The Na+/Cl--dependent glycine transporter GlyT2 is responsible for the re-uptake of glycine into presynaptic terminals for eventual packaging into synaptic vesicles. Mutations in SLC6A5, encoding GlyT2, are a major cause of a rare childhood disorder known as startle disease/hyperekplexia. The image shows a homology model of GlyT2 that was pivotal in understanding how startle mutations disrupt GlyT2 function.
Image by Victoria James
Two new papers shed light on causes of startle disease
Two recent papers in the Journal of Biological Chemistry have identified novel mutations in the GlyT2 gene in startle disease, a disorder usually evident in newborn infants.
Startle disease, also known as hyperekplexia, is characterised by an exaggerated reaction to unexpected stimuli, such as touch or loud noises. The startle reaction can manifest as an abnormal increase in muscle tension causing rigidity and the inability to move. During these rigid periods, there can also be a suspension of breathing. Although rare, this disorder can have serious consequences, including infant death.
In the past, mutations in the glycine receptor (GlyR) α1 subunit gene (GLRA1) were thought to be the only major cause of this disorder. However, a new study1, led by Professor Robert Harvey of the UCL School of Pharmacy and Professor Mark Rees / Dr Seo Kyung Chung and Dr Rhys Thomas at ILS, College of Medicine, Swansea University, identified mutations in the GlyT2 gene in 21 individuals from the UK, Australia, Canada, France, Italy, Jordan, the Netherlands, Portugal, Spain and the USA. This firmly establishes the GlyT2 gene (SLC6A5) as a second major disease locus. Individuals with GlyT2 mutations also had a high-rate of neonatal breathing and learning difficulties.
Professor Harvey commented:
“DNA sequencing of cases at Swansea University revealed a number of new mutations in the GlyT2 gene, which encodes a presynaptic glycine transporter. At UCL we were able to demonstrate how these mutations disrupt GlyT2 function, leading to a loss of glycine release at synapses, and causing the clinical symptoms observed in these infants”.
Professor Rees added:
“This study underpins the importance of multi-institutional research into rare paediatric disorders. The careful collection of the hyperkplexia cohort and clinical tracking of outcomes over 20 years is now revealing opportunities to stratify this disorder and develop bespoke clinical care interventions.”
In a further collaborative study2 led by Dr Beatriz López-Corcuera at the Universidad Autónoma de Madrid, the first common dominant GlyT2 mutation was identified in individuals from Spain and the UK. Individuals with the Y705C mutation presented a range of symptoms, including abnormal startle and respiration, facial dysmorphism, delayed motor development or intellectual disability.
Professor Harvey explained:
“The Y705C mutation impairs the action of GlyT2 in a number of ways which may explain the diverse symptoms of individuals with this mutation.”
“Taken together, these new findings suggest that that genetic screening for hyperekplexia should encompass both presynaptic and postsynaptic causes of disease. We would like to thank Action Medical Research and the Medical Research Council for supporting our research into this rare disorder”.
Page last modified on 11 jul 13 15:17