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

• DOI: 10.1007/s00439-023-02571-z
• Publication Date: 2023-05-24T08:02:27Z
• Authors: Tiina Heinonen; Thomas Flegel; Hanna Müller; Alexandra Kehl; Sruthi Hundi; Kaspar Matiasek; Andrea Fischer; Jonas Donner; Oliver P. Forman; Hannes Lohi; Marjo K. Hytönen
• Keywords: Neurodevelopmental disorder

Hereditary hyperekplexia is a rare neuronal disorder characterized by an exaggerated startle response to sudden tactile or acoustic stimuli. In this study, we present 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 Whole genome sequence data analysis two affected dogs revealed 36-bp deletion spanning the exon-intron boundary in glycine receptor alpha 1 (GLRA1) gene. Further validation pedigree samples additional cohort 127 Shepherds, 45 American Shepherds 74 demonstrated complete segregation variant disease, according autosomal recessive inheritance pattern. The protein encoded GLRA1 subunit receptor, mediates postsynaptic inhibition brain stem spinal cord. canine located signal peptide predicted cause exon skipping subsequent premature stop codon resulting significant defect signaling. Variants are known humans; however, first study associate disorder, establishing spontaneous large animal disease model for condition.