title: A CHRNE frameshift mutation causes congenital myasthenic syndrome in young Jack Russell Terriers.
abstract: Congenital myasthenic syndromes (CMSs) are a group of rare genetic disorders of the neuromuscular junction resulting in structural or functional causes of fatigable weakness that usually begins early in life. Mutations in pre-synaptic, synaptic and post-synaptic proteins have been demonstrated in human cases, with more than half involving aberrations in nicotinic acetylcholine receptor (AChR) subunits. CMS was first recognized in dogs in 1974 as an autosomal recessive trait in Jack Russell Terriers (JRTs). A deficiency of junctional AChRs was demonstrated. Here we characterize a CMS in 2 contemporary cases of JRT littermates with classic clinical and electromyographic findings, and immunochemical confirmation of an approximately 90% reduction in AChR protein content. Loci encoding the 5 AChR subunits were evaluated using microsatellite markers, and CHRNB1 and CHRNE were identified as candidate genes. Sequences of the splice sites and exons of both genes revealed a single base insertion in exon 7 of CHRNE that predicts a frameshift mutation and a premature stop codon. We further demonstrated this pathogenic mutation in CHRNE in archival tissues from unrelated JRTs studied 34 years ago.
authors.affiliation: Department of Genetics and Biochemistry, College of Agriculture, Forestry, and Life Sciences, Clemson University, Clemson, SC 29634, USA.
authors.forename: Caitlin J
authors.initials: CJ
authors.lastname: Rinz
authors.affiliation: Departments of Laboratory Medicine, Immunology and Neurology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Vanda A
authors.initials: VA
authors.lastname: Lennon
authors.affiliation: Department of Clinical Studies, Ontario Veterinary College, University of Guelph, ON, Canada N1G 2W1.
authors.forename: Fiona
authors.initials: F
authors.lastname: James
authors.affiliation: Departments of Laboratory Medicine, Immunology and Neurology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: James B
authors.initials: JB
authors.lastname: Thoreson
authors.affiliation: Department of Genetics and Biochemistry, College of Agriculture, Forestry, and Life Sciences, Clemson University, Clemson, SC 29634, USA.
authors.forename: Kate L
authors.initials: KL
authors.lastname: Tsai
authors.affiliation: Department of Genetics and Biochemistry, College of Agriculture, Forestry, and Life Sciences, Clemson University, Clemson, SC 29634, USA.
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, CA 92093-0709, USA.
authors.forename: H Dale
authors.initials: HD
authors.lastname: Humphries
authors.affiliation: Department of Pathology, School of Medicine, University of California San Diego, La Jolla, CA 92093-0709, USA.
authors.forename: Ling T
authors.initials: LT
authors.lastname: Guo
authors.affiliation: School of Veterinary Medicine, Cambridge University, Cambridge, UK.
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Palmer
authors.affiliation: Department of Genetics and Biochemistry, College of Agriculture, Forestry, and Life Sciences, Clemson University, Clemson, SC 29634, USA. Electronic address: lclark4@clemson.edu.
authors.forename: Leigh Anne
authors.initials: LA
authors.lastname: Clark
authors.affiliation: Department of Pathology, School of Medicine, University of California San Diego, La Jolla, CA 92093-0709, USA. Electronic address: gshelton@ucsd.edu.
authors.forename: G Diane
authors.initials: GD
authors.lastname: Shelton
mesh_terms: D000818:Animals; D004285:Dogs; D016368:Frameshift Mutation; D007366:Intercostal Muscles / Q000473:pathology; D008297:Male; D020294:Myasthenic Syndromes, Congenital / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D011978:Receptors, Nicotinic / Q000235:genetics*
chemical_list: D011978:Receptors, Nicotinic
keywords: Animal model; Canine; Muscle nicotinic acetylcholine receptor; Myasthenia gravis; Neuromuscular junction