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

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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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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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Authors and Affiliations

  1. Department of Veterinary Pathobiology, University of Missouri, 322 Connaway Hall, Columbia, MO, 65211, USA

    Xuhua Chen, Gary S. Johnson, Gayle C. Johnson, Martin L. Katz, Tomoyuki Awano & Shahwanaz Khan

  2. Division of Animal Sciences, University of Missouri, Columbia, MO, 65211, USA

    Robert D. Schnabel & Jeremy F. Taylor

  3. Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA

    Heidi G. Parker

  4. Department of Veterinary Clinical Sciences, University of Minnesota, St. Paul, MN, 55108, USA

    Edward E. Patterson

  5. Mason Eye Institute, University of Missouri, Columbia, MO, 65211, USA

    Martin L. Katz

  6. Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO, 65211, USA

    Dennis P. O’Brien

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  1. Xuhua Chen
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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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  • DOI: https://doi.org/10.1007/s10048-007-0112-2

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