HGNC Approved Gene Symbol: NSF
Cytogenetic location: 17q21.31 Genomic coordinates (GRCh38): 17:46,590,669-46,757,464 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21.31 | Developmental and epileptic encephalopathy 96 | 619340 | Autosomal dominant | 3 |
The NSF gene encodes a molecule important for intracellular vesicle transport and membrane fusion. It also plays a role in synaptic transmission (summary by Suzuki et al., 2019).
Mammalian N-ethylmaleimide-sensitive protein was first described by Glick and Rothman (1987) as the protein that restored the ability of Golgi membranes that had been inactivated with the reagent N-ethylmaleimide to re-engage in vesicular transport. The NSF gene was subsequently cloned from Chinese hamster cells by Block et al. (1988) and Wilson et al. (1989). NSF is a member of the AAA (ATPases associated with diverse cellular activities) gene family. Hoyle et al. (1996) stated that the genes are most related throughout the approximately 200-amino acid domain (the AAA domain) that binds ATP; however, the family is notable not only for its conservation but also for diverse functions of its proteins in eukaryotic cells. The family can be subdivided into those with either 1 or 2 ATP-binding domains. NSF is a 2-domain member of the AAA family. Valosin-containing protein (601023), which is also involved in membrane fusion, is another 2-AAA domain protein.
The process of vesicle targeting and fusion in the secretory and endocytic pathways has been described by the SNAREs hypothesis (Rothman, 1994). This proposes that vesicles dock with specific target membranes by binding to membrane-specific SNAREs (soluble N-ethylmaleimide-sensitive factors attachment protein receptors) (see 604026). Hoyle et al. (1996) noted that targeting specificity is also affected by the Rabs, a group of small soluble GTPases. After the vesicle has bound to the target membrane, the SNARE multimer is joined by the soluble SNAP proteins and N-ethylmaleimide-sensitive factor (NSF). The resulting large complex is thought to allow membrane fusion and the ATPase activity of the NSF appears to be essential for the process. Hoyle et al. (1996) stated that while many of different SNAREs, Rabs, and SNAPs are involved in membrane fusion, there is only 1 NSF, and the SNARE hypothesis describes NSF-dependent fusion.
By use of microarray expression profiling of prefrontal cortex from matched pairs of patients with schizophrenia (181500) and control subjects and hierarchical data analysis, Mirnics et al. (2000) found that transcripts encoding proteins involved in the regulation of presynaptic function were decreased in all subjects with schizophrenia. Genes of presynaptic function showed a different combination of decreased expression across subjects. Over 250 other gene groups did not show altered expression. Selected presynaptic function gene microarray observations were verified by in situ hybridization. Two of the most consistently changed transcripts in the presynaptic functional gene group, N-ethylmaleimide-sensitive factor and synapsin-2 (600755), were decreased in 10 of 10 and 9 of 10 subjects with schizophrenia, respectively. The combined data suggested that subjects with schizophrenia share a common abnormality in presynaptic function.
By PCR amplification in a human monochromosomal somatic cell hybrid mapping panel, Hoyle et al. (1996) mapped the NSF gene to human chromosome 17. To determine a regional mapping position for NSF and to confirm their cell hybrid results, they isolated NSF-containing human cosmids for fluorescence in situ hybridization (FISH) mapping. The results showed that the gene mapped to 17q21-q22. They mapped the mouse homolog, Nsf, to mouse chromosome 11 by analysis of DNA from interspecific backcrosses. Hoyle et al. (1996) noted that there are neurologic disorders mapping in that region of chromosome 17, such as DDBAC (600274) and PPND (600274), which may be allelic disorders. They noted that NSF is preferentially expressed in the mammalian nervous system. An aberrant Nsf gene in Drosophila results in defective synaptic transmission.
In 2 unrelated Japanese girls with developmental and epileptic encephalopathy-96 (DEE96; 619340), Suzuki et al. (2019) identified de novo heterozygous missense mutations in the NSF gene (A459T, 601633.0001 and P563L, 601633.0002). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were absent from the ExAC database and from a cohort of 2,049 Japanese control individuals. Studies of patient cells were not performed. Transfection of the mutations into the Drosophila eye disc resulted in defective eye development with increased cellular apoptosis, suggesting that the gene is involved in neuronal development. Pan-neuronal expression of the mutation was embryonic lethal. The authors postulated a dominant-negative effect. They also noted that the Drosophila 'comatose' mutant, which shows temperature-sensitive paralysis, is caused by mutation in the NSF ortholog (see ANIMAL MODEL) (Pallanck et al., 1995). These findings suggested a role for NSF in synaptic transmission.
Pallanck et al. (1995) determined that the Drosophila 'comatose' phenotype (comt) is due to mutation in the ortholog of the NSF gene. Mutant flies show temperature-sensitive paralysis that can be rescued by transfection of the wildtype dNSF gene. The findings further supported a role for NSF in synaptic transmission.
In a girl, born of unrelated Japanese parents, with developmental and epileptic encephalopathy-96 (DEE96; 619340), Suzuki et al. (2019) identified a de novo heterozygous c.1375G-A transition (c.1375G-A, NM_006178.3) in the NSF gene, resulting in an ala459-to-thr (A459T) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was absent from the ExAC database and from a cohort of 2,049 Japanese control individuals Studies of patient cells were not performed. Transfection of the mutation into the Drosophila eye disc resulted in defective eye development with increased cellular apoptosis, suggesting that the gene is involved in neuronal development. Pan-neuronal expression of the mutation in Drosophila was embryonic lethal.
In a 3-year-old girl, born of unrelated Japanese parents, with developmental and epileptic encephalopathy-96 (DEE96; 619340), Suzuki et al. (2019) identified a de novo heterozygous c.1688C-T transition (c.1688C-T, NM_006178.3) in the NSF gene, resulting in a pro563-to-leu (P563L) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was absent from the ExAC database and from a cohort of 2,049 Japanese control individuals. Studies of patient cells were not performed. Transfection of the mutation into the Drosophila eye disc resulted in defective eye development with increased cellular apoptosis, suggesting that the gene is involved in neuronal development. Pan-neuronal expression of the mutation in Drosophila was embryonic lethal.
Block, M. R., Glick, B. S., Wilcox, C. A., Wieland, F. T., Rothman, J. E. Purification of an N-ethylmaleimide-sensitive protein catalyzing vesicular transport. Proc. Nat. Acad. Sci. 85: 7852-7856, 1988. [PubMed: 3186695] [Full Text: https://doi.org/10.1073/pnas.85.21.7852]
Glick, B. S., Rothman, J. E. Possible role for fatty acyl-coenzyme A in intracellular protein transport. Nature 326: 309-312, 1987. [PubMed: 3821906] [Full Text: https://doi.org/10.1038/326309a0]
Hoyle, J., Phelan, J. P., Bermingham, N., Fisher, E. M. C. Localization of human and mouse N-ethylmaleimide-sensitive factor (NSF) gene: a two-domain member of the AAA family that is involved in membrane fusion. Mammalian Genome 7: 850-852, 1996. [PubMed: 8875895] [Full Text: https://doi.org/10.1007/s003359900249]
Mirnics, K., Middleton, F. A., Marquez, A., Lewis, D. A., Levitt, P. Molecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex. Neuron 28: 53-67, 2000. [PubMed: 11086983] [Full Text: https://doi.org/10.1016/s0896-6273(00)00085-4]
Pallanck, L., Ordway, R. W., Ganetzky, B. A Drosophila NSF mutant. Nature 376: 25 only, 1995. [PubMed: 7596428] [Full Text: https://doi.org/10.1038/376025a0]
Rothman, J. E. Mechanisms of intracellular protein transport. Nature 372: 55-63, 1994. [PubMed: 7969419] [Full Text: https://doi.org/10.1038/372055a0]
Suzuki, H., Yoshida, T., Morisada, N., Uehara, T., Kosaki, K., Sato, K., Matsubara, K., Takano-Shimizu, T., Takenouchi, T. De novo NSF mutations cause early infantile epileptic encephalopathy. Ann. Clin. Transl. Neurol. 6: 2334-2339, 2019. [PubMed: 31675180] [Full Text: https://doi.org/10.1002/acn3.50917]
Wilson, D. W., Wilcox, C. A., Flynn, G. C., Chen, E., Kuang, W.-J., Henzel, W. J., Block, M. R., Ullrich, A., Rothman, J. E. A fusion protein required for vesicle-mediated transport in both mammalian cells and yeast. Nature 339: 355-359, 1989. [PubMed: 2657434] [Full Text: https://doi.org/10.1038/339355a0]