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          Institute: MPI für molekulare Genetik     Collection: Department of Human Molecular Genetics     Display Documents



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ID: 308502.0, MPI für molekulare Genetik / Department of Human Molecular Genetics
Truncation of the CNS-expressed JNK3 in a patient with a severe developmental epileptic encephalopathy
Authors:Shoichet, Sarah A.; Duprez, Laurence; Hagens, Olivier; Waetzig, Vicki; Menzel, Corinna; Herdegen, Thomas; Schweiger, Susann; Dan, Bernard; Vamos, Esther; Ropers, Hans-Hilger; Kalscheuer, Vera M.
Language:English
Date of Publication (YYYY-MM-DD):2006-01-01
Title of Journal:Human Genetics
Journal Abbrev.:Hum. Gen.
Volume:118
Issue / Number:5
Start Page:559
End Page:567
Copyright:© Springer. Part of Springer Science+Business Media
Review Status:not specified
Audience:Experts Only
Abstract / Description: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.
Comment of the Author/Creator:Vera M. Kalscheuer
Email: kalscheu@molgen.mpg.de
Phone: +49-30-84131293
Fax: +49-30-84131383
External Publication Status:published
Document Type:Article
Communicated by:Hans-Hilger Ropers
Affiliations:MPI für molekulare Genetik
External Affiliations:1.Department of Medical Genetics, Laboratory of Cytogenetics, Hôpital Erasme-ULB, Brussels, Belgium;
2.Institute of Pharmacology, University of Kiel, Kiel, Germany;
3.Department of Neurology, University Children’s Hospital Queen Fabiola, Free University of Brussels, Brussels, Belgium;
4.Department of Medical Genetics, Hôpital Erasme-ULB, Brussels, Belgium.
Identifiers:ISSN:0340-6717
DOI:10.1007/s00439-005-0084-y
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