ArticleHuman molecular genetics2016
Missense variants in the middle domain of DNM1L in cases of infantile encephalopathy alter peroxisomes and mitochondria when assayed in Drosophila.
Article in Human molecular genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed, 74 citations in OpenAlex.
- Epilepsy-associated digenic variants affecting an actin/mitochondria/glutamate pathway promote seizure susceptibility.The Journal of clinical investigation · 2026Article
- Reversibility and therapeutic feasibility of DNM1L-associated neurodevelopmental disorders.Experimental & molecular medicine · 2026Article
- Clinical phenotype spectrum and prognostic analysis ofFrontiers in neurology · 2026Article
- Functional identification of two variants in unrelated Chinese patients with DNM1L-related mitochondrial disorders.BMC pediatrics · 2025Article
- Cardiac dysfunction due to mitochondrial impairment assessed by human iPS cells caused by DNM1L mutations.Pediatric research · 2025Article
- Mitochondrial and peroxisomal fission in cortical neurogenesis.The international journal of biochemistry & cell biology · 2025Review
- De NovoInternational journal of molecular sciences · 2025Review
- Clinical and genetic characterization ofFrontiers in pediatrics · 2025Article
- ROS-mediated cytoplasmic localization of CARM1 induces mitochondrial fission through DRP1 methylation.Redox biology · 2024Article
- Cdk8/CDK19 promotes mitochondrial fission through Drp1 phosphorylation and can phenotypically suppress pink1 deficiency in Drosophila.Nature communications · 2024Article
- A novel variant of DNM1L expanding the clinical phenotypic spectrum: a case report and literature review.BMC pediatrics · 2024Review
- Disease-associated mutations in Drp1 have fundamentally different effects on the mitochondrial fission machinery.Human molecular genetics · 2023Article
- Sphingolipid desaturase DEGS1 is essential for mitochondria-associated membrane integrity.The Journal of clinical investigation · 2023Article
- DRP1 mutations associated with EMPF1 encephalopathy alter mitochondrial membrane potential and metabolic programs.Journal of cell science · 2023Article
- Mitochondrial Fission and Fusion: Molecular Mechanisms, Biological Functions, and Related Disorders.Membranes · 2022Review
- NovelLife science alliance · 2022Article
- Mitochondrial Calcium-Triggered Oxidative Stress and Developmental Defects in Dopaminergic Neurons Differentiated from Deciduous Teeth-Derived Dental Pulp Stem Cells with MFF Insufficiency.Antioxidants (Basel, Switzerland) · 2022Article
- Review
- Clueless/CLUH regulates mitochondrial fission by promoting recruitment of Drp1 to mitochondria.Nature communications · 2022Article
- Inter-Species Rescue of Mutant Phenotype-The Standard for Genetic Analysis of Human Genetic Disorders inInternational journal of molecular sciences · 2022Review
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9 authors at 2 institutions in 1 country.
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Abstract
Defects in organelle dynamics underlie a number of human degenerative disorders, and whole exome sequencing (WES) is a powerful tool for studying genetic changes that affect the cellular machinery. WES may uncover variants of unknown significance (VUS) that require functional validation. Previously, a pathogenic de novo variant in the middle domain of DNM1L (p.A395D) was identified in a single patient with a lethal defect of mitochondrial and peroxisomal fission. We identified two additional patients with infantile encephalopathy and partially overlapping clinical features, each with a novel VUS in the middle domain of DNM1L (p.G350R and p.E379K). To evaluate pathogenicity, we generated transgenic Drosophila expressing wild-type or variant DNM1L. We find that human wild-type DNM1L rescues the lethality as well as specific phenotypes associated with the loss of Drp1 in Drosophila. Neither the p.A395D variant nor the novel variant p.G350R rescue lethality or other phenotypes. Moreover, overexpression of p.A395D and p.G350R in Drosophila neurons, salivary gland and muscle strikingly altered peroxisomal and mitochondrial morphology. In contrast, the other novel variant (p.E379K) rescued lethality and did not affect organelle morphology, although it was associated with a subtle mitochondrial trafficking defect in an in vivo assay. Interestingly, the patient with the p.E379K variant also has a de novo VUS in pyruvate dehydrogenase 1 (PDHA1) affecting the same amino acid (G150) as another case of PDHA1 deficiency suggesting the PDHA1 variant may be pathogenic. In summary, detailed clinical evaluation and WES with functional studies in Drosophila can distinguish different functional consequences of newly-described DNM1L alleles.
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