title: Pedigree analysis and exclusion of alpha-tocopherol transfer protein (TTPA) as a candidate gene for neuroaxonal dystrophy in the American Quarter Horse.
abstract: BACKGROUND
  Equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (NAD/EDM) is a neurodegenerative disorder affecting young horses of various breeds that resembles ataxia with vitamin E deficiency in humans, an inherited disorder caused by mutations in the alpha-tocopherol transfer protein gene (TTPA). To evaluate variants found upon sequencing TTPA in the horse, the mode of inheritance for NAD/EDM had to be established.
  
  
  OBJECTIVE
  NAD/EDM in the American Quarter Horse (QH) is caused by a mutation in TTPA.
  
  
  METHODS
  88 clinically phenotyped (35 affected [ataxia score ≥2], 53 unaffected) QHs with a diagnosis of NAD/EDM with 6 affected and 4 unaffected cases confirmed at postmortem examination.
  
  
  METHODS
  Pedigrees and genotypes across 54,000 single nucleotide polymorphism (SNP) markers were assessed to determine heritability and mode of inheritance of NAD/EDM. TTPA sequence of exon/intron boundaries was evaluated in 2 affected and 2 control horses. An association analysis was performed by 71 SNPs surrounding TTPA and 8 SNPs within TTPA that were discovered by sequencing. RT-PCR for TTPA was performed on mRNA from the liver of 4 affected and 4 control horses.
  
  
  RESULTS
  Equine NAD/EDM appears to be inherited as a polygenic trait and, within this family of QHs, demonstrates high heritability. Sequencing of TTPA identified 12 variants. No significant association was found using the 79 available variants in and surrounding TTPA. RT-PCR yielded PCR products of equivalent sizes between affected cases and controls.
  
  
  CONCLUSIONS
  NAD/EDM demonstrates heritability in this family of QHs. Variants in TTPA are not responsible for NAD/EDM in this study population.
authors.affiliation: Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA, USA. finn0100@umn.edu
authors.forename: C J
authors.initials: CJ
authors.lastname: Finno
authors.forename: T
authors.initials: T
authors.lastname: Famula
authors.forename: M
authors.initials: M
authors.lastname: Aleman
authors.forename: R J
authors.initials: RJ
authors.lastname: Higgins
authors.forename: J E
authors.initials: JE
authors.lastname: Madigan
authors.forename: D L
authors.initials: DL
authors.lastname: Bannasch
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006734:Horse Diseases / Q000235:genetics*; D006736:Horses; D008297:Male; D019150:Neuroaxonal Dystrophies / Q000235:genetics / Q000662:veterinary*; D010375:Pedigree
chemical_list: D002352:Carrier Proteins; C017763:alpha-tocopherol transfer protein