Experiments in Drosophila contribute to study of human gene variants associated with an early onset epileptic encephalopathy

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. 2019 Nov 1. doi: 10.1002/acn3.50917. PubMed PMID: 31675180.

Abstract: "N-ethylmaleimide-sensitive factor (NSF) plays a critical role in intracellular vesicle transport, which is essential for neurotransmitter release. Herein, we, for the first time, document human monogenic disease phenotype of de novo pathogenic variants in NSF, that is, epileptic encephalopathy of early infantile onset. When expressed in the developing eye of Drosophila, the mutant NSF severely affected eye development, while the wild-type allele had no detectable effect under the same conditions. Our findings suggest that the two pathogenic variants exert a dominant negative effect. De novo heterozygous mutations in the NSF gene cause early infantile epileptic encephalopathy."

Functional studies in flies help contributed to identification of novel disease-causing variant of GED associated with static encephalopathy

Assia Batzir N, Bhagwat P, Eble T, Liu P, Eng C, Elsea SH, Robak LA, Scaglia F, Goldman A, Dhar SU, Wangler MF. De novo missense variant in the GTPase effector domain (GED) of DNM1L leads to static encephalopathy and seizures. Cold Spring Harb Mol Case Stud. 2019 Mar 8. pii: mcs.a003673. PMID: 30850373.

Abstract: "DNM1L encodes a GTPase of the dynamin superfamily which plays a crucial role in mitochondrial and peroxisomal fission. Pathogenic variants affecting the middle domain and the GTPase domain of DNM1L have been implicated in encephalopathy due to defective mitochondrial and peroxisomal fission 1 (EMPF1, MIM #614388). Patients show variable phenotypes ranging from severe hypotonia leading to death in the neonatal period to developmental delay/regression, with or without seizures. Familial pathogenic variants in the GTPase domain have also been associated with isolated optic atrophy. We present a 27 year old woman with static encephalopathy, a history of seizures and nystagmus, in whom a novel de novo heterozygous variant was detected in the GTPase Effector Domain (GED) of DNM1L (c.2072A>G, p.Tyr691Cys). Functional studies in Drosophila demonstrate large, abnormally-distributed peroxisomes and mitochondria, an effect very similar to that of middle domain missense alleles observed in pediatric subjects with EMPF1. To our knowledge, not only is this the first report of a disease-causing variant in the GED domain in humans, but this is also the oldest living individual reported with EMPF1. Longitudinal data of this kind helps to expand our knowledge of the natural history of a growing list of DNM1L-related disorders."