This report describes epilepsy, progressive myoclonic 6 (EPM6), which is a subtype of progressive myoclonic epilepsy; EPM6 exhibits autosomal recessive inheritance. The human gene implicated in this disease is Golgi SNAP receptor complex member 2 (GOSR2), which encodes a member of the target (or t-) SNARE family of vesicle docking proteins and is involved in ER-to-Golgi trafficking. There is a single orthologous gene in Drosophila, Membrin, for which an amorphic allele, RNAi targeting constructs, and an allele caused by insertional mutagenesis have been generated.
Multiple UAS constructs of the human Hsap\GOSR2 gene have been introduced into flies, including wild-type GOSR2 and genes carrying mutational lesions implicated in EPM6. Partial heterologous rescue (partial functional complementation) is observed: wild-type Hsap\GOSR2 rescues the larval lethal phenotype of an amorphic mutation of Dmel\Membrin, however adults exhibit severe locomotor impairment and extremely reduced lifespan.
Variant(s) implicated in human disease tested (as transgenic human gene, GOSR2): the G144W and K164del variant forms of the human gene has been introduced into flies. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): G147W in the fly Membrin gene (corresponds to G147W in the human GOSR2 gene; K166del in the fly Membrin gene (corresponds to K164del in the human GOSR2 gene. Both disease-implicated variant forms act as partial loss-of-function mutations.
Animals homozygous for an amorphic allele of Membrin die during early larval stages. Transgenic genes carrying mutational lesions analogous to disease-implicated variants were characterized in the Membrin-null background; both variants tested result in lethality at a later larval stage. Dendritic and synaptic morphological abnormalities, locomotor defects, and hyperexcitability are observed. Physical interactions have been described for Dmel\Membrin; see below and in the Membrin gene report.
Work in Drosophila supports the hypothesis that dendritic growth is extremely sensitive to secretory pathway deficits and that impairment in dendritic growth underlies the phenotypes of EPM6.
[updated Jan. 2018 by FlyBase; FBrf0222196
Progressive myoclonic epilepsy (PME) is characterized by the presence of both muscle contractions (myoclonus) and seizures (epilepsy). Myoclonus occurs separately from seizures; the two types of symptoms respond differently to the same drugs and may evolve differently during the course of the disease. Myoclonus is frequently a greater problem than seizures, because it less amenable to control by available drugs. [from NORD, Progressive Myoclonus Epilepsy; 2016.06.13]
Progressive myoclonic epilepsy refers to a clinically and genetically heterogeneous group of neurodegenerative disorders, usually with debilitating symptoms, although severity varies. [from MIM:254800; 2016.06.13]
[EPILEPSY, PROGRESSIVE MYOCLONIC, 6; EPM6](https://omim.org/entry/614018)
[GOLGI SNAP RECEPTOR COMPLEX MEMBER 2; GOSR2](https://omim.org/entry/604027)
Progressive myoclonic epilepsy-6 is an autosomal recessive neurologic disorder characterized by onset of ataxia in the first years of life, followed by action myoclonus and seizures later in childhood, and loss of independent ambulation in the second decade. Cognition is not usually affected (summary by Corbett et al., 2011; pubmed:21549339). [from MIM:614018; 2018.01.29]
Progressive myoclonic epilepsy-6 (EPM6) is caused by homozygous mutation in the GOSR2 gene. [from MIM:614018; 2018.01.29]
GOSR2 encodes a trafficking membrane protein involved in transport of proteins from the cis/medial-Golgi to the trans-Golgi network. [Gene Cards, GOSR2; 2018.01.31]
The GOSR2 gene encodes a member of the soluble NSF attachment protein receptor (SNARE) family of vesicle docking proteins (Hay et al., 1997; pubmed:9094723) [from MIM:604027; 2018.01.29]
One to one: 1 human to 1 Drosophila
High-scoring ortholog of human GOSR2; Dmel\Membrin shares 42% identity and 62% similarity with the human gene.
