Identification of Two Novel Isoforms of the ZNF162 Gene: A Growing Family of Signal Transduction and Activator of RNA Proteins

Caslini, Corrado; Spinelli, Orietta; Cazzaniga, Giovanni; Golay, Joseé; Gioia, Luca De; Pedretti, Alessandro; Breviario, Ferruccio; Amaru, Ricardo; Barbui, Tiziano; Biondi, Andrea; Introna, Martino

doi:10.1006/geno.1997.4705

Cited by 11 publications

(7 citation statements)

References 34 publications

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“…Repeated contacts with factors differentially expressed during development or in a particular cell type would make splice site recognition processes particularly vulnerable in pre-mRNAs with BPS mutations. Although U2 snRNA is ubiquitously expressed, ASF/SF2, U2AF 65 , and SF1 show tissue-specific expression [Toda et al, 1994;Arning et al, 1996;Caslini et al, 1997;Hanamura et al, 1998]. However, splice site selection can be influenced by other factors, including altered secondary structure [Buratti and Baralle, 2004], the rate of transcription [Kornblihtt, 2006], and the order of intron removal [Schwarze et al, 1999].…”

Section: Discussionmentioning

confidence: 96%

Phenotypic consequences of branch point substitutions

2006

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The branch point sequence (BPS) is a conserved splicing signal important for spliceosome assembly and lariat intron formation. BPS mutations may result in aberrant pre-mRNA splicing and genetic disorders, but their phenotypic consequences have been difficult to predict, largely due to a highly degenerate nature of the BPS consensus. Here, we have examined the splicing pattern of nine reporter pre-mRNAs that have previously been shown to give rise to human hereditary diseases as a result of single-nucleotide substitutions in the predicted BPS. Increased exon skipping and intron retention observed in vivo were recapitulated for each mutated pre-mRNA, but the reproducibility of cryptic splice site activation was lower. BP mutations in reporter pre-mRNAs frequently induced aberrant 3' splice sites and also activated a cryptic 5' splice site. Systematic mutagenesis of BP adenosines showed that in most pre-mRNAs, the expression of canonical transcripts was lower for BP transitions than BP transversions. Differential splicing outcome for transitions vs. transversions was abrogated or reduced if introns were truncated to 200 nt or less, suggesting that the nature of the BP residue is less critical for interactions across very short introns. Together, these results improve prediction of phenotypic consequences of point mutations upstream of splice acceptor sites and suggest that the overrepresentation of disease-causing adenosine-to-guanosine BP substitutions observed in Mendelian disorders is due to more profound defects of gene expression at the level of pre-mRNA splicing.

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Section: Discussionmentioning

confidence: 96%

Phenotypic consequences of branch point substitutions

2006

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“…There have been four isoforms of ZFP 162 identified to date, all of which contain a KH domain, thought to be important in regulating cellular RNA metabolism (Caslini and others 1997). Although two isoforms are expressed in resting cells, all four isoforms are up-regulated following exposure to granulocyle-macrophage colony stimulating factor (Caslini and others 1997), which is known to activate signal transduction pathways. The role in neurons is yet to be elucidated, but a function in regulating RNA stability could have dramatic consequences in the setting of PD.…”

Section: Zfp 162mentioning

confidence: 99%

Altered Gene Expression Profiles Reveal Similarities and Differences Between Parkinson Disease and Model Systems

Miller

Federoff

2005

Neuroscientist

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Parkinson disease (PD) targets dopaminergic neurons in the substantia nigra, resulting in motor disturbances such as resting tremor, bradykinesia, and rigidity. Pathogenic processes likely occur over several decades, in that an overwhelming percentage of neurons are already dead at the time of clinical diagnosis. For this reason, the usage of animal model systems to discover the early steps in the pathologic cascade is required. These include exposure to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which selectively kills dopamine neurons in the substantia nigra, and genetic models incorporating mutations in the alpha-synuclein gene that cause disease in human patients. Through the evaluation of these models at multiple time points, it is possible to discover novel gene expression changes that may underlie disease pathogenesis. Specifically, the authors hypothesize that animal models of PD and human PD brains share a gene expression profile that signifies certain aspects of pathogenesis and/or recovery-resistance. To test this and similar hypotheses, the authors and others have utilized new microarray technology that enables the sampling of thousands of genes' expression level in one assay. Because the technology is fairly new and results can vary depending on methods used, results must be evaluated with care. Multiple array and data-mining options can be used to make the most accurate inferences as to differentially expressed genes in each set of samples. The authors developed a fusion classifier approach whereby individual data-mining algorithms generate lists of significant genes. The lists are subsequently queried, and only genes unanimously called significant are retained for further validation. Although the authors' approach identified hundreds of differentially expressed genes in each of three PD systems, only a few were common between the human and animal substantia nigra. These were related to dopamine phenotype, synaptic function, and the mitochondrial metabolism, implicating the presynaptic terminal as a primary site of injury. The time course of the authors' experiments indicates that if the synaptic changes could be prevented, this may alleviate some cell death, in that these changes precede neuronal loss.

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“…Table 1 summarizes the different alleles of the quaking gene and their phenotypes. A candidate gene, QKI, encodes a KH domain-containing protein that binds RNA (probably as a dimer) and may be involved in some aspect of RNA metabolism Caslini et al, 1997;Zaffran et al, 1997;see Vernet and Artzt, 1997). Transcription of the gene is complex, producing at least three isoforms.…”

Section: Introductionmentioning

confidence: 98%