title: Missense variants in the middle domain of DNM1L in cases of infantile encephalopathy alter peroxisomes and mitochondria when assayed in Drosophila.
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.
authors.affiliation: Department of Molecular and Human Genetics.
authors.forename: Yu-Hsin
authors.initials: YH
authors.lastname: Chao
authors.affiliation: Department of Molecular and Human Genetics, Neurological Research Institute, Texas Children Hospital, Houston, TX 77030, USA.
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Robak
authors.affiliation: Department of Molecular and Human Genetics.
authors.forename: Fan
authors.initials: F
authors.lastname: Xia
authors.affiliation: Department of Pediatric Neurology, University of Texas Medical School at Houston, Houston, TX 77030, USA and.
authors.forename: Mary K
authors.initials: MK
authors.lastname: Koenig
authors.affiliation: Department of Pathology.
authors.forename: Adekunle
authors.initials: A
authors.lastname: Adesina
authors.affiliation: Department of Molecular and Human Genetics.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Bacino
authors.affiliation: Department of Molecular and Human Genetics.
authors.forename: Fernando
authors.initials: F
authors.lastname: Scaglia
authors.affiliation: Department of Molecular and Human Genetics, Howard Hughes Medical Institute and Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA, Neurological Research Institute, Texas Children Hospital, Houston, TX 77030, USA.
authors.forename: Hugo J
authors.initials: HJ
authors.lastname: Bellen
authors.affiliation: Department of Molecular and Human Genetics, Neurological Research Institute, Texas Children Hospital, Houston, TX 77030, USA michael.wangler@bcm.edu.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Wangler
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism; D034281:Dynamins; D059472:Exome / Q000235:genetics; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D024101:Mitochondrial Proteins / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D020675:Peroxisomes / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D000072417:Protein Domains; D017386:Sequence Homology, Amino Acid; D013036:Spasms, Infantile / Q000235:genetics* / Q000473:pathology
chemical_list: D003598:Cytoskeletal Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; C504426:DRP1 protein, Drosophila; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; C110768:DNM1L protein, human; D034281:Dynamins