A BCAN Microdeletion is Associated with Episodic Falling Syndrome in the Cavalier King Charles Spaniel
Tufts' Canine and Feline Breeding and Genetics Conference, 2011
Kate L. Tsai1; Jennifer L. Gill2; Christa Krey3; Rooksana E. Noorai1; Jean-François Vanbellinghen4; Laurent S. Garosi5; G. Diane Shelton6; Robert J. Harvey2; Leigh Anne Clark1
1Department of Genetics and Biochemistry, College of Agriculture, Forestry, and Life Sciences, Clemson University, Clemson, SC, USA; 2Department of Pharmacology, The School of Pharmacy, London, UK; 3Levin, New Zealand; 4Secteur Commun de Biologie Moléculaire - Unilab-Lg, Centre Hospitalier Universitaire de Liège, Liège, Belgium; 5Davies Veterinary Specialists, Manor Farm Business Park, Higham Gobion, Hertfordshire, UK; 6Department of Pathology, University of California, San Diego, La Jolla, CA, USA
Episodic falling syndrome (EFS) is an autosomal recessive disorder of Cavalier King Charles Spaniels (CKCS). EFS is characterized by muscle hypertonicity that causes dogs to stiffen and often fall. Episodes are usually triggered by exercise, stress, or excitement and may be mistaken for seizures. Dogs remain conscious throughout the event and are neurologically normal between events. Episodes may begin between fourteen weeks and four years of age and are variable in frequency and severity. The objective of this work was to identify the genetic basis for EFS in the CKCS. To this end, SNP profiles for 13 CKCS (5 affected, 1 obligate carrier, and 7 controls) were generated using the Affymetrix canine version 2 SNP array. Genome-wide association revealed a major locus on canine chromosome 7 and recombination events delimited the critical interval to a 3.48 Mb region. Sequence analysis of biologically plausible candidate genes revealed a 15.7 kb microdeletion that includes the promoter and first three exons of the brevican gene (BCAN). All affected animals in our cohort were homozygous for the microdeletion. The mutation was not detected in 93 dogs from 54 other breeds. Brevican encodes a brain-specific extracellular matrix proteoglycan and is highly expressed in the central nervous system. This is the first mutation to be identified in the BCAN gene. Multiplex PCR and Multiplex Ligation-dependent Probe Amplification genotyping tests were developed to distinguish normal, carrier, and affected animals. The mutation is not uncommon in the USA, having a frequency of 12.9% in a population of 155 CKCS with no history of EFS. A genetic test is now available through LABOKLIN (www.laboklin.co.uk).