SYT1-associated neurodevelopmental disorder: a case series

Baker, Kate; Gordon, Sarah; Melland, Holly; Bumbak, Fabian; Scott, Daniel J.; Jiang, Tess J.; Owen, David J.; Turner, Bradley J.; Boyd, Stewart; Rossi, Mari; Al-Raqad, Mohammed; Elpeleg, Orly; Peck, Dawn; Mancini, Grazia M.S.; Wilke, Martina; Zollino, Marcella; Marangi, Giuseppe; Weigand, Heike; Borggraefe, Ingo; Haack, Tobias B.; Stark, Zornitza; Sadedin, Simon; Tan, Tiong Yang; Jiang, Yunyun; Gibbs, Richard A.; Ellingwood, Sara; Amaral, Michelle D.; Kelley, Whitley V.; Kurian, Manju A.; Cousin, Michael A.; Raymond, F. Lucy

doi:10.1093/brain/awy209

Cited by 110 publications

(218 citation statements)

References 36 publications

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“… 29 , 30 Rare variants in genes that encode a number of presynaptic proteins involved in Ca 2+ -regulated neurotransmitter release have been identified in individuals affected by a spectrum of neurological disorders. These include the following: 1. variants in SNAP25 (MIM: 60322) isoforms SNAP25a and SNAP25b; these variants have been identified in association with ID, seizures, and myasthenia 31 , 32 2. variants in SYT1 (MIM: 185605 ), which encodes the Ca 2+ -sensor synaptotagmin-1 required for evoked synchronous fusion; these variants are found in individuals with NDDs and hyperkinetic movements 33 , 34 3. variants in genes encoding the RIM interactor PNKD or the SNAP25 and synaptotagmin-1 interactor PRRT2; these variants have been identified in different forms of dyskinesias and seizures (MIM: 128200 ; MIM: 60575) 35 , 36 4. variants in UNC13A (MIM: 609894 ), encoding the synaptic regulator Munc13-1; these variants have been linked to an NDD with involuntary movements 37 5. variants in STXBP1 (MIM: 602926 ), encoding Munc18-1; these variants cause NDDs with epilepsy and autistic features 38 …”

Section: Main Textmentioning

confidence: 99%

Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment

Llano-Rivas

Spaeth

Striano

et al. 2019

The American Journal of Human Genetics

110

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VAMP2 encodes the vesicular SNARE protein VAMP2 (also called synaptobrevin-2). Together with its partners syntaxin-1A and synaptosomal-associated protein 25 (SNAP25), VAMP2 mediates fusion of synaptic vesicles to release neurotransmitters. VAMP2 is essential for vesicular exocytosis and activity-dependent neurotransmitter release. Here, we report five heterozygous de novo mutations in VAMP2 in unrelated individuals presenting with a neurodevelopmental disorder characterized by axial hypotonia (which had been present since birth), intellectual disability, and autistic features. In total, we identified two single-amino-acid deletions and three non-synonymous variants affecting conserved residues within the C terminus of the VAMP2 SNARE motif. Affected individuals carrying de novo non-synonymous variants involving the C-terminal region presented a more severe phenotype with additional neurological features, including central visual impairment, hyperkinetic movement disorder, and epilepsy or electroencephalography abnormalities. Reconstituted fusion involving a lipid-mixing assay indicated impairment in vesicle fusion as one of the possible associated disease mechanisms. The genetic synaptopathy caused by VAMP2 de novo mutations highlights the key roles of this gene in human brain development and function.

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Section: Main Textmentioning

confidence: 99%

Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment

Llano-Rivas

Spaeth

Striano

et al. 2019

The American Journal of Human Genetics

110

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“…Furthermore, developmental expression studies suggest that SYT1 is essential in pre-and early postnatal neuromuscular transmission, with an observed delayed expression and subsequent isoform switch to SYT2 (Berton, Iborra, Boudier, Seagar, & Marqueze, 1997;Kochubey, Babai, & Schneggenburger, 2016). Interestingly, de novo dominant variants in SYT1 were recently reported to cause a rare form of neurodevelopmental disorders (Baker et al, 2018). Unfortunately, access to patient tissue for further validation work is challenging as SYT2 is not expressed in human fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

Biallelic loss of function variants in SYT2 cause a treatable congenital onset presynaptic myasthenic syndrome

Donkervoort

Mohassel

Laugwitz

et al. 2020

American J of Med Genetics Pt A

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Synaptotagmins are integral synaptic vesicle membrane proteins that function as calcium sensors and regulate neurotransmitter release at the presynaptic nerve terminal. Synaptotagmin‐2 (SYT2), is the major isoform expressed at the neuromuscular junction. Recently, dominant missense variants in SYT2 have been reported as a rare cause of distal motor neuropathy and myasthenic syndrome, manifesting with stable or slowly progressive distal weakness of variable severity along with presynaptic NMJ impairment. These variants are thought to have a dominant‐negative effect on synaptic vesicle exocytosis, although the precise pathomechanism remains to be elucidated. Here we report seven patients of five families, with biallelic loss of function variants in SYT2, clinically manifesting with a remarkably consistent phenotype of severe congenital onset hypotonia and weakness, with variable degrees of respiratory involvement. Electrodiagnostic findings were consistent with a presynaptic congenital myasthenic syndrome (CMS) in some. Treatment with an acetylcholinesterase inhibitor pursued in three patients showed clinical improvement with increased strength and function. This series further establishes SYT2 as a CMS‐disease gene and expands its clinical and genetic spectrum to include recessive loss‐of‐function variants, manifesting as a severe congenital onset presynaptic CMS with potential treatment implications.

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“…Indeed, all mutations in synaptotagmin 1 that cause diseases in humans target the C2B domain (Baker et al, 2018;Bradberry et al, 2020), while removal of the residues critical for Ca 2+…”

Section: C2 Domains In Class 1 Synaptotagminsmentioning

confidence: 99%

“…In mammals (Dai et al, 2004;Bhalla et al, 2008;Xue et al, 2010;Voleti et al, 2017), Ca 2+ binding to the C2B domain of synaptotagmin 1 is crucial for synchronous release (Mackler & Reist, 2001;Mackler et al, 2002;Nishiki & Augustine, 2004;Shin et al, 2009;Bacaj et al, 2013;Lee et al, 2013), probably because the C2B domain has significantly higher sensitivity to Ca 2+ (Bradberry et al, 2020) and phospholipid-binding activity (Bai et al, 2004;Li et al, 2006;van den Bogaart et al, 2012;Bradberry et al, 2020) than the C2A domain in this protein. Indeed, all mutations in synaptotagmin 1 that cause diseases in humans target the C2B domain (Baker et al, 2018;Bradberry et al, 2020), while removal of the residues critical for Ca 2+ binding in the C2A domain is relatively innocuous (Stevens & Sullivan, 2003).…”

Section: Homology Of Zebrafish Synaptotagminsmentioning

confidence: 99%

Expression and distribution of synaptotagmin isoforms in the zebrafish retina

Henry

Joselevitch

Matthews

et al. 2020

Preprint

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Synaptotagmins belong to a large family of proteins. While various synaptotagmins have been implicated as Ca2+ sensors for vesicle replenishment and release at conventional synapses, their roles at retinal ribbon synapses remain incompletely understood. Zebrafish is a widely used experimental model for retinal research. We therefore investigated the homology between human, rat, mouse, and zebrafish synaptotagmins 1 to 10 using a bioinformatics approach. We also characterized the expression and distribution of various synaptotagmin (syt) genes in the zebrafish retina using RT-PCR and in situ hybridization, focusing on the family members whose products likely underlie Ca2+-dependent exocytosis in the central nervous system (synaptotagmins 1, 2, 5 and 7). We find that most zebrafish synaptotagmins are well conserved and can be grouped in the same classes as mammalian synaptotagmins, based on crucial amino acid residues needed for coordinating Ca2+ binding and determining phospholipid binding affinity. The only exception is synaptotagmin 1b, which lacks 34 amino acid residues in the C2B domain and is therefore unlikely to bind Ca2+ there. Additionally, the products of zebrafish syt5a and syt5b genes share identity with mammalian class 1 and 5 synaptotagmins. Zebrafish syt1, syt2, syt5 and syt7 paralogues are found in the zebrafish brain, eye, and retina, excepting syt1b, which is only present in the brain. The complementary expression pattern of the remaining paralogues in the retina suggests that syt1a and syt5a may underlie synchronous release and syt7a and syt7b may mediate asynchronous release or other Ca2+ dependent processes in different types of retinal neurons.

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SYT1-associated neurodevelopmental disorder: a case series

Cited by 110 publications

References 36 publications

Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment

Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment

Biallelic loss of function variants in SYT2 cause a treatable congenital onset presynaptic myasthenic syndrome

Expression and distribution of synaptotagmin isoforms in the zebrafish retina

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