A New GlyT2 Variant Associated with Hyperekplexia

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Hyperekplexia is a serious neonatal neurological disorder characterized by an exaggerated startle reflex and potentially fatal apnea.
• The condition stems from impaired glycinergic neurotransmission, crucial for regulating motor control.
• The glycine transporter GlyT2 (encoded by *SLC6A5*) is vital for maintaining synaptic glycine levels.

Purpose of the Study:

• To investigate a novel GlyT2 gene variant identified in an infant with hyperekplexia.
• To elucidate the molecular mechanisms underlying the pathogenicity of this new GlyT2 variant.
• To understand the impact of the mutation on GlyT2 function, trafficking, and cellular proteostasis.

Main Methods:

• Genetic sequencing of the *SLC6A5*, *GLRA1*, and *GLRB* genes.
• Expression of the recombinant GlyT2 variant in heterologous cells.
• Analysis of transporter activity, membrane insertion, and protein trafficking.
• Proteomic analysis to assess cellular responses, including the unfolded protein response and lipid raft association.

Main Results:

• A homozygous missense mutation (G449E) in the *SLC6A5* gene was identified, leading to a non-functional GlyT2 transporter.
• The mutant GlyT2 exhibited abnormal membrane insertion and premature degradation from the endoplasmic reticulum.
• Proteomics revealed that the mutant induced the unfolded protein response and disrupted raft-dependent cellular processes, acting as a proteostasis disturber.

Conclusions:

• The novel G449E GlyT2 variant represents a loss-of-function mutation causing presynaptic hyperekplexia.
• Beyond loss of transporter activity, the mutant acts as a gain-of-function proteostasis disturber, impacting cellular health.
• This finding deepens our understanding of hyperekplexia pathogenesis and highlights the complex roles of membrane transporters in cellular function.