also a subset of MIGs that are only affected in one condition (Cologne et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

The minor and major spliceosome interact to regulate alternative splicing around minor introns

Olthof

White

Lee

et al. 2020

Preprint

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Mutations in minor spliceosome components are linked to diseases such as Roifman syndrome, Lowry-Wood syndrome, and early-onset cerebellar ataxia (EOCA). Here we report that besides increased minor intron retention, Roifman syndrome and EOCA can also be characterized by elevated alternative splicing (AS) around minor introns. Consistent with the idea that the assembly/activity of the minor spliceosome informs AS in minor intron-containing genes (MIGs), inhibition of all minor spliceosome snRNAs led to upregulated AS. Notably, alternatively spliced MIG isoforms were bound to polysomes in the U11-null dorsal telencephalon, which suggested that aberrant MIG protein expression could contribute to disease pathogenesis. In agreement, expression of an aberrant isoform of the MIG Dctn3 by in utero electroporation, affected radial glial cell divisions. Finally, we show that AS around minor introns is executed by the major spliceosome and is regulated by U11-59K of the minor spliceosome, which forms exon-bridging interactions with proteins of the major spliceosome. Overall, we extend the exon-definition model to MIGs and postulate that disruptions of exon-bridging interactions might contribute to disease severity and pathogenesis.Keywords: Minor spliceosome/U11-59K/alternative splicing/exon-definition model/Lowry-Wood syndrome

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Mutation in noncoding RNA RNU12 causes early onset cerebellar ataxia

Cited by 77 publications

References 30 publications

Human mutations in integrator complex subunits link transcriptome integrity to brain development

Human mutations in integrator complex subunits link transcriptome integrity to brain development

Early developmental arrest and impaired gastrointestinal homeostasis in U12-dependent splicing-defective Rnpc3-deficient mice

The minor and major spliceosome interact to regulate alternative splicing around minor introns

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