title: Characterisation of de novo MAPK10/JNK3 truncation mutations associated with cognitive disorders in two unrelated patients.
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.
authors: Neuroscience Research Center, Charité CrossOver, Charité-Universitaetsmedizin Berlin, Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany.
authors: Stella-Amrei
authors: SA
authors: Kunde
authors: Nils
authors: N
authors: Rademacher
authors: Andreas
authors: A
authors: Tzschach
authors: Eberhard
authors: E
authors: Wiedersberg
authors: Reinhard
authors: R
authors: Ullmann
authors: Vera M
authors: VM
authors: Kalscheuer
authors: Sarah A
authors: SA
authors: Shoichet
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence / Q000235:genetics*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D000076122:Disks Large Homolog 4 Protein; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D048057:Mitogen-Activated Protein Kinase 10 / Q000235:genetics* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017384:Sequence Deletion; D013569:Synapses / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014178:Translocation, Genetic
chemical_list: C116869:DLG3 protein, human; C501444:DLG4 protein, human; D000076122:Disks Large Homolog 4 Protein; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C492357:SHANK3 protein, human; D014157:Transcription Factors; D048057:Mitogen-Activated Protein Kinase 10