A neonatal encephalopathy with seizures in standard poodle dogs with a missense mutation in the canine ortholog of ATF2
- 309 Downloads
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.
KeywordsATF2 Activating transcription factor 2 Neonatal encephalopathy Seizures Dogs
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.
- 1.American Collge of Obstetricians and Gynecologists (2004) Neonatal encephalopathy and cerebral palsy: executive summary. Obstet Gynecol 103:780–781Google Scholar
- 3.Moon PF, Massat BJ, Pascoe PJ (2001) Neonatal critical care. Vet Clin N Am Small Anim Pract 31:343–365Google Scholar
- 20.Redding RW (1987) Electroencephalography. In: Oliver JE, Hoerlein BF, Mayhew IG (eds) Veterinary neurology. Saunders, Philadelphia, pp 111–144Google Scholar
- 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 8:916–924CrossRefGoogle Scholar
- 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 21:3782–3793PubMedCrossRefGoogle Scholar
- 34.Bardwell L (2006) Mechanisms of MAPK signalling specificity. Biochem Soc Trans 34:5–41Google Scholar