title: A COLQ missense mutation in Labrador Retrievers having congenital myasthenic syndrome.
abstract: Congenital myasthenic syndromes (CMSs) are heterogeneous neuromuscular disorders characterized by skeletal muscle weakness caused by disruption of signal transmission across the neuromuscular junction (NMJ). CMSs are rarely encountered in veterinary medicine, and causative mutations have only been identified in Old Danish Pointing Dogs and Brahman cattle to date. Herein, we characterize a novel CMS in 2 Labrador Retriever littermates with an early onset of marked generalized muscle weakness. Because the sire and dam share 2 recent common ancestors, CMS is likely the result of recessive alleles inherited identical by descent (IBD). Genome-wide SNP profiles generated from the Illumina HD array for 9 nuclear family members were used to determine genomic inheritance patterns in chromosomal regions encompassing 18 functional candidate genes. SNP haplotypes spanning 3 genes were consistent with autosomal recessive transmission, and microsatellite data showed that only the segment encompassing COLQ was inherited IBD. COLQ encodes the collagenous tail of acetylcholinesterase, the enzyme responsible for termination of signal transduction in the NMJ. Sequences from COLQ revealed a variant in exon 14 (c.1010T>C) that results in the substitution of a conserved amino acid (I337T) within the C-terminal domain. Both affected puppies were homozygous for this variant, and 16 relatives were heterozygous, while 288 unrelated Labrador Retrievers and 112 dogs of other breeds were wild-type. A recent study in which 2 human CMS patients were found to be homozygous for an identical COLQ mutation (c.1010T>C; I337T) provides further evidence that this mutation is pathogenic. This report describes the first COLQ mutation in canine CMS and demonstrates the utility of SNP profiles from nuclear family members for the identification of private mutations.
authors.affiliation: Department of Genetics and Biochemistry, College of Agriculture, Forestry, and Life Sciences, Clemson University, Clemson, South Carolina, United States of America.
authors.forename: Caitlin J
authors.initials: CJ
authors.lastname: Rinz
authors.affiliation: Department of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, United States of America.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Levine
authors.affiliation: Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota, United States of America.
authors.forename: Katie M
authors.initials: KM
authors.lastname: Minor
authors.affiliation: Department of Pathology, School of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Hammon D
authors.initials: HD
authors.lastname: Humphries
authors.affiliation: Kingdom Animal Hospital, Bryan, Texas, United States of America.
authors.forename: Renee
authors.initials: R
authors.lastname: Lara
authors.affiliation: Department of Genetics and Biochemistry, College of Agriculture, Forestry, and Life Sciences, Clemson University, Clemson, South Carolina, United States of America.
authors.forename: Alison N
authors.initials: AN
authors.lastname: Starr-Moss
authors.affiliation: Department of Pathology, School of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Ling T
authors.initials: LT
authors.lastname: Guo
authors.affiliation: R. Prichard Veterinary Medical Teaching Hospital, University of California Davis, Davis, California, United States of America.
authors.forename: D Colette
authors.initials: DC
authors.lastname: Williams
authors.affiliation: Department of Pathology, School of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: G Diane
authors.initials: GD
authors.lastname: Shelton
authors.affiliation: Department of Genetics and Biochemistry, College of Agriculture, Forestry, and Life Sciences, Clemson University, Clemson, South Carolina, United States of America.
authors.forename: Leigh Anne
authors.initials: LA
authors.lastname: Clark
mesh_terms: D000110:Acetylcholinesterase / Q000235:genetics* / Q000378:metabolism; D019943:Amino Acid Substitution; D000818:Animals; D003094:Collagen / Q000235:genetics; D004285:Dogs; D005260:Female; D056726:Genetic Association Studies / Q000379:methods*; D006801:Humans; D008297:Male; D009124:Muscle Proteins / Q000235:genetics; D020125:Mutation, Missense; D020294:Myasthenic Syndromes, Congenital / Q000235:genetics / Q000473:pathology* / Q000662:veterinary*; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA
chemical_list: D009124:Muscle Proteins; D003094:Collagen; D000110:Acetylcholinesterase; C114027:COLQ protein, human