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dc.contributor.authorBaker, Kateen
dc.contributor.authorGordon, Sarah Len
dc.contributor.authorMelland, Hollyen
dc.contributor.authorBumbak, Fabianen
dc.contributor.authorScott, Daniel Jen
dc.contributor.authorJiang, Tess Jen
dc.contributor.authorOwen, Daviden
dc.contributor.authorTurner, Bradley Jen
dc.contributor.authorBoyd, Stewart Gen
dc.contributor.authorRossi, Marien
dc.contributor.authorAl-Raqad, Mohammeden
dc.contributor.authorElpeleg, Orlyen
dc.contributor.authorPeck, Dawnen
dc.contributor.authorMancini, Grazia MSen
dc.contributor.authorWilke, Martinaen
dc.contributor.authorZollino, Marcellaen
dc.contributor.authorMarangi, Giuseppeen
dc.contributor.authorWeigand, Heikeen
dc.contributor.authorBorggraefe, Ingoen
dc.contributor.authorHaack, Tobiasen
dc.contributor.authorStark, Zornitzaen
dc.contributor.authorSadedin, Simonen
dc.contributor.authorBroad Center for Mendelian Genomics,en
dc.contributor.authorTan, Tiong Yangen
dc.contributor.authorJiang, Yunyunen
dc.contributor.authorGibbs, Richard Aen
dc.contributor.authorEllingwood, Saraen
dc.contributor.authorAmaral, Michelleen
dc.contributor.authorKelley, Whitleyen
dc.contributor.authorKurian, Manju Aen
dc.contributor.authorCousin, Michael Aen
dc.contributor.authorRaymond, Lucyen
dc.date.accessioned2018-11-23T00:30:23Z
dc.date.available2018-11-23T00:30:23Z
dc.date.issued2018-09en
dc.identifier.issn0006-8950
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/285739
dc.description.abstractSynaptotagmin 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, SYT1I368T and SYT1N371K 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.
dc.format.mediumPrinten
dc.languageengen
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectBroad Center for Mendelian Genomicsen
dc.subjectNeuronsen
dc.subjectSynaptic Vesiclesen
dc.subjectAnimalsen
dc.subjectMice, Inbred C57BLen
dc.subjectHumansen
dc.subjectMiceen
dc.subjectRatsen
dc.subjectMovement Disordersen
dc.subjectCalciumen
dc.subjectEndocytosisen
dc.subjectSynaptic Transmissionen
dc.subjectAction Potentialsen
dc.subjectMutation, Missenseen
dc.subjectAdolescenten
dc.subjectChilden
dc.subjectChild, Preschoolen
dc.subjectFemaleen
dc.subjectMaleen
dc.subjectSynaptotagmin Ien
dc.subjectElectrophysiological Phenomenaen
dc.subjectYoung Adulten
dc.subjectIntellectual Disabilityen
dc.subjectNeurodevelopmental Disordersen
dc.titleSYT1-associated neurodevelopmental disorder: a case series.en
dc.typeArticle
prism.endingPage2591
prism.issueIdentifier9en
prism.publicationDate2018en
prism.publicationNameBrain : a journal of neurologyen
prism.startingPage2576
prism.volume141en
dc.identifier.doi10.17863/CAM.33083
dcterms.dateAccepted2018-06-19en
rioxxterms.versionofrecord10.1093/brain/awy209en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2018-09en
dc.contributor.orcidBaker, Kate [0000-0003-2986-0584]
dc.contributor.orcidMelland, Holly [0000-0003-0311-6474]
dc.contributor.orcidBumbak, Fabian [0000-0003-2739-8197]
dc.contributor.orcidScott, Daniel J [0000-0001-6332-2793]
dc.contributor.orcidOwen, David [0000-0002-8351-6322]
dc.contributor.orcidPeck, Dawn [0000-0003-2783-792X]
dc.contributor.orcidTan, Tiong Yang [0000-0001-8455-7778]
dc.contributor.orcidCousin, Michael A [0000-0002-1762-160X]
dc.contributor.orcidRaymond, Lucy [0000-0003-2652-3355]
dc.identifier.eissn1460-2156
rioxxterms.typeJournal Article/Reviewen


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International