title: Identification of the PLA2G6 c.1579G>A Missense Mutation in Papillon Dog Neuroaxonal Dystrophy Using Whole Exome Sequencing Analysis.
abstract: 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.
authors.affiliation: Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Tsuboi
authors.affiliation: Laboratory of Functional Genomics, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Japan Animal Referral Medical Center, Kanagawa, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Nibe
authors.affiliation: D&C Veterinary Clinic, Ibaraki, Japan.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Yoshimi
authors.affiliation: D&C Veterinary Clinic, Ibaraki, Japan.
authors.forename: Akihisa
authors.initials: A
authors.lastname: Kato
authors.affiliation: Laboratory of Veterinary Microbiology I, School of Veterinary Medicine, Azabu University, Kanagawa, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sakaguchi
authors.affiliation: Laboratory of Clinical Pathology, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Yamato
authors.affiliation: Laboratory of Veterinary Pathology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka, Japan.
authors.forename: Miyuu
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Laboratory of Veterinary Pathology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Osaka, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Kuwamura
authors.affiliation: Laboratory of Clinical Pathology, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Kushida
authors.affiliation: Thermo Fisher Scientific, Life Technologies Japan Ltd., Tokyo, Japan.
authors.forename: Takashi
authors.identifier: http://orcid.org/0000-0002-2683-0147
authors.initials: T
authors.lastname: Ishikura
authors.affiliation: Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Harada
authors.affiliation: Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: James Kenn
authors.initials: JK
authors.lastname: Chambers
authors.affiliation: Laboratory of Functional Genomics, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Sumio
authors.initials: S
authors.lastname: Sugano
authors.affiliation: Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Uchida
authors.affiliation: Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakayama
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004283:Dog Diseases / Q000235:genetics*; D004285:Dogs; D059472:Exome; D005260:Female; D054522:Group VI Phospholipases A2 / Q000737:chemistry / Q000235:genetics*; D007150:Immunohistochemistry; D008297:Male; D020125:Mutation, Missense; D019150:Neuroaxonal Dystrophies / Q000235:genetics / Q000662:veterinary*; D010375:Pedigree; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid
chemical_list: D012333:RNA, Messenger; D054522:Group VI Phospholipases A2