Startle disease in Irish wolfhounds associated with a microdeletion in the glycine transporter GlyT2 gene

Neurobiology of Disease

Robert J. Harvey¹  Robert J. Higgins²  G. Diane Shelton³  Jennifer L. Gill⁴  Deborah Capper⁵  Seo-Kyung Chung⁶  Mark I. Rees⁶  Jean-François Vanbellinghen⁷ 

[1] Correspondence to: G.D. Shelton, Department of Pathology, University of California, San Diego, La Jolla, CA 92093–0709, USA. Fax: [phone].;Department of Pathology, Microbiology and Immunology, University of California, Davis, CA 95616, USA;Department of Pathology, University of California, San Diego, La Jolla, CA 92093–0709, USA;Department of Pharmacology, The School of Pharmacy, 29–39 Brunswick Square, London WC1N 1AX, UK;Halsey East Animal Clinic, 16057 NE Halsey Street, Portland, OR 97230, USA;Institute of Life Science, College of Medicine, Swansea University, Swansea SA2 8PP, UK;Secteur Commun de Biologie Moléculaire–Unilab-Lg, Centre Hospitalier Universitaire de Liège, 4000 Liège, Belgium;

关键词: Glycine transporter;    GlyT2;    Hyperekplexia;    Irish wolfhound;    SLC6A5;    Startle disease;   

DOI  :  

来源: DOAJ

【 摘 要 】

Defects in glycinergic synaptic transmission in humans, cattle, and rodents result in an exaggerated startle reflex and hypertonia in response to either acoustic or tactile stimuli. Molecular genetic studies have determined that mutations in the genes encoding the postsynaptic glycine receptor (GlyR) α1 and β subunits (GLRA1 and GLRB) and the presynaptic glycine transporter GlyT2 (SLC6A5) are the major cause of these disorders. Here, we report the first genetically confirmed canine cases of startle disease. A litter of seven Irish wolfhounds was identified in which two puppies developed muscle stiffness and tremor in response to handling. Although sequencing of GLRA1 and GLRB did not reveal any pathogenic mutations, analysis of SLC6A5 revealed a homozygous 4.2 kb microdeletion encompassing exons 2 and 3 in both affected animals. This results in the loss of part of the large cytoplasmic N-terminus and all subsequent transmembrane domains due to a frameshift. This genetic lesion was confirmed by defining the deletion breakpoint, Southern blotting, and multiplex ligation-dependent probe amplification (MLPA). This analysis enabled the development of a rapid genotyping test that revealed heterozygosity for the deletion in the dam and sire and three other siblings, confirming recessive inheritance. Wider testing of related animals has identified a total of 13 carriers of the SLC6A5 deletion as well as non-carrier animals. These findings will inform future breeding strategies and enable a rational pharmacotherapy of this new canine disorder.

【 授权许可】

Unknown