SYT1-related disorder: a neurodevelopmental SNAREopathy

SYT1. To continue our series on SNAREopathies—developmental disorders caused by genes encoding proteins involved in the SNARE complex—we next provide a brief overview of SYT1-related disorders. The gene SYT1 encodes synaptotagmin-1 (SYT1), which belongs to the group of synaptotagmin proteins that are essential for neurotransmission. Disease-causing mutations in SYT1 have a spectrum of clinical presentations ranging in severity and phenotypic complexity but also with certain unifying features, making SYT1-related disorders a complex neurodevelopmental SNAREopathy.

Figure 1. SYT1 encodes the synaptotagmin-1 protein (SYT1), a calcium sensor that is essential for vesicle exocytosis in the pre-synapse. Binding of SYT1 with calcium triggers vesicle fusion with the membrane of the axon terminal and neurotransmitter release. Created with BioRender.

Mechanism. Synaptotagmins bind calcium entering the nerve terminal due to action potentials and enable the synaptic vesicle to fuse with the pre-synaptic membrane. This allows neurotransmitter release into the synaptic cleft. SYT1 has two domains which can bind Ca2+: C2B and C2A. The first has a higher affinity for calcium and its mechanistic role is better understood than that of the latter. Apart from Ca2+, the C2B domain also binds the SNARE complex and the pre-synaptic lipids, which is key to the fusing and docking of the vesicle onto the pre-synaptic membrane. At the same time, it has been shown that the two domains cooperate with each other to allow efficient vesicular fusion to occur. While more specific functions of the two domains still need to be delineated, mutations in both domains interfere with synaptic exocytosis.

Additional mechanism. Interestingly, SYT1 also plays a role in endocytosis, making it an important factor in vesicular recycling. For that reason, it is considered a bidirectional calcium sensor as it is involved in Ca2+ detection in both exocytosis and endocytosis. SYT1 was shown to promote small-size clathrin-mediated endocytosis and inhibit large-size endocytosis in time of higher neural activity. This mechanism is meant to preserve the structural integrity of the membrane, while allowing the spatially and temporally coupled exocytosis-endocytosis cycle to continue. Hence, abnormalities in SYT1 lead to the dysregulation of the vesicular machinery at the synapse in a broader sense, significantly affecting the exocytosis-endocytosis coupling and efficient neurotransmission as a result.

Genetics. To date, 15 variants in SYT1 have been discovered, and all of them were de novo, including 14 missense and 1 in-frame insertion. Among these, three recurrent variants were reported: p.Ile368Thr, p.Asp366Glu, p.Asn371Lys. p.Met303 was found to be a recurrent locus. The p.Ile368Thr variant, the most prevalent recurrent variant that was reported in 5 individuals, showed high phenotypic consistency in terms of neurological and behavioral symptoms. Interestingly, all of the recurrent variants above were located in the C2B domain and, overall, only 4 out of all 15 known SYT1 variants were discovered in the C2A domain.

Phenotype. While no established genotype-phenotype associations exist for SYT1-related neurodevelopmental disorders, there are clinical features that all currently reported individuals share, including developmental delay, EEG abnormalities, abnormal motor function, sleep disturbances, and abnormal eye physiology. While occur in some individuals (4/22 in one study), neurodevelopmental and motor issues such as ataxia, myoclonus, dystonia, and tremor are more prominent features of this disorder (Melland et al., 2022). Behavioral phenotypes, including self-harm and emotional features were occasionally observed. Future research is needed to delve into genotype-phenotype relationships in SYT1-related disorder to allow for a more in-depth understanding of the heterogenous phenotypic spectrum of this SNAREopathy.

What you need to know. SYT1-related disorder is a SNAREopathy with a broad phenotypic presentation. SYT1 plays a key role in exocytosis-endocytosis coupling that allows effective neurotransmission to take place. While this disorder shares characteristic features of developmental delay, movement disorders, intellectual disability with other SNAREopathies such as STXBP1 and STX1A/1B, epilepsy is not a hallmark phenotype of SYT1-related disorder. Deeper characterization of the SYT1-related disorders will be necessary to better understand the phenotypic diversity of this group of disorders.

Jan Magielski

Jan is a student researcher in the Helbig lab.