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Recurrent de novo variants in the spliceosomal factor CRNKL1 cause severe microcephaly and pontocerebellar hypoplasia with seizures [HeLa]

ABSTRACT: Recurrent de novo variants in the spliceosomal factor CRNKL1 cause severe microcephaly and pontocerebellar hypoplasia with seizures [HeLa]

PROVIDER: PRJNA1248764 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR33064400_1.fastq.gz	Fastqsanger.gz
	SRR33064400_2.fastq.gz	Fastqsanger.gz
	SRR33064397_1.fastq.gz	Fastqsanger.gz
	SRR33064397_2.fastq.gz	Fastqsanger.gz
	SRR33064398_1.fastq.gz	Fastqsanger.gz

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Recurrent de novo variants in the spliceosomal factor CRNKL1 cause severe microcephaly and pontocerebellar hypoplasia with seizures

Project description:Splicing is a complex process, required to create the transcriptomic diversity needed for specialised functions in higher eukaryotes. The spliceosome contains more than 100 proteins and RNA molecules which coordinate this dynamic process, and interestingly, despite the ubiquity of splicing, pathogenic variants in spliceosomal components often cause a tissue-specific phenotype, hinting at further complexities which are not yet fully understood. We have identified a cohort of ten families with de novo missense variants in a spliceosomal component, CRNKL1, where nine individuals harbour one of two missense variants that both affect the same amino acid, p.Arg267. All patients share a common and specific phenotype: profound pre- and post-natal microcephaly, with pontocerebellar hypoplasia, seizures and severe intellectual disability. Microinjection of mutant crnkl1 into a zebrafish model caused significant lack of brain development accompanied by a significant reduction in proliferating cells and widespread cellular stress, as indicated by p53 staining. RNA-seq analysis of injected zebrafish embryos showed widespread transcriptomic changes, with altered expression of neuronal and cell cycle genes. Together, we have identified CRNKL1 as a novel disease gene and demonstrate the requirement for this protein in brain development and functioning. Our findings contribute to a growing disease cluster, where components act at the same spliceosomal stage and cause a brain-specific but severe phenotype, suggesting a more intricate role for these spliceosomal subcomplexes than previously thought.

2025-04-15 | GSE294226 | GEO

Recurrent de novo variants in the spliceosomal factor CRNKL1 cause severe microcephaly and pontocerebellar hypoplasia with seizures [HeLa]

2025-04-15 | GSE294227 | GEO

Recurrent de novo variants in the spliceosomal factor CRNKL1 cause severe microcephaly and pontocerebellar hypoplasia with seizures

Project description:Recurrent de novo variants in the spliceosomal factor CRNKL1 cause severe microcephaly and pontocerebellar hypoplasia with seizures

| PRJNA1248757 | ENA

Molecular Characterization of Pontocerebellar Hypoplasia

Project description:Molecular Characterization of Pontocerebellar Hypoplasia

| PRJNA1062912 | ENA

Molecular Characterization of Pontocerebellar Hypoplasia

Project description:Molecular Characterization of Pontocerebellar Hypoplasia

| PRJNA1062911 | ENA

Recessive mutation in EXOSC3 associates with mitochondrial dysfunction and pontocerebellar hypoplasia

Project description:Recessive mutations in EXOSC3, encoding a subunit of the human RNA exosome complex, cause Pontocerebellar hypoplasia type 1b (PCH1B). We report a boy with severe muscular hypotonia, psychomotor retardation, progressive microcephaly, and cerebellar atrophy. Biochemical abnormalities comprised mitochondrial Complex I and PDHc deficiency. Whole exome sequencing uncovered a known EXOSC3-mutation p.(D132A) as the underlying cause. In patient fibroblasts, >50% of the EXOSC3 protein was trapped in the cytosol. mtDNA-copy numbers in muscle were reduced to 40%, but mutations in the mtDNA and nuclear mitochondrial genes were excluded. RNA-seq of patient muscle showed highly increased mRNA-copy numbers, especially for genes encoding structural subunits of OXPHOS-complexes I, III, and IV, possibly due to reduced degradation by a dysfunctional exosome complex. This is the first case of mitochondrial dysfunction associated with an EXOSC3 mutation, which expands the phenotypic spectrum of PCH1B. We discuss the links between exosome and mitochondrial dysfunction.

2017-08-22 | GSE99715 | GEO

Mutations in Spliceosomal Genes PPIL1 and PRP17 Cause Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly.

Project description:Autosomal-recessive cerebellar hypoplasia and ataxia constitute a group of heterogeneous brain disorders caused by disruption of several fundamental cellular processes. Here, we identified 10 families showing a neurodegenerative condition involving pontocerebellar hypoplasia with microcephaly (PCHM). Patients harbored biallelic mutations in genes encoding the spliceosome components Peptidyl-Prolyl Isomerase Like-1 (PPIL1) or Pre-RNA Processing-17 (PRP17). Mouse knockouts of either gene were lethal in early embryogenesis, whereas PPIL1 patient mutation knockin mice showed neuron-specific apoptosis. Loss of either protein affected splicing integrity, predominantly affecting short and high GC-content introns and genes involved in brain disorders. PPIL1 and PRP17 form an active isomerase-substrate interaction, but we found that isomerase activity is not critical for function. Thus, we establish disrupted splicing integrity and "major spliceosome-opathies" as a new mechanism underlying PCHM and neurodegeneration and uncover a non-enzymatic function of a spliceosomal proline isomerase.

| S-EPMC8800389 | biostudies-literature

Project description:Mutations in spliceosomal genes PPIL1 and PRP17 cause neurodegenerative pontocerebellar hypoplasia with microcephaly

| PRJNA669300 | ENA

RNA exosome mutations in pontocerebellar hypoplasia alter ribosome biogenesis and p53 levels

Project description:RNA exosome mutations in pontocerebellar hypoplasia alter ribosome biogenesis and p53 levels

| PRJNA635887 | ENA

RNA exosome mutations in pontocerebellar hypoplasia alter ribosome biogenesis and p53 levels

Project description:The eukaryotic RNA exosome is a ubiquitously expressed complex of nine core proteins (EXOSC1-9) and associated nucleases responsible for RNA processing and degradation. Autosomal recessive mutations in EXOSC3, EXOSC8, EXOSC9 and the exosome cofactor RBM7 cause pontocerebellar hypoplasia and motor neuronopathy. To understand the importance of the exosome in neurodegeneration, we investigated the consequences of exosome mutations on RNA metabolism and cellular survival in zebrafish and human cell models. We observed that levels of mRNAs encoding p53 and ribosome biogenesis factors are upregulated in zebrafish lines with homozygous mutations of exosc8 or exosc9, respectively. In addition, exosome deficiency leads to increased levels of multiple non-coding RNAs (e.g. tRNAs, snoRNAs, scaRNAs). Consistent with higher p53 levels, mutant zebrafish have a reduced head size, smaller brain and cerebellum caused by an increased number of apoptotic cells during development. Downregulation of EXOSC9 in human cells leads to p53 protein stabilisation and G2/M cell cycle arrest. The work provides explanation for the pathogenesis of exosome-related disorders and highlights the link between exosome function, ribosome biogenesis and p53-dependent signalling.

2020-05-30 | GSE151452 | GEO

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