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

PROVIDER: PRJNA669300 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12880724_1.fastq.gz	Fastqsanger.gz
	SRR12880724_2.fastq.gz	Fastqsanger.gz
	SRR12880725_1.fastq.gz	Fastqsanger.gz
	SRR12880725_2.fastq.gz	Fastqsanger.gz
	SRR12880726_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

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

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AMPD2 Regulates GTP Synthesis and is Mutated in a Potentially-Treatable Neurodegenerative Brainstem Disorder

Project description:Purine biosynthesis and metabolism, conserved in all living organisms, is essential for cellular energy homeostasis and nucleic acids synthesis. The de novo synthesis of purine precursors is under tight negative feedback regulation mediated by adenine and guanine nucleotides. We describe a new early-onset distinct neurodegenerative condition resulting from mutations in the adenosine monophosphate deaminase 2 gene (AMPD2). Patients have characteristic brain imaging features of pontocerebellar hypoplasia (PCH), due to loss of brainstem and cerebellar parenchyma. We found that AMPD2 plays an evolutionary conserved role in the maintenance of cellular guanine nucleotide pools by regulating the feedback inhibition of adenosine derivatives on de novo purine synthesis. AMPD2 deficiency results in defective GTP-dependent initiation of protein translation, which can be rescued by administration of purine precursors. These data suggest AMPD2-related PCH as a new potentially treatable early-onset neurodegenerative disease. An 18 chip study, that compares iPSC derived neural progenitor cells from two individuals: a patient with pontocerebellar hypoplasia and an unaffected parent. Samples are run as either non-treated, treated with Adenosine, or treated with Adenosine and AICAr. Three replicates are included for every individuals in every treatment condition.

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

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.

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