TY - JOUR
T1 - SYT1-associated neurodevelopmental disorder: A case series
AU - Baker, Kate
AU - Gordon, Sarah L.
AU - Melland, Holly
AU - Bumbak, Fabian
AU - Scott, Daniel J.
AU - Jiang, Tess J.
AU - Owen, David
AU - Turner, Bradley J.
AU - Boyd, Stewart G.
AU - Rossi, Mari
AU - Al-Raqad, Mohammed
AU - Elpeleg, Orly
AU - Peck, Dawn
AU - Mancini, Grazia M.S.
AU - Wilke, Martina
AU - Zollino, Marcella
AU - Marangi, Giuseppe
AU - Weigand, Heike
AU - Borggraefe, Ingo
AU - Haack, Tobias
AU - Stark, Zornitza
AU - Sadedin, Simon
AU - Genomics, Mendelian
AU - Tan, Tiong Yang
AU - Jiang, Yunyun
AU - Gibbs, Richard A.
AU - Ellingwood, Sara
AU - Amaral, Michelle
AU - Kelley, Whitley
AU - Kurian, Manju A.
AU - Cousin, Michael A.
AU - Raymond, F. Lucy
PY - 2018
Y1 - 2018
N2 - Synaptotagmin 1 (SYT1) is a critical mediator of fast, synchronous, calcium-dependent neurotransmitter release and also modulates synaptic vesicle endocytosis. This paper describes 11 patients with de novo heterozygous missense mutations in SYT1. All mutations alter highly conserved residues, and cluster in two regions of the SYT1 C2B domain at positions Met303 (M303K), Asp304 (D304G), Asp366 (D366E), Ile368 (I368T) and Asn371 (N371K). Phenotypic features include infantile hypotonia, congenital ophthalmic abnormalities, childhood-onset hyperkinetic movement disorders, motor stereotypies, and developmental delay varying in severity from moderate to profound. Behavioural characteristics include sleep disturbance and episodic agitation. Absence of epileptic seizures and normal orbitofrontal head circumference are important negative features. Structural MRI is unremarkable but EEG disturbance is universal, characterized by intermittent low frequency high amplitude oscillations. The functional impact of these five de novo SYT1 mutations has been assessed by expressing rat SYT1 protein containing the equivalent human variants in wild-type mouse primary hippocampal cultures. All mutant forms of SYT1 were expressed at levels approximately equal to endogenous wild-type protein, and correctly localized to nerve terminals at rest, except for SYT1M303K, which was expressed at a lower level and failed to localize at nerve terminals. Following stimulation, SYT1 I368T and SYT1 N371K relocalized to nerve terminals at least as efficiently as wild-type SYT1. However, SYT1D304G and SYT1D366E failed to relocalize to nerve terminals following stimulation, indicative of impairments in endocytic retrieval and trafficking of SYT1. In addition, the presence of SYT1 variants at nerve terminals induced a slowing of exocytic rate following sustained action potential stimulation. The extent of disturbance to synaptic vesicle kinetics is mirrored by the severity of the affected individuals' phenotypes, suggesting that the efficiency of SYT1-mediated neurotransmitter release is critical to cognitive development. In summary, de novo dominant SYT1 missense mutations are associated with a recognizable neurodevelopmental syndrome, and further cases can now be diagnosed based on clinical features, electrophysiological signature and mutation characteristics. Variation in phenotype severity may reflect mutation-specific impact on the diverse physiological functions of SYT1.
AB - Synaptotagmin 1 (SYT1) is a critical mediator of fast, synchronous, calcium-dependent neurotransmitter release and also modulates synaptic vesicle endocytosis. This paper describes 11 patients with de novo heterozygous missense mutations in SYT1. All mutations alter highly conserved residues, and cluster in two regions of the SYT1 C2B domain at positions Met303 (M303K), Asp304 (D304G), Asp366 (D366E), Ile368 (I368T) and Asn371 (N371K). Phenotypic features include infantile hypotonia, congenital ophthalmic abnormalities, childhood-onset hyperkinetic movement disorders, motor stereotypies, and developmental delay varying in severity from moderate to profound. Behavioural characteristics include sleep disturbance and episodic agitation. Absence of epileptic seizures and normal orbitofrontal head circumference are important negative features. Structural MRI is unremarkable but EEG disturbance is universal, characterized by intermittent low frequency high amplitude oscillations. The functional impact of these five de novo SYT1 mutations has been assessed by expressing rat SYT1 protein containing the equivalent human variants in wild-type mouse primary hippocampal cultures. All mutant forms of SYT1 were expressed at levels approximately equal to endogenous wild-type protein, and correctly localized to nerve terminals at rest, except for SYT1M303K, which was expressed at a lower level and failed to localize at nerve terminals. Following stimulation, SYT1 I368T and SYT1 N371K relocalized to nerve terminals at least as efficiently as wild-type SYT1. However, SYT1D304G and SYT1D366E failed to relocalize to nerve terminals following stimulation, indicative of impairments in endocytic retrieval and trafficking of SYT1. In addition, the presence of SYT1 variants at nerve terminals induced a slowing of exocytic rate following sustained action potential stimulation. The extent of disturbance to synaptic vesicle kinetics is mirrored by the severity of the affected individuals' phenotypes, suggesting that the efficiency of SYT1-mediated neurotransmitter release is critical to cognitive development. In summary, de novo dominant SYT1 missense mutations are associated with a recognizable neurodevelopmental syndrome, and further cases can now be diagnosed based on clinical features, electrophysiological signature and mutation characteristics. Variation in phenotype severity may reflect mutation-specific impact on the diverse physiological functions of SYT1.
KW - Neurology (clinical)
KW - SYT1
KW - intellectual disability
KW - movement disorder
KW - synaptic vesicle
KW - synaptotagmin 1
KW - Neurology (clinical)
KW - SYT1
KW - intellectual disability
KW - movement disorder
KW - synaptic vesicle
KW - synaptotagmin 1
UR - http://hdl.handle.net/10807/134207
UR - http://brain.oxfordjournals.org/
U2 - 10.1093/brain/awy209
DO - 10.1093/brain/awy209
M3 - Article
SN - 0113-812X
VL - 141
SP - 2576
EP - 2591
JO - BRAIN
JF - BRAIN
ER -