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  Characterisation of de novo MAPK10/JNK3 truncation mutations associated with cognitive disorders in two unrelated patients

Kunde, S.-A., Rademacher, N., Tzschach, A., Wiedersberg, E., Ullmann, R., Kalscheuer, V. M., et al. (2013). Characterisation of de novo MAPK10/JNK3 truncation mutations associated with cognitive disorders in two unrelated patients. Human Genetics, 132(4), 461-471. doi:10.1007/s00439-012-1260-5.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0018-EDE9-1 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0018-EDEC-C
Genre: Journal Article

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Kunde, Stella-Amrei, Author
Rademacher, Nils, Author
Tzschach, Andreas, Author
Wiedersberg, Eberhard, Author
Ullmann, Reinhard1, Author              
Kalscheuer, Vera M.2, Author              
Shoichet, Sarah A., Author
Affiliations:
1Molecular Cytogenetics (Reinhard Ullmann), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, Ihnestr. 73, 14195 Berlin, Germany, ou_1479645              
2Chromosome Rearrangements and Disease (Vera Kalscheuer), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, Ihnestr, 73, 14195 Berlin, Germany, ou_1479642              

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Free keywords: Adolescent Amino Acid Sequence/*genetics Animals COS Cells Cercopithecus aethiops Female Gene Expression Regulation/genetics Hippocampus/metabolism/pathology Humans Intellectual Disability/*genetics/metabolism/pathology Intracellular Signaling Peptides and Proteins/genetics/metabolism Male Membrane Proteins/genetics/metabolism Mitogen-Activated Protein Kinase 10/*genetics/metabolism Nerve Tissue Proteins/genetics/metabolism Neurons/metabolism/pathology Nuclear Proteins/genetics/metabolism Protein Structure, Tertiary Rats Rats, Wistar Seizures/genetics/*metabolism/pathology *Sequence Deletion Synapses/genetics/metabolism Transcription Factors/genetics/metabolism *Translocation, Genetic
 Abstract: The c-Jun N-terminal kinases (JNKs) are stress-activated serine-threonine kinases that have recently been linked to various neurological disorders. We previously described a patient with intellectual disability (ID) and seizures (Patient 1), carrying a de novo chromosome translocation affecting the CNS-expressed MAPK10/JNK3 gene. Here, we describe a second ID patient (Patient 2) with a similar translocation that likewise truncates MAPK10/JNK3, highlighting a role for JNK3 in human brain development. We have pinpointed the breakpoint in Patient 2, which is just distal to that in Patient 1. In both patients, the rearrangement resulted in a predicted protein interrupted towards the C-terminal end of the kinase domain. We demonstrate that these truncated proteins, although capable of weak interaction with various known JNK scaffolds, are not capable of phosphorylating the classical JNK target c-Jun in vitro, which suggests that the patient phenotype potentially arises from partial loss of JNK3 function. We next investigated JNK3-binding partners to further explore potential disease mechanisms. We identified PSD-95, SAP102 and SHANK3 as novel interaction partners for JNK3, and we demonstrate that JNK3 and PSD-95 exhibit partially overlapping expression at synaptic sites in cultured hippocampal neurons. Moreover, JNK3, like JNK1, is capable of phosphorylating PSD-95 in vitro, whereas disease-associated mutant JNK3 proteins do not. We conclude that reduced JNK3 activity has potentially deleterious effects on neuronal function via altered regulation of a set of post-synaptic proteins.

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Language(s): eng - English
 Dates: 2013-01-182013-04
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1007/s00439-012-1260-5
ISSN: 1432-1203 (Electronic)0340-6717 (Print)
URI: http://www.ncbi.nlm.nih.gov/pubmed/23329067
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Title: Human Genetics
Source Genre: Journal
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Publ. Info: Berlin : Springer-Verlag
Pages: - Volume / Issue: 132 (4) Sequence Number: - Start / End Page: 461 - 471 Identifier: ISSN: 0340-6717
CoNE: /journals/resource/954925519623