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A neonatal encephalopathy with seizures in standard poodle dogs with a missense mutation in the canine ortholog of ATF2

Abstract

Neonatal encephalopathy with seizures (NEWS) is a previously undescribed autosomal recessive disease of standard poodle puppies. Affected puppies are small and weak at birth. Many die in their first week of life. Those surviving past 1 week develop ataxia, a whole-body tremor, and, by 4 to 6 weeks of age, severe generalized clonic–tonic seizures. None have survived to 7 weeks of age. Cerebella from affected puppies were reduced in size and often contained dysplastic foci consisting of clusters of intermixed granule and Purkinje neurons. We used deoxyribonucleic acid samples from related standard poodles to map the NEWS locus to a 2.87-Mb segment of CFA36, which contains the canine ortholog of ATF2. This gene encodes activating transcription factor 2 (ATF-2), which participates in the cellular responses to a wide variety of stimuli. We amplified and sequenced all coding regions of canine ATF2 from a NEWS-affected puppy and identified a T > G transversion that predicts a methionine-to-arginine missense mutation at amino acid position 51. Methionine-51 lies within a hydrophobic docking site for mitogen-activated protein kinases that activate ATF-2 so the arginine substitution is likely to interfere with ATF-2 activation. All 20 NEWS-affected puppies in the standard poodle family were homozygous for the mutant G allele. The 58 clinically normal family members were either G/T heterozygotes or homozygous for the ancestral T allele. There are no previous reports of spontaneous ATF2 mutations in people or animals; however, atf2-knockout mice have cerebellar lesions that are similar to those in puppies with NEWS.

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References

  1. 1.

    American Collge of Obstetricians and Gynecologists (2004) Neonatal encephalopathy and cerebral palsy: executive summary. Obstet Gynecol 103:780–781

    Google Scholar 

  2. 2.

    Wirrell E, Farrell K, Whiting S (2005) The epileptic encephalopathies of infancy and childhood. Can J Neurol Sci 32:409–418

    PubMed  Google Scholar 

  3. 3.

    Moon PF, Massat BJ, Pascoe PJ (2001) Neonatal critical care. Vet Clin N Am Small Anim Pract 31:343–365

    CAS  Google Scholar 

  4. 4.

    Maekawa T, Sakura H, Kanei-Ishii C, Sudo T, Yoshimura T, Fujisawa J, Yoshida M, Ishii S (1989) Leucine zipper structure of the protein CRE-BP1 binding to the cyclic AMP response element in brain. EMBO J 8:2023–2028

    PubMed  CAS  Google Scholar 

  5. 5.

    Newman JR, Keating AE (2003) Comprehensive identification of human bZIP interactions with coiled-coil arrays. Science 300:2097–2101

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Shimizu M, Nomura Y, Suzuki H, Ichikawa E, Takeuchi A, Suzuki M, Nakamura T, Nakajima T, Oda K (1998) Activation of the rat cyclin A promoter by ATF2 and Jun family members and its suppression by ATF4. Exp Cell Res 239:93–103

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Monzen K, Hiroi Y, Kudoh S, Akazawa H, Oka T, Takimoto E, Hayashi D, Hosoda T, Kawabata M, Miyazono K, Ishii S, Yazaki Y, Nagai R, Komuro I (2001) Smads, TAK1, and their common target ATF-2 play a critical role in cardiomyocyte differentiation. J Cell Biol 153:687–698

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Hong S, Choi HM, Park MJ, Kim YH, Choi YH, Kim HH, Choi YH, Cheong J (2004) Activation and interaction of ATF2 with the coactivator ASC-2 are responsive for granulocytic differentiation by retinoic acid. J Biol Chem 279:16996–17003

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Hayakawa J, Depatie C, Ohmichi M, Mercola D (2003) The activation of c-Jun NH2-terminal kinase (JNK) by DNA-damaging agents serves to promote drug resistance via activating transcription factor 2 (ATF2)-dependent enhanced DNA repair. J Biol Chem 278:20582–20592

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    van Dam H, Wilhelm D, Herr I, Steffen A, Herrlich P, Angel P (1995) ATF-2 is preferentially activated by stress-activated protein kinases to mediate c-jun induction in response to genotoxic agents. EMBO J 14:1798–1811

    PubMed  Google Scholar 

  11. 11.

    van Dam H, Castellazzi M (2001) Distinct roles of Jun: Fos and Jun: ATF dimers in oncogenesis. Oncogene 20:2453–2464

    PubMed  Article  Google Scholar 

  12. 12.

    Walton M, Woodgate AM, Sirimanne E, Gluckman P, Dragunow M (1998) ATF-2 phosphorylation in apoptotic neuronal death. Brain Res Mol Brain Res 63:198–204

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    Reimold AM, Grusby MJ, Kosaras B, Fries JW, Mori R, Maniwa S, Clauss IM, Collins T, Sidman RL, Glimcher MJ, Glimcher LH (1996) Chondrodysplasia and neurological abnormalities in ATF-2-deficient mice. Nature 379(6562):262–265

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Maekawa T, Bernier F, Sato M, Nomura S, Singh M, Inoue Y, Tokunaga T, Imai H, Yokoyama M, Reimold A, Glimcher LH, Ishii S (1999) Mouse ATF-2 null mutants display features of a severe type of meconium aspiration syndrome. J Biol Chem 274:17813–17819

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    Reimold AM, Kim J, Finberg R, Glimcher LH (2001) Decreased immediate inflammatory gene induction in activating transcription factor-2 mutant mice. Int Immunol 13:241–248

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Otun HA, MacDougall MW, Bailey J, Europe-Finner GN, Robson SC (2005) Spatial and temporal expression of the myometrial mitogen-activated protein kinases p38 and ERK1/2 in the human uterus during pregnancy and labor. J Soc Gynecol Invest 12:185–90

    Article  CAS  Google Scholar 

  17. 17.

    Hu MC, Wasserman D, Hartwig S, Rosenblum ND (2004) p38MAPK acts in the BMP7-dependent stimulatory pathway during epithelial cell morphogenesis and is regulated by Smad1. J Biol Chem 279:12051–12059

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Beier F, Taylor AC, Luvalle P (2000) Activating transcription factor 2 is necessary for maximal activity and serum induction of the cyclin A promoter in chondrocytes. J Biol Chem 275:12948–12953

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Katz ML, Khan S, Awano T, Shahid SA, Siakotos AN, Johnson GS (2005) A mutation in the CLN8 gene in English Setter dogs with neuronal ceroid-lipofuscinosis. Biochem Biophys Res Commun 327:541–547

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    Redding RW (1987) Electroencephalography. In: Oliver JE, Hoerlein BF, Mayhew IG (eds) Veterinary neurology. Saunders, Philadelphia, pp 111–144

    Google Scholar 

  21. 21.

    Clark LA, Tsai KL, Steiner JM, Williams DA, Guerra T, Ostrander EA, Galibert F, Murphy KE (2004) Chromosome-specific microsatellite multiplex sets for linkage studies in the domestic dog. Genomics 84:550–554

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Thallman RM, Bennett GL, Keele JW, Kappes SM (2001) Efficient computation of genotype probabilities for loci with many alleles: II. Iterative method for large, complex pedigrees. J Anim Sci 79:34–44

    PubMed  CAS  Google Scholar 

  23. 23.

    Thallman RM, Bennett GL, Keele JW, Kappes SM (2001) Efficient computation of genotype probabilities for loci with many alleles: I. Allelic peeling. J Anim Sci 79:26–33

    PubMed  CAS  Google Scholar 

  24. 24.

    Sobel E, Lange K (1996) Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker-sharing statistics. Am J Hum Genet 58:1323–1337

    PubMed  CAS  Google Scholar 

  25. 25.

    Ramensky V, Bork P, Sunyaev S (2002) Human non-synonymous SNPs: server and survey. Nucleic Acids Res 30:3894–3900

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    Bacchelli E, Blasi F, Biondolillo M, Lamb JA, Bonora E, Barnby G, Parr J, Beyer KS, Klauck SM, Poustka A, Bailey AJ, Monaco AP, Maestrini E (2003) Screening of nine candidate genes for autism on chromosome 2q reveals rare nonsynonymous variants in the cAMP-GEFII gene. Mol Psychiatr 8:916–924

    Article  CAS  Google Scholar 

  27. 27.

    Kawasaki H, Schiltz L, Chiu R, Itakura K, Taira K, Nakatani Y, Yokoyama KK (2000) ATF-2 has intrinsic histone acetyltransferase activity which is modulated by phosphorylation. Nature 405:195–200

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    Livingstone C, Patel G, Jones N (1995) ATF-2 contains a phosphorylation-dependent transcriptional activation domain. EMBO J 14:1785–1797

    PubMed  CAS  Google Scholar 

  29. 29.

    Morton S, Davis RJ, Cohen P (2004) Signalling pathways involved in multisite phosphorylation of the transcription factor ATF-2. FEBS Lett 572:177–183

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Ouwens DM, de Ruiter ND, van der Zon GC, Carter AP, Schouten J, van der Burgt C, Kooistra K, Bos JL, Maassen JA, van Dam H (2002) Growth factors can activate ATF2 via a two-step mechanism: phosphorylation of Thr71 through the Ras-MEK-ERK pathway and of Thr69 through RalGDS-Src-p38. EMBO J 21:3782–3793

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Ventura JJ, Kennedy NJ, Lamb JA, Flavell RA, Davis RJ (2003) c-Jun NH2-terminal kinase is essential for the regulation of AP-1 by tumor necrosis factor. Mol Cell Biol 23:2871–82

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Breitwieser W, Lyons S, Flenniken AM, Ashton G, Bruder G, Willington M, Lacaud G, Kouskoff V, Jones N (2007) Feedback regulation of p38 via ATF2 is essential for survival of embryonic liver cells. Genes Dev 21:2069–82

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Nagadoi A, Nakazawa K, Uda H, Okuno K, Maekawa T, Ishii S, Nishimura Y (1999) Solution structure of the transactivation domain of ATF-2 comprising a zinc finger-like subdomain and a flexible subdomain. J Mol Biol 287:593–607

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    Bardwell L (2006) Mechanisms of MAPK signalling specificity. Biochem Soc Trans 34:5–41

    Google Scholar 

  35. 35.

    Sharrocks AD, Yang SH, Galanis A (2000) Docking domains and substrate-specificity determination for MAP kinases. Trends Biochem Sci 25:448–453

    PubMed  Article  CAS  Google Scholar 

  36. 36.

    Maekawa T, Shinagawa T, Sano Y, Sakuma T, Nomura S, Nagasaki K, Miki Y, Saito-Ohara F, Inazawa J, Kohno T, Yokota J, Ishii S (2007) Reduced levels of ATF-2 predispose mice to mammary tumors. Mol Cell Biol 27:1730–1744

    PubMed  Article  CAS  Google Scholar 

  37. 37.

    Woo IS, Kohno T, Inoue K, Ishii S, Yokota J (2002) Infrequent mutations of the activating transcription factor-2 gene in human lung cancer, neuroblastoma and breast cancer. Int J Oncol 20:527–531

    PubMed  CAS  Google Scholar 

  38. 38.

    Badawi N, Kurinczuk JJ, Keogh JM, Alessandri LM, O’Sullivan F, Burton PR, Pemberton PJ, Fiona J Stanley FJ (1998) Intrapartum risk factors for newborn encephalopathy: the Western Australian case–control study. BMJ 317:1554–1558

    PubMed  CAS  Google Scholar 

  39. 39.

    Badawi N, Kurinczuk JJ, Keogh JM, Alessandri LM, O’Sullivan F, Burton PR, Pemberton PJ, Fiona J Stanley FJ (1998) Antepartum risk factors for newborn encephalopathy: the Western Australian case–control study. BMJ 317:1549–1553

    PubMed  CAS  Google Scholar 

  40. 40.

    Scher MS (2006) Neonatal seizure classification: a fetal perspective concerning childhood epilepsy. Epilepsy Res 70:S41–S57

    PubMed  Article  Google Scholar 

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Acknowledgments

This work was supported by grant number 709A from the American Kennel Club Canine Health Foundation, an unrestricted grant from Research to Prevent Blindness, and gifts from the Poodle Club of America, the Saint Joseph Missouri Kennel Club, the Poodle Club of Southern California, and individual standard poodle breeders. The authors thank Dr. Elaine A. Ostrander (NHGRI/NIH) for providing us with oligonucleotides for microsatellite markers from the canine Minimal Mapping Set 2. The experiments comply with the current laws of the USA.

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Correspondence to Gary S. Johnson.

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Supplementary Video 1

Video clip of a seizure in a 4-week-old standard poodle with neonatal encephalopathy with seizures (NEWS). The seizure has focal onset with facial twitching, lip smacking, and myoclonic jerking of the head. It then generalizes to vocalization and clonic limb movements and ends with tonic extension of the limbs. There was a postictal period (not shown) of agitation and disorientation.

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Chen, X., Johnson, G.S., Schnabel, R.D. et al. A neonatal encephalopathy with seizures in standard poodle dogs with a missense mutation in the canine ortholog of ATF2 . Neurogenetics 9, 41–49 (2008). https://doi.org/10.1007/s10048-007-0112-2

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Keywords

  • ATF2
  • Activating transcription factor 2
  • Neonatal encephalopathy
  • Seizures
  • Dogs