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FB2026_01
,
released March 12, 2026
This report describes congenital myasthenic syndrome 7, presynaptic (CMS7), which is a subtype of congenital myasthenic syndrome; CMS7 exhibits autosomal dominant inheritance. The human gene implicated in this disease is Synaptotagmin-2 (SYT2), which encodes a synaptic vesicle membrane protein. There is a single fly ortholog, Dmel\Syt1, for which classical amorphic and loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\Syt1 is also orthologous to three additional human genes, SYT1, SYT5, and SYT8.
A UAS construct of the wild-type human Hsap\SYT2 gene has been introduced into flies, but has not been characterized.
Variant(s) implicated in human disease tested (as analogous mutation in fly gene): D362A in the fly Syt1 gene (corresponds to D307A in the human SYT2 gene); P363L in the fly Syt1 gene (corresponds to P308L in the human SYT2 gene; designated Syt1P-L.UAS); I426K in the fly Syt1 gene (corresponding to I371K in the human SYT2 gene). A wild-type transgenic copy of Dmel\Syt1 (expressed using the GAL4-UAS system) is able to rescue amorphic Syt1 phenotypes in larval NMJs; transgenes carrying mutations analogous to either human variant, D362A or P363L, fail to rescue amorphic Syt1 phenotypes. The I426K variant was assessed for ability to rescue larval lethality; it not only failed to rescue, but caused lethality at an earlier stage compared to the null mutation alone.
Animals homozygous for amorphic mutations of Dmel\Syt1 die in the embryonic stage. Loss-of-function mutants that survive to late larval stage exhibit neurophysiology defects and locomotor behavior defects. In animals heterozygous for an amorphic mutation of Syt1 (i.e. carrying one wild-type copy of Syt1), expression of the Syt1P-L.UAS transgene also results in neurophysiology defects, locomotor behavior defects, and reduced lifespan; this is consistent with the dominant inheritance pattern of CMS7. Physical and genetic interactions of Dmel\Syt1 have been described; see below and in the Syt1 gene report.
[updated Apr. 2020 by FlyBase; FBrf0222196]
Congenital myasthenic syndrome is a group of conditions characterized by muscle weakness (myasthenia) that worsens with physical exertion. The muscle weakness typically begins in early childhood but can also appear in adolescence or adulthood. Facial muscles, including muscles that control the eyelids, muscles that move the eyes, and muscles used for chewing and swallowing, are most commonly affected. However, any of the muscles used for movement (skeletal muscles) can be affected in this condition. Due to muscle weakness, affected infants may have feeding difficulties. Development of motor skills such as crawling or walking may be delayed. The severity of the myasthenia varies greatly, with some people experiencing minor weakness and others having such severe weakness that they are unable to walk. [from Genetics Home Reference, congenital myasthenic syndrome; 2016.10.07]
Congenital myasthenic syndromes (CMS) are a group of inherited disorders affecting the neuromuscular junction (NMJ). Patients present clinically with onset of variable muscle weakness between infancy and adulthood. These disorders have been classified according to the location of the NMJ defect: presynaptic, synaptic, and postsynaptic. [from MIM:616040; 2016.10.07]
[MYASTHENIC SYNDROME, CONGENITAL, 7A, PRESYNAPTIC, AND DISTAL MOTOR NEUROPATHY, AUTOSOMAL DOMINANT; CMS7A](https://omim.org/entry/616040)
[SYNAPTOTAGMIN 2; SYT2](https://omim.org/entry/600104)
See general description of congenital myasthenic syndrome (CMS), above. CMS7 is an autosomal dominant CMS resulting from a presynaptic defect; patients have onset of symptoms in early childhood (summary by Engel et al., 2015; pubmed:25792100). [from MIM:616040; 2016.10.07]
Presynaptic congenital myasthenic syndrome 7 (CMS7) is caused by heterozygous mutation in the Synaptotagmin-2 (SYT2) gene (autosomal dominant). [from MIM:616040; 2016.10.07]
Synaptotagmins are integral membrane proteins of synaptic vesicles thought to serve as Ca(2+) sensors in the process of vesicular trafficking and exocytosis (Hilbush and Morgan, 1994; pubmed:8058779). [from MIM:600104; 2016.10.07]
Many to one (4 human to 1 Drosophila); additional human orthologs are SYT1, SYT5, and SYT8.
High-scoring ortholog of human genes SYT2 and SYT1; lower-scoring ortholog of SYT5 and SYT8. (1 Drosophila to 4 human). Dmel\Syt1 shares 55-57% identity and 69-76% similarity with the human genes SYT2, SYT1, and SYT5; SYT8 is less similar.