SYT1-associated neurodevelopmental disorder: A case series

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

Risultato della ricerca: Contributo in rivistaArticolo in rivista

30 Citazioni (Scopus)

Abstract

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.
Lingua originaleEnglish
pagine (da-a)2576-2591
Numero di pagine16
RivistaBRAIN
Volume141
DOI
Stato di pubblicazionePubblicato - 2018

Keywords

  • Neurology (clinical)
  • SYT1
  • intellectual disability
  • movement disorder
  • synaptic vesicle
  • synaptotagmin 1

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