This report describes developmental and epileptic encephalopathy 96 (DEE96); DEE96 exhibits autosomal dominant inheritance. The human gene implicated in this disease is NSF, an ATPase involved in membrane fusion. There are two high-ranking orthologs of NSF in Drosophila, comt and Nsf2. Many genetic reagents have been generated for each gene, including classical loss-of-function alleles, and alleles carrying RNAi targeting constructs and overexpression constructs.
The human Hsap\NSF gene has been introduced into flies, both as wild-type and as variants; the variants represent two spontaneously generated alleles associated with developmental and epileptic encephalopathy. See the 'Disease-Implicated Variants' table, below.
Expression of the two mutant alleles of human NSF in fly eyes, Hsap\NSF p.Ala459Thr and p.Pro563Leu, causes excessive cell death in developing eye discs, and reduced size of the adult eyes, indicating that these mutations act as dominant negative alleles. The severity of each allele's phenotype correlates with the severity of the individual carrying that variant.
[updated Aug. 2021 by FlyBase; FBrf0222196]
[DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 96; DEE96](https://omim.org/entry/619340)
[N-ETHYLMALEIMIDE-SENSITIVE FACTOR; NSF](https://omim.org/entry/601633)
Epilepsy, and in particular intractable epilepsy in infancy, often results in an encephalopathic picture, known under these circumstances as an epileptic encephalopathy. The infantile epileptic encephalopathies are a group of disorders described as "age-dependent epileptic encephalopathies". These syndromes start with intractable epilepsy within the first few weeks to months of life (infantile), are marked by recurrent unprovoked seizures (epilepsy), and result in devastating global developmental delay and intellectual disability (encephalopathy), which are often permanent as the developing brain is particularly susceptible to the potentially severe effects of epilepsy. This clinical course is usually accompanied by concomitant arrest in brain growth resulting in microcephaly and brain atrophy. (From Tavyev Asher et al. 2012 and references therein, pubmed:22548976.)
Developmental and epileptic encephalopathy 96 (DEE96) is characterized by onset of seizures in the first days or weeks of life. Affected infants have tonic or myoclonic seizures associated with burst-suppression pattern on EEG. They also have hypotonia with respiratory insufficiency that may result in premature death. Those that survive have profound developmental delay and persistent seizures (summary by Suzuki et al., 2019; pubmed:31675180). [from MIM:619340; 2021.08.10]
Developmental and epileptic encephalopathy-96 (DEE96) is caused by heterozygous mutation in the NSF gene. [from MIM:619340; 2021.08.10]
EIEE is a rare form of epilepsy characterized by intractable seizures, tonic spasms or more frequently partial seizures, and a characteristic pattern on electroencephalogram (EEG) with onset in the first months of life [10]. Structural brain lesions and malformations of cortical development such as lissencephaly or other cortical dysplasias have been described in association with this epileptic phenotype. (From Tavyev Asher et al. 2012 and references therein, pubmed:22548976.)
Intracellular vesicle transport and endo/exocytosis are fundamental processes underlying a wide range of biological activities, including neurotransmitter release and hormone secretion. The delivery and release of cargo proteins are precisely regulated by a number of proteins. N-ethylmaleimide-sensitive factor (NSF) is a homo-hexameric AAA ATPase that is involved in membrane fusion. The membrane receptors for NSF were identified and named as the soluble NSF attachment protein receptor (SNARE) complex. Assembly and disassembly of NSF and the SNARE complex, along with calcium triggering at appropriate location and time, are critical steps in vesicular transport and membrane fusion. (From Suzuki et al. 2019, FBrf0244012.)
One to many: one human gene to two Drosophila genes.
