Mutations in the GlyT2 Gene (SLC6A5) Are a Second Major Cause of Startle Disease

Carta, Eloisa; Chung, Seo‐Kyung; James, Victoria M.; Robinson, Angela K.; Gill, Jennifer; Rémy, Nathalie; Vanbellinghen, Jean-François; Drew, Cheney; Cagdas, S.; Cameron, Duncan; Cowan, Frances; Toro, Mireria Del; Graham, Gail E.; Manzur, Adnan; Masri, Amira; Rivera, Eleanor; Scalais, Emmanuel; Shiang, Rita; Sinclair, Kate; Stuart, Catriona A.; Tijssen, Marina A. J.; Wise, Grahame; Zuberi, Sameer M.; Harvey, Kirsten; Pearce, Brian; Topf, Maya; Thomas, Rhys H.; Supplisson, Stéphane; Rees, Mark I.; Harvey, Richard J.

doi:10.1074/jbc.m112.372094

Cited by 76 publications

(66 citation statements)

References 46 publications

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“…Slc6a5 is also a component of the NRF2 pathway involved in oxidative stress response. Mutations in Slc6a5 cause hyperekplexia, a neurological disorder with pronounced startle responses and neonatal apnea (Carta et al., 2012). …”

Section: Resultsmentioning

confidence: 99%

Spontaneous development of Alzheimer's disease‐associated brain pathology in a Shugoshin‐1 mouse cohesinopathy model

et al. 2018

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SummarySpontaneous late‐onset Alzheimer's disease (LOAD) accounts for more than 95% of all human AD. As mice do not normally develop AD and as understanding on molecular processes leading to spontaneous LOAD has been insufficient to successfully model LOAD in mouse, no mouse model for LOAD has been available. Existing mouse AD models are all early‐onset AD (EOAD) models that rely on forcible expression of AD‐associated protein(s), which may not recapitulate prerequisites for spontaneous LOAD. This limitation in AD modeling may contribute to the high failure rate of AD drugs in clinical trials. In this study, we hypothesized that genomic instability facilitates development of LOAD and tested two genomic instability mice models in the brain pathology at the old age. Shugoshin‐1 (Sgo1) haploinsufficient (∓) mice, a model of chromosome instability (CIN) with chromosomal and centrosomal cohesinopathy, spontaneously exhibited a major feature of AD pathology; amyloid beta accumulation that colocalized with phosphorylated Tau, beta‐secretase 1 (BACE), and mitotic marker phospho‐Histone H3 (p‐H3) in the brain. Another CIN model, spindle checkpoint‐defective BubR1−/+ haploinsufficient mice, did not exhibit the pathology at the same age, suggesting the prolonged mitosis‐origin of the AD pathology. RNA‐seq identified ten differentially expressed genes, among which seven genes have indicated association with AD pathology or neuronal functions (e.g., ARC, EBF3). Thus, the model represents a novel model that recapitulates spontaneous LOAD pathology in mouse. The Sgo1−/+ mouse may serve as a novel tool for investigating mechanisms of spontaneous progression of LOAD pathology, for early diagnosis markers, and for drug development.

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Section: Resultsmentioning

confidence: 99%

Spontaneous development of Alzheimer's disease‐associated brain pathology in a Shugoshin‐1 mouse cohesinopathy model

et al. 2018

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“…Two additional hyperekplexia-associated missense mutations have been identified in the same TM7 region, both predicting clashes or disturbances of crucial residues involved in Na1 and Cl Ϫ coordination (N511S and S515I, rat position numbering) (10,12). Hence, substitutions in this important region alter the protein's function, although only severe structural alterations may provoke its misfolding.…”

Section: Discussionmentioning

confidence: 99%

Molecular Basis of the Dominant Negative Effect of a Glycine Transporter 2 Mutation Associated with Hyperekplexia

Arribas-González

Juan-Sanz

Aragón

et al. 2015

Journal of Biological Chemistry

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Background: Hyperekplexia is caused by defective glycinergic neurotransmission. Results: A dominant negative glycine transporter-2 mutant is trapped in a calnexin-bound state and retains wild type GlyT2 in the endoplasmic reticulum. Conclusion: Chemical chaperones rescue the folding defect of the mutant and overcome its dominant negative effect. Significance: This opens the way to revert the dominant negative effect exerted by the mutant associated with hyperekplexia in neurons.

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“…Similarly, a spontaneous mutation in mouse Slc6a5, caused by a MusD retrotransposon insertion, also results in handling-induced spasms at 5 days of age, and mice that only survive for 2 weeks, presenting alterations in neuromuscular junction maturation [51]. Several missense, nonsense and frameshift mutations in the SLC6A5 gene cause HPX in humans [52][53][54], as well as related congenital neurological disorders in dogs [55], and cattle [56]. Nonsense and frameshift mutations produce inactive truncated transporters that are retained in the endoplasmic reticulum (W151X, R191X, Y297X, Y377X, R439X, V432F+fs97, Q630X, P108L+fs25, L198R+fs123, S489F+fs39, I665K+fs1).…”

Section: Movement Diseases: Hyperekplexiamentioning

confidence: 99%

“…Nonsense and frameshift mutations produce inactive truncated transporters that are retained in the endoplasmic reticulum (W151X, R191X, Y297X, Y377X, R439X, V432F+fs97, Q630X, P108L+fs25, L198R+fs123, S489F+fs39, I665K+fs1). However, missense mutations generate proteins that in general reach the plasma membrane but contain modifications in residues important for the catalytic cycle, like the binding sites for Na + (N509S, A275T), Cl − (S513I), or glycine (W482R affects directly while A275T and E248K affect indirectly), and others probably interfere with the folding or conformational changes that occur during the translocation cycle (L237P, L243T, T425M, Y491C, F547S, Y656H, G657A) [52][53][54]. Most of the described SLC5A5 mutations have an autosomal recessive inheritance and the parental carriers are typically asymptomatic indicating that dominant negative effects are not a common mutational mechanism [52].…”

Section: Movement Diseases: Hyperekplexiamentioning

confidence: 99%

Glycinergic transmission: glycine transporter GlyT2 in neuronal pathologies

2016

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Glycinergic neurons are major contributors to the regulation of neuronal excitability, mainly in caudal areas of the nervous system. These neurons control fluxes of sensory information between the periphery and the CNS and diverse motor activities like locomotion, respiration or vocalization. The phenotype of a glycinergic neuron is determined by the expression of at least two proteins: GlyT2, a plasma membrane transporter of glycine, and VIAAT, a vesicular transporter shared by glycine and GABA. In this article, we review recent advances in understanding the role of GlyT2 in the pathophysiology of inhibitory glycinergic neurotransmission. GlyT2 mutations are associated to decreased glycinergic function that results in a rare movement disease termed hyperekplexia (HPX) or startle disease. In addition, glycinergic neurons control pain transmission in the dorsal spinal cord and their function is reduced in chronic pain states. A moderate inhibition of GlyT2 may potentiate glycinergic inhibition and constitutes an attractive target for pharmacological intervention against these devastating conditions.

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Mutations in the GlyT2 Gene (SLC6A5) Are a Second Major Cause of Startle Disease

Cited by 76 publications

References 46 publications

Spontaneous development of Alzheimer's disease‐associated brain pathology in a Shugoshin‐1 mouse cohesinopathy model

Spontaneous development of Alzheimer's disease‐associated brain pathology in a Shugoshin‐1 mouse cohesinopathy model

Molecular Basis of the Dominant Negative Effect of a Glycine Transporter 2 Mutation Associated with Hyperekplexia

Glycinergic transmission: glycine transporter GlyT2 in neuronal pathologies

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