A loss-of-function variant in canine GLRA1 associates with a neurological disorder resembling human hyperekplexia.

Autor: Heinonen T; Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.; Folkhälsan Research Center, Helsinki, Finland.; Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland., Flegel T; Department of Small Animals, Leipzig University, Leipzig, Germany., Müller H; Tieraerztliches Fachzentrum Muehlhausen Dr. Ortmann & Dr. Stief, Muehlhausen/Thueringen, Germany., Kehl A; Laboklin GmbH&CO.KG, Bad Kissingen, Germany., Hundi S; Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.; Folkhälsan Research Center, Helsinki, Finland.; Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland., Matiasek K; Section of Clinical and Comparative Neuropathology, Institute of Veterinary Pathology, Centre for Clinical Veterinary Medicine, LMU Munich, Munich, Germany., Fischer A; Clinic of Small Animal Medicine, Centre for Clinical Veterinary Medicine, LMU Munich, Munich, Germany., Donner J; Wisdom Panel Research Team, Wisdom Panel, Kinship, Helsinki, Finland., Forman OP; Wisdom Panel Research Team, Wisdom Panel, Kinship, Leicestershire, UK., Lohi H; Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland. Hannes.lohi@helsinki.fi.; Folkhälsan Research Center, Helsinki, Finland. Hannes.lohi@helsinki.fi.; Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland. Hannes.lohi@helsinki.fi., Hytönen MK; Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland. Marjo.hytonen@helsinki.fi.; Folkhälsan Research Center, Helsinki, Finland. Marjo.hytonen@helsinki.fi.; Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland. Marjo.hytonen@helsinki.fi.
Jazyk: angličtina
Zdroj: Human genetics [Hum Genet] 2023 Aug; Vol. 142 (8), pp. 1221-1230. Date of Electronic Publication: 2023 May 24.
DOI: 10.1007/s00439-023-02571-z
Abstrakt: Hereditary hyperekplexia is a rare neuronal disorder characterized by an exaggerated startle response to sudden tactile or acoustic stimuli. In this study, we present a Miniature Australian Shepherd family showing clinical signs, which have genetic and phenotypic similarities with human hereditary hyperekplexia: episodes of muscle stiffness that could occasionally be triggered by acoustic stimuli. Whole genome sequence data analysis of two affected dogs revealed a 36-bp deletion spanning the exon-intron boundary in the glycine receptor alpha 1 (GLRA1) gene. Further validation in pedigree samples and an additional cohort of 127 Miniature Australian Shepherds, 45 Miniature American Shepherds and 74 Australian Shepherds demonstrated complete segregation of the variant with the disease, according to an autosomal recessive inheritance pattern. The protein encoded by GLRA1 is a subunit of the glycine receptor, which mediates postsynaptic inhibition in the brain stem and spinal cord. The canine GLRA1 deletion is located in the signal peptide and is predicted to cause exon skipping and subsequent premature stop codon resulting in a significant defect in glycine signaling. Variants in GLRA1 are known to cause hereditary hyperekplexia in humans; however, this is the first study to associate a variant in canine GLRA1 with the disorder, establishing a spontaneous large animal disease model for the human condition.
(© 2023. The Author(s).)
Databáze: MEDLINE
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