Startle Disease: New Molecular Insights into an Old Neurological Disorder

Schaefer, Natascha; Harvey, Robert J.; Villmann, Carmen

doi:10.1177/10738584221104724

Cited by 3 publications

(5 citation statements)

References 78 publications

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“…To investigate the impact of GlyRβ in startle disease due to distinct Glra1 mutations, Glrb eos animals were crossed with heterozygous oscillator and shaky mice. Glrb eos had no impact on the lethality of the homozygous carrier of the oscillator and shaky alleles which died at the reported time points [ oscillator 3 weeks; shaky 4–6 weeks ( Buckwalter et al, 1994 ; Schaefer et al, 2017 ; Schaefer et al, 2018 )]. Oscillator mice lack GlyRα1 while shaky animals express mutated GlyRα1 with impaired function.…”

Section: Discussionmentioning

confidence: 90%

“…Genotyping of the Glrb eos mouse line ( Glrb tm1(Eos4)Ics , MGI:6331065) and two hybrid mouse lines Glra1 spdot / Glrb eos ( oscillator , JAX stock #000536, RRID:IMSR_JAX:000536) and Glra1 shy / Glrb eos [ shaky , ( Schaefer et al, 2017 ); C. Paige, University Health Network Research, Toronto, Canada] was performed as described in Maynard et al (2021) and Schaefer et al (2018) , respectively.…”

Section: Methodsmentioning

confidence: 99%

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Role of the Glycine Receptor β Subunit in Synaptic Localization and Pathogenicity in Severe Startle Disease

Wiessler,

Hasenmüller,

Fuhl

et al. 2023

J. Neurosci.

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Startle disease is due to the disruption of recurrent inhibition in the spinal cord. Most common causes are genetic variants in genes (GLRA1, GLRB) encoding inhibitory glycine receptor (GlyR) subunits. The adult GlyR is a heteropentameric complex composed of α1 and β subunits that localizes at postsynaptic sites and replaces embryonically expressed GlyRα2 homomers. Human GlyR variants ofGLRA1andGLRB, dominant and recessive, have been intensively studiedin vitro. However, the role of unaffected GlyRβ, essential for synaptic GlyR localization, in the presence of mutated GlyRα1in vivois not fully understood. Here, we used knock-in mice expressing endogenous mEos4b-tagged GlyRβ that were crossed with mouseGlra1startle disease mutants. We explored the role of GlyRβ under disease conditions in mice carrying a missense mutation (shaky) or resulting from the loss of GlyRα1 (oscillator). Interestingly, synaptic targeting of GlyRβ was largely unaffected in both mouse mutants. While synaptic morphology appears unaltered inshakyanimals, synapses were notably smaller in homozygousoscillatoranimals. Hence, GlyRβ enables transport of functionally impaired GlyRα1 missense variants to synaptic sites inshakyanimals, which has an impact on the efficacy of possible compensatory mechanisms. The observed enhanced GlyRα2 expression inoscillatoranimals points to a compensation by other GlyRα-subunits. However, trafficking of GlyRα2β complexes to synaptic sites remains functionally insufficient and homozygousoscillatormice still die at three weeks after birth. Thus, both functional and structural deficits can affect glycinergic neurotransmission in severe startle disease, eliciting different compensatory mechanismsin vivo.Scientific statementGlycinergic dysfunction results in a neurological disorder called startle disease. The most common affected gene isGLRA1that encodes the glycine receptor α1 subunit. A comprehensive analysis of the role of GlyRβ in startle disease has been hampered by the lack of reliable GlyRβ-specific antibodies. The novel mouse modelGlrbeoshas allowed us to identify compensatory processes during pathology. Targeting of heteromeric GlyRαβ receptors to synaptic sites is maintained in the presence of mutated GlyRα1 and even in the absence of GlyRα1. Thus, insufficient quality control of mutant heteromeric GlyRs in the endoplasmic reticulum underlies the ineffectiveness of functional compensation, even though the presence of a mature postsynaptic specialization could serve as a structural platform to overcome disease severity.

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Section: Discussionmentioning

confidence: 90%

Section: Methodsmentioning

confidence: 99%

Role of the Glycine Receptor β Subunit in Synaptic Localization and Pathogenicity in Severe Startle Disease

Wiessler,

Hasenmüller,

Fuhl

et al. 2023

J. Neurosci.

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“…Startle disease is a rare neurologic disorder with disturbed glycinergic neurotransmission because of genetic variants in glycine receptors, transporters, or synaptically associated proteins of the receptor complex (Bode and Lynch, 2014;Schaefer et al, 2022). Within our patient cohort several patients diagnosed for startle disease do not carry a mutation in the known common genes, i.e., GLRA1, GLRB, SLC6A5.…”

Section: Discussionmentioning

confidence: 99%

“…Amino acid uptake and efflux by Asc-1 is important for glycine homeostasis in the central nervous system and essential for inhibitory and excitatory neurotransmission processes. Glycine represents an agonist at inhibitory glycine receptors finally coordinating muscle activity important for motor behavior and respiratory processes (Mesuret et al, 2018;Schaefer et al, 2022) and an essential coagonist at excitatory NMDA receptors enabling processes such as memory, learning, and synaptic plasticity (Martineau et al, 2014). Asc-1 is expressed in a subset of astrocytes of the spinal cord (Ehmsen et al, 2016) and enables glycine transport opposite to D-serine transport, providing a substrate for GlyT2 which takes glycine up into glycinergic presynapses.…”

Section: Discussionmentioning

confidence: 99%

“…The current understanding of human startle disease (hyperekplexia) is based on mutations in genes encoding glycine receptor subunits (GLRA1, GLRB), the glycine transporter GlyT2 (SLC6A5) as well as in rare cases the synaptic scaffolding proteins collybistin (ARHGEF9) and gephyrin (GPHN) that lead to significant muscle hypertonia and neonatal apnea episodes (Rees et al, 2002(Rees et al, , 2003(Rees et al, , 2006Harvey et al, 2004;Chung et al, 2013;Bode and Lynch, 2014;Schaefer et al, 2022). Our patient cohort contains individuals diagnosed with hyperekplexia that do not apparently harbor mutations in the common genes described.…”

Section: Introductionmentioning

confidence: 99%

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Dual Role of Dysfunctional Asc-1 Transporter in Distinct Human Pathologies, Human Startle Disease, and Developmental Delay

Drehmann,

Milanos,

Schaefer

et al. 2023

eNeuro

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Human startle disease is associated with mutations in distinct genes encoding glycine receptors, transporters or interacting proteins at glycinergic synapses in spinal cord and brainstem. However, a significant number of diagnosed patients does not carry a mutation in the common genesGLRA1,GLRB, andSLC6A5. Recently, studies onSLC7A10(Asc-1 alanine-serine-cysteine transporter) knockout mice displaying a startle disease-like phenotype hypothesized that this transporter might represent a novel candidate for human startle disease. Here, we screened 51 patients from our patient cohort negative for the common genes and found three exonic (one missense, two synonymous), seven intronic, and single nucleotide changes in the 5’ and 3’ untranslated regions. The identified missense mutation Asc-1G307Rfrom a patient with startle disease and developmental delay was investigated in functional studies. At the molecular level, the mutation Asc-1G307Rdid not interfere with cell-surface expression, but disrupted glycine uptake. Substitution of glycine at position 307 to other amino acids e.g. to alanine or tryptophan did not affect trafficking or glycine transport. By contrast, G307K disrupted glycine transport similar to the G307R mutation found in the patient. Structurally, the disrupted function in variants carrying positively charged residues can be explained by local structural rearrangements due to the large positively charged side chain. Thus, our data suggest thatSLC7A10may represent a rare but novel gene associated with human startle disease and developmental delay.Statement of SignificancePatients diagnosed with startle disease/hyperekplexia do not always carry mutations in the known associated disease genes (GLRA1, GLRB, SLC6A5). Recently, murine studies suggestedSLC7A10as candidate gene for human startle disease. Within our patient cohort, we found one missense mutation, three exonic silent mutations but also intronic single nucleotide variations as well as variations in the 5’ and 3’ untranslated regions inSLC7A10. We further concentrated on the structural and functional alterations due to identified missense mutations in Asc-1. The exchange of Gly307 with positively charged residues leads to structural rearrangements accompanied by loss of function. Our data provide evidence that in humansSLC7A10is a rare gene associated with human startle disease.

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Interactions Involving Glycine and Other Amino Acid Neurotransmitters: Focus on Transporter-Mediated Regulation of Release and Glycine–Glutamate Crosstalk

Raiteri

2024

Biomedicines

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Glycine plays a pivotal role in the Central Nervous System (CNS), being a major inhibitory neurotransmitter as well as a co-agonist of Glutamate at excitatory NMDA receptors. Interactions involving Glycine and other neurotransmitters are the subject of different studies. Functional interactions among neurotransmitters include the modulation of release through release-regulating receptors but also through transporter-mediated mechanisms. Many transporter-mediated interactions involve the amino acid transmitters Glycine, Glutamate, and GABA. Different studies published during the last two decades investigated a number of transporter-mediated interactions in depth involving amino acid transmitters at the nerve terminal level in different CNS areas, providing details of mechanisms involved and suggesting pathophysiological significances. Here, this evidence is reviewed also considering additional recent information available in the literature, with a special (but not exclusive) focus on glycinergic neurotransmission and Glycine–Glutamate interactions. Some possible pharmacological implications, although partly speculative, are also discussed. Dysregulations in glycinergic and glutamatergic transmission are involved in relevant CNS pathologies. Pharmacological interventions on glycinergic targets (including receptors and transporters) are under study to develop novel therapies against serious CNS pathological states including pain, schizophrenia, epilepsy, and neurodegenerative diseases. Although with limitations, it is hoped to possibly contribute to a better understanding of the complex interactions between glycine-mediated neurotransmission and other major amino acid transmitters, also in view of the current interest in potential drugs acting on “glycinergic” targets.

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Startle Disease: New Molecular Insights into an Old Neurological Disorder

Cited by 3 publications

References 78 publications

Role of the Glycine Receptor β Subunit in Synaptic Localization and Pathogenicity in Severe Startle Disease

Role of the Glycine Receptor β Subunit in Synaptic Localization and Pathogenicity in Severe Startle Disease

Dual Role of Dysfunctional Asc-1 Transporter in Distinct Human Pathologies, Human Startle Disease, and Developmental Delay

Interactions Involving Glycine and Other Amino Acid Neurotransmitters: Focus on Transporter-Mediated Regulation of Release and Glycine–Glutamate Crosstalk

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