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


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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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.

Electronic supplementary material

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).

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