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Missense variants in the middle domain of DNM1L in cases of infantile encephalopathy alter peroxisomes and mitochondria when assayed in Drosophila.
- Source :
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Human molecular genetics [Hum Mol Genet] 2016 May 01; Vol. 25 (9), pp. 1846-56. Date of Electronic Publication: 2016 Feb 29. - Publication Year :
- 2016
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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.<br /> (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Subjects :
- Amino Acid Sequence
Animals
Cytoskeletal Proteins metabolism
Drosophila melanogaster genetics
Drosophila melanogaster metabolism
Dynamins
Exome genetics
Female
GTP-Binding Proteins metabolism
Humans
Infant
Infant, Newborn
Male
Mitochondria genetics
Mitochondria metabolism
Pedigree
Peroxisomes genetics
Peroxisomes metabolism
Phenotype
Protein Domains
Sequence Homology, Amino Acid
Spasms, Infantile pathology
Drosophila melanogaster growth & development
GTP Phosphohydrolases genetics
Microtubule-Associated Proteins genetics
Mitochondria pathology
Mitochondrial Proteins genetics
Mutation, Missense genetics
Peroxisomes pathology
Spasms, Infantile genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2083
- Volume :
- 25
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Human molecular genetics
- Publication Type :
- Academic Journal
- Accession number :
- 26931468
- Full Text :
- https://doi.org/10.1093/hmg/ddw059