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  Truncation of the CNS-expressed JNK3 in a patient with a severe developmental epileptic encephalopathy

Shoichet, S. A., Duprez, L., Hagens, O., Waetzig, V., Menzel, C., Herdegen, T., et al. (2006). Truncation of the CNS-expressed JNK3 in a patient with a severe developmental epileptic encephalopathy. Human Genetics, 118(5), 559-567. doi:10.1007/s00439-005-0084-y.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-84E3-2 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-84E4-F
Genre: Journal Article
Alternative Title : Hum. Gen.

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 Creators:
Shoichet, Sarah A.1, Author              
Duprez, Laurence, Author
Hagens, Olivier1, Author              
Waetzig, Vicki, Author
Menzel, Corinna2, Author
Herdegen, Thomas, Author
Schweiger, Susann1, Author              
Dan, Bernard, Author
Vamos, Esther, Author
Ropers, Hans-Hilger1, Author              
Kalscheuer, Vera M.3, Author              
Affiliations:
1Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433549              
2Max Planck Society, ou_persistent13              
3Chromosome Rearrangements and Disease (Vera Kalscheuer), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479642              

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 Abstract: We have investigated the breakpoints in a male child with pharmacoresistant epileptic encephalopathy and a de novo balanced translocation t(Y;4)(q11.2;q21). By fluorescence in situ hybridisation, we have identified genomic clones from both chromosome 4 and chromosome Y that span the breakpoints. Precise mapping of the chromosome 4 breakpoint indicated that the c-Jun N-terminal kinase 3 (JNK3) gene is disrupted in the patient. This gene is predominantly expressed in the central nervous system, and it plays an established role in both neuronal differentiation and apoptosis. Expression studies in the patient lymphoblastoid cell line show that the truncated JNK3 protein is expressed, i.e. the disrupted transcript is not immediately subject to nonsense-mediated mRNA decay, as is often the case for truncated mRNAs or those harbouring premature termination codons. Over-expression studies with the mutant protein in various cell lines, including neural cells, indicate that both its solubility and cellular localisation differ from that of the wild-type JNK3. It is plausible, therefore, that the presence of the truncated JNK3 disrupts normal JNK3 signal transduction in neuronal cells. JNK3 is one of the downstream effectors of the GTPase-regulated MAP kinase cascade, several members of which have been implicated in cognitive function. In addition, two known JNK3-interacting proteins, β-arrestin 2 and JIP3, play established roles in neurite outgrowth and neurological development. These interactions are likely affected by a truncated JNK3 protein, and thereby provide an explanation for the link between alterations in MAP kinase signal transduction and brain disorders.

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Language(s): eng - English
 Dates: 2006-01-01
 Publication Status: Published in print
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 Identifiers: eDoc: 308502
DOI: 10.1007/s00439-005-0084-y
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Title: Human Genetics
  Alternative Title : Hum. Gen.
Source Genre: Journal
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Pages: - Volume / Issue: 118 (5) Sequence Number: - Start / End Page: 559 - 567 Identifier: ISSN: 0340-6717