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

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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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References

  • Brecht S, Kirchhof R, Chromik A, Willesen M, Nicolaus T, Raivich G, Wessig J, Waetzig V, Goetz M, Claussen M, Pearse D, Kuan CY, Vaudano E, Behrens A, Wagner E, Flavell RA, Davis RJ, Herdegen T (2005) Specific pathophysiological functions of JNK isoforms in the brain. Eur J Neurosci 21:363–377

    Article  PubMed  Google Scholar 

  • Chelly J, Mandel JL (2001) Monogenic causes of X-linked mental retardation. Nat Rev Genet 2:669–680

    Article  PubMed  CAS  Google Scholar 

  • Cheung ZH, Ip NY (2004) Cdk5: mediator of neuronal death and survival. Neurosci Lett 361:47–51

    Article  PubMed  CAS  Google Scholar 

  • Coffey ET, Hongisto V, Dickens M, Davis RJ, Courtney MJ (2000) Dual roles for c-Jun N-terminal kinase in developmental and stress responses in cerebellar granule neurons. J Neurosci 20:7602–7613

    PubMed  CAS  Google Scholar 

  • Coso OA, Chiariello M, Yu JC, Teramoto H, Crespo P, Xu N, Miki T, Gutkind JS (1995) The small GTP-binding proteins Rac1 and Cdc42 regulate the activity of the JNK/SAPK signaling pathway. Cell 81:1137–1146

    Article  PubMed  CAS  Google Scholar 

  • Endris V, Wogatzky B, Leimer U, Bartsch D, Zatyka M, Latif F, Maher ER, Tariverdian G, Kirsch S, Karch D, Rappold GA (2002) The novel Rho-GTPase activating gene MEGAP/ srGAP3 has a putative role in severe mental retardation. Proc Natl Acad Sci USA 99:11754–11759

    Article  PubMed  CAS  Google Scholar 

  • Frangiskakis JM, Ewart AK, Morris CA, Mervis CB, Bertrand J, Robinson BF, Klein BP, Ensing GJ, Everett LA, Green ED, Proschel C, Gutowski NJ, Noble M, Atkinson DL, Odelberg SJ, Keating MT (1996) LIM-kinase1 hemizygosity implicated in impaired visuospatial constructive cognition. Cell 86:59–69

    Article  PubMed  CAS  Google Scholar 

  • Gray EG, Whittaker VP (1962) The isolation of nerve endings from brain: an electron-microscopic study of cell fragments derived by homogenization and centrifugation. J Anat 96:79–88

    PubMed  CAS  Google Scholar 

  • Hanks SK, Quinn AM, Hunter T (1988) The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science 241:42–52

    Article  PubMed  CAS  Google Scholar 

  • Ip YT, Davis RJ (1998) Signal transduction by the c-Jun N-terminal kinase (JNK)–from inflammation to development. Curr Opin Cell Biol 10:205–219

    Article  PubMed  CAS  Google Scholar 

  • Ito M, Yoshioka K, Akechi M, Yamashita S, Takamatsu N, Sugiyama K, Hibi M, Nakabeppu Y, Shiba T, Yamamoto KI (1999) JSAP1, a novel jun N-terminal protein kinase (JNK)-binding protein that functions as a Scaffold factor in the JNK signaling pathway. Mol Cell Biol 19:7539–7548

    PubMed  CAS  Google Scholar 

  • Kelkar N, Gupta S, Dickens M, Davis RJ (2000) Interaction of a mitogen-activated protein kinase signaling module with the neuronal protein JIP3. Mol Cell Biol 20:1030–1043

    Article  PubMed  CAS  Google Scholar 

  • Kobayashi K, Kuroda S, Fukata M, Nakamura T, Nagase T, Nomura N, Matsuura Y, Yoshida-Kubomura N, Iwamatsu A, Kaibuchi K (1998) p140Sra-1 (specifically Rac1-associated protein) is a novel specific target for Rac1 small GTPase. J Biol Chem 273:291–295

    Article  PubMed  CAS  Google Scholar 

  • Kuan CY, Yang DD, Samanta Roy DR, Davis RJ, Rakic P, Flavell RA (1999) The Jnk1 and Jnk2 protein kinases are required for regional specific apoptosis during early brain development. Neuron 22:667–676

    Article  PubMed  CAS  Google Scholar 

  • Kutsche K, Yntema H, Brandt A, Jantke I, Nothwang HG, Orth U, Boavida MG, David D, Chelly J, Fryns JP, Moraine C, Ropers HH, Hamel BC, van Bokhoven H, Gal A (2000) Mutations in ARHGEF6, encoding a guanine nucleotide exchange factor for Rho GTPases, in patients with X-linked mental retardation. Nat Genet 26:247–250

    Article  PubMed  CAS  Google Scholar 

  • Kyriakis JM, Avruch J (2001) Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev 81:807–869

    PubMed  CAS  Google Scholar 

  • Luo L (2000) Rho GTPases in neuronal morphogenesis. Nat Rev Neurosci 1:173–180

    Article  PubMed  CAS  Google Scholar 

  • McDonald PH, Chow CW, Miller WE, Laporte SA, Field ME, Lin FT, Davis RJ, Lefkowitz RJ (2000) Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3. Science 290:1574–1577

    Article  PubMed  CAS  Google Scholar 

  • Miller WE, McDonald PH, Cai SF, Field ME, Davis RJ, Lefkowitz RJ (2001) Identification of a motif in the carboxyl terminus of beta -arrestin2 responsible for activation of JNK3. J Biol Chem 276:27770–27777

    Article  PubMed  CAS  Google Scholar 

  • Minden A, Lin A, Claret FX, Abo A, Karin M (1995) Selective activation of the JNK signaling cascade and c-Jun transcriptional activity by the small GTPases Rac and Cdc42Hs. Cell 81:1147–1157

    Article  PubMed  CAS  Google Scholar 

  • Neidhart S, Antonsson B, Gillieron C, Vilbois F, Grenningloh G, Arkinstall S (2001) c-Jun N-terminal kinase-3 (JNK3)/stress-activated protein kinase-beta (SAPKbeta) binds and phosphorylates the neuronal microtubule regulator SCG10. FEBS Lett 508:259–264

    Article  PubMed  CAS  Google Scholar 

  • Nikolic M (2002) The role of Rho GTPases and associated kinases in regulating neurite outgrowth. Int J Biochem Cell Biol 34:731–745

    Article  PubMed  CAS  Google Scholar 

  • Nikolic M, Chou MM, Lu W, Mayer BJ, Tsai LH (1998) The p35/Cdk5 kinase is a neuron-specific Rac effector that inhibits Pak1 activity. Nature 395:194–198

    Article  PubMed  CAS  Google Scholar 

  • Ohshima T, Ward JM, Huh CG, Longenecker G, Veeranna, Pant HC, Brady RO, Martin LJ, Kulkarni AB (1996) Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death. Proc Natl Acad Sci USA 93:11173–11178

    Article  PubMed  CAS  Google Scholar 

  • Ramakers GJ (2000) Rho proteins and the cellular mechanisms of mental retardation. Am J Med Genet 94:367–371

    Article  PubMed  CAS  Google Scholar 

  • Ramakers GJ (2002) Rho proteins, mental retardation and the cellular basis of cognition. Trends Neurosci 25:191–199

    Article  PubMed  CAS  Google Scholar 

  • Ropers HH, Hamel BC (2005) X-linked mental retardation. Nat Rev Genet 6:46–57

    Article  PubMed  CAS  Google Scholar 

  • Schenck A, Bardoni B, Moro A, Bagni C, Mandel JL (2001) A highly conserved protein family interacting with the fragile X mental retardation protein (FMRP) and displaying selective interactions with FMRP-related proteins FXR1P and FXR2P. Proc Natl Acad Sci USA 98:8844–8849

    Article  PubMed  CAS  Google Scholar 

  • Shoichet SA, Hoffmann K, Menzel C, Trautmann U, Moser B, Hoeltzenbein M, Echenne B, Partington M, Van Bokhoven H, Moraine C, Fryns JP, Chelly J, Rott HD, Ropers HH, Kalscheuer VM (2003) Mutations in the ZNF41 gene are associated with cognitive deficits: identification of a new candidate for X-linked mental retardation. Am J Hum Genet 73:1341–1354

    Article  PubMed  CAS  Google Scholar 

  • Soderling SH, Langeberg LK, Soderling JA, Davee SM, Simerly R, Raber J, Scott JD (2003) Loss of WAVE-1 causes sensorimotor retardation and reduced learning and memory in mice. Proc Natl Acad Sci USA 100:1723–1728

    Article  PubMed  CAS  Google Scholar 

  • Waetzig V, Herdegen T (2003) A single c-Jun N-terminal kinase isoform (JNK3-p54) is an effector in both neuronal differentiation and cell death. J Biol Chem 278:567–572

    Article  PubMed  CAS  Google Scholar 

  • Warburton D (1991) De novo balanced chromosome rearrangements and extra marker chromosomes identified at prenatal diagnosis: clinical significance and distribution of breakpoints. Am J Hum Genet 49:995–1013

    PubMed  CAS  Google Scholar 

  • Wirth J, Nothwang HG, van der Maarel S, Menzel C, Borck G, Lopez-Pajares I, Brondum-Nielsen K, Tommerup N, Bugge M, Ropers HH, Haaf T (1999) Systematic characterisation of disease associated balanced chromosome rearrangements by FISH: cytogenetically and genetically anchored YACs identify microdeletions and candidate regions for mental retardation genes. J Med Genet 36:271–278

    PubMed  CAS  Google Scholar 

  • Yamauchi J, Hirasawa A, Miyamoto Y, Itoh H, Tsujimoto G (2001) Beta2-adrenergic receptor/cyclic adenosine monophosphate (cAMP) leads to JNK activation through Rho family small GTPases. Biochem Biophys Res Commun 284:1199–1203

    Article  PubMed  CAS  Google Scholar 

  • Yang DD, Kuan CY, Whitmarsh AJ, Rincon M, Zheng TS, Davis RJ, Rakic P, Flavell RA (1997) Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene. Nature 389:865–870

    Article  PubMed  CAS  Google Scholar 

  • Yoshida S, Fukino K, Harada H, Nagai H, Imoto I, Inazawa J, Takahashi H, Teramoto A, Emi M (2001) The c-Jun NH2-terminal kinase3 (JNK3) gene: genomic structure, chromosomal assignment, and loss of expression in brain tumors. J Hum Genet 46:182–187

    Article  PubMed  CAS  Google Scholar 

  • Zemni R, Bienvenu T, Vinet MC, Sefiani A, Carrie A, Billuart P, McDonell N, Couvert P, Francis F, Chafey P, Fauchereau F, Friocourt G, des Portes V, Cardona A, Frints S, Meindl A, Brandau O, Ronce N, Moraine C, van Bokhoven H, Ropers HH, Sudbrak R, Kahn A, Fryns JP, Beldjord C, Chelly J (2000) A new gene involved in X-linked mental retardation identified by analysis of an X;2 balanced translocation. Nat Genet 24:167–170

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors are grateful to the patient and his family. We also thank M. Hoeltzenbein for help with collecting clinical information. This work was supported by the National Genome Research Network (01GR0105) and by the Sonderforschungsbereich 415 (A12).

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Authors and Affiliations

  1. Max Planck Institute for Molecular Genetics, Ihnestrasse 73, 14195, Berlin, Germany

    Sarah A. Shoichet, Olivier Hagens, Corinna Menzel, Susann Schweiger, Hans-Hilger Ropers & Vera M. Kalscheuer

  2. Department of Medical Genetics, Laboratory of Cytogenetics, Hôpital Erasme-ULB, Brussels, Belgium

    Laurence Duprez

  3. Institute of Pharmacology, University of Kiel, Kiel, Germany

    Vicki Waetzig & Thomas Herdegen

  4. Department of Neurology, University Children’s Hospital Queen Fabiola, Free University of Brussels, Brussels, Belgium

    Bernard Dan

  5. Department of Medical Genetics, Hôpital Erasme-ULB, Brussels, Belgium

    Esther Vamos

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  1. Sarah A. Shoichet
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Correspondence to Vera M. Kalscheuer.

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Shoichet, S.A., Duprez, L., Hagens, O. et al. Truncation of the CNS-expressed JNK3 in a patient with a severe developmental epileptic encephalopathy. Hum Genet 118, 559–567 (2006). https://doi.org/10.1007/s00439-005-0084-y

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  • DOI: https://doi.org/10.1007/s00439-005-0084-y

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