A CNGB1 frameshift mutation in Papillon and Phalène dogs with progressive retinal atrophy

PLoS One. 2013 Aug 28;8(8):e72122. doi: 10.1371/journal.pone.0072122. eCollection 2013.

Abstract

Progressive retinal degenerations are the most common causes of complete blindness both in human and in dogs. Canine progressive retinal atrophy (PRA) or degeneration resembles human retinitis pigmentosa (RP) and is characterized by a progressive loss of rod photoreceptor cells followed by a loss of cone function. The primary clinical signs are detected as vision impairment in a dim light. Although several genes have been associated with PRAs, there are still PRAs of unknown genetic cause in many breeds, including Papillons and Phalènes. We have performed a genome wide association and linkage studies in cohort of 6 affected Papillons and Phalènes and 14 healthy control dogs to map a novel PRA locus on canine chromosome 2, with a 1.9 Mb shared homozygous region in the affected dogs. Parallel exome sequencing of a trio identified an indel mutation, including a 1-bp deletion, followed by a 6-bp insertion in the CNGB1 gene. This mutation causes a frameshift and premature stop codon leading to probable nonsense mediated decay (NMD) of the CNGB1 mRNA. The mutation segregated with the disease and was confirmed in a larger cohort of 145 Papillons and Phalènes (PFisher = 1.4×10(-8)) with a carrier frequency of 17.2 %. This breed specific mutation was not present in 334 healthy dogs from 10 other breeds or 121 PRA affected dogs from 44 other breeds. CNGB1 is important for the photoreceptor cell function its defects have been previously associated with retinal degeneration in both human and mouse. Our study indicates that a frameshift mutation in CNGB1 is a cause of PRA in Papillons and Phalènes and establishes the breed as a large functional animal model for further characterization of retinal CNGB1 biology and possible retinal gene therapy trials. This study enables also the development of a genetic test for breeding purposes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Cyclic Nucleotide-Gated Cation Channels / genetics*
  • DNA Mutational Analysis
  • DNA Primers / genetics
  • Dog Diseases / genetics*
  • Dogs
  • Frameshift Mutation*
  • Genome-Wide Association Study
  • Homozygote
  • Linkage Disequilibrium
  • Molecular Sequence Data
  • Pedigree
  • Retinal Diseases / genetics
  • Retinal Diseases / veterinary*

Substances

  • Cyclic Nucleotide-Gated Cation Channels
  • DNA Primers

Grants and funding

This study was supported partly by the Academy of Finland, the Sigrid Juselius Foundation, Biocentrum Helsinki, the Jane and Aatos Erkko Foundation. SA is a student in Helsinki Graduate Program in Biotechnology and Molecular Biology. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.