Identification of the PLA2G6 c.1579G>A Missense Mutation in Papillon Dog Neuroaxonal Dystrophy Using Whole Exome Sequencing Analysis

PLoS One. 2017 Jan 20;12(1):e0169002. doi: 10.1371/journal.pone.0169002. eCollection 2017.


Whole exome sequencing (WES) has become a common tool for identifying genetic causes of human inherited disorders, and it has also recently been applied to canine genome research. We conducted WES analysis of neuroaxonal dystrophy (NAD), a neurodegenerative disease that sporadically occurs worldwide in Papillon dogs. The disease is considered an autosomal recessive monogenic disease, which is histopathologically characterized by severe axonal swelling, known as "spheroids," throughout the nervous system. By sequencing all eleven DNA samples from one NAD-affected Papillon dog and her parents, two unrelated NAD-affected Papillon dogs, and six unaffected control Papillon dogs, we identified 10 candidate mutations. Among them, three candidates were determined to be "deleterious" by in silico pathogenesis evaluation. By subsequent massive screening by TaqMan genotyping analysis, only the PLA2G6 c.1579G>A mutation had an association with the presence or absence of the disease, suggesting that it may be a causal mutation of canine NAD. As a human homologue of this gene is a causative gene for infantile neuroaxonal dystrophy, this canine phenotype may serve as a good animal model for human disease. The results of this study also indicate that WES analysis is a powerful tool for exploring canine hereditary diseases, especially in rare monogenic hereditary diseases.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Dog Diseases / genetics*
  • Dogs
  • Exome*
  • Female
  • Group VI Phospholipases A2 / chemistry
  • Group VI Phospholipases A2 / genetics*
  • Immunohistochemistry
  • Male
  • Mutation, Missense*
  • Neuroaxonal Dystrophies / genetics
  • Neuroaxonal Dystrophies / veterinary*
  • Pedigree
  • RNA, Messenger / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Homology, Amino Acid


  • RNA, Messenger
  • Group VI Phospholipases A2

Grants and funding

This work was supported by Grant-in-Aid for JSPS KAKENHI ( 20721963 (to M. Tsuboi). One of our authors (TI) is employed by a commercial company (Thermo Fisher Scientific, Life Technologies Japan Ltd.). The funder provided support in the form of salary, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of the author is articulated in the ‘author contributions’ section.