دورية أكاديمية
أعرض في EDS

DNM1L Variant Alters Baseline Mitochondrial Function and Response to Stress in a Patient with Severe Neurological Dysfunction.

التفاصيل البيبلوغرافية
العنوان: DNM1L Variant Alters Baseline Mitochondrial Function and Response to Stress in a Patient with Severe Neurological Dysfunction.
المؤلفون: Hogarth KA; Department of Anesthesia and Pain Medicine, The Hospital for Sick Children, 555 University Avenue, Toronto, M5G 1X8, Canada., Costford SR; Division of Genetics and Genome Biology, SickKids Research Institute, 686 Bay Street, Toronto, M5G 0A4, Canada., Yoon G; Department of Paediatrics, University of Toronto, 555 University Avenue, Toronto, M5G 1X8, Canada., Sondheimer N; Division of Genetics and Genome Biology, SickKids Research Institute, 686 Bay Street, Toronto, M5G 0A4, Canada.; Department of Paediatrics, University of Toronto, 555 University Avenue, Toronto, M5G 1X8, Canada., Maynes JT; Department of Anesthesia and Pain Medicine, The Hospital for Sick Children, 555 University Avenue, Toronto, M5G 1X8, Canada. jason.maynes@sickkids.ca.; Department of Biochemistry, University of Toronto, 1 King's College Circle, Toronto, M5S 1A8, Canada. jason.maynes@sickkids.ca.
المصدر: Biochemical genetics [Biochem Genet] 2018 Apr; Vol. 56 (1-2), pp. 56-77. Date of Electronic Publication: 2017 Nov 06.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Kluwer Academic/Plenum Publishers Country of Publication: United States NLM ID: 0126611 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1573-4927 (Electronic) Linking ISSN: 00062928 NLM ISO Abbreviation: Biochem Genet Subsets: MEDLINE
أسماء مطبوعة: Publication: 1999- : New York : Kluwer Academic/Plenum Publishers
Original Publication: New York, Plenum Press.
مواضيع طبية MeSH: Mutation, Missense*, GTP Phosphohydrolases/*genetics , Microtubule-Associated Proteins/*genetics , Mitochondria/*genetics , Mitochondrial Dynamics/*genetics , Mitochondrial Proteins/*genetics , Nervous System Diseases/*genetics , Oxidative Stress/*genetics, Amino Acid Substitution ; Dynamins ; Female ; Fibroblasts/metabolism ; Fibroblasts/pathology ; GTP Phosphohydrolases/metabolism ; Homozygote ; Humans ; Male ; Microtubule-Associated Proteins/metabolism ; Mitochondria/metabolism ; Mitochondria/pathology ; Mitochondrial Proteins/metabolism ; Nervous System Diseases/metabolism ; Nervous System Diseases/pathology ; Reactive Oxygen Species/metabolism
مستخلص: Mitochondria play vital roles in brain development and neuronal activity, and mitochondrial dynamics (fission and fusion) maintain organelle function through the removal of damaged components. Dynamin-like protein-1 (DRP-1), encoded by DNM1L, is an evolutionarily conserved GTPase that mediates mitochondrial fission by surrounding the scission site in concentric ring-like structures via self-oligomerization, followed by GTPase-dependant constriction. Here, we describe the clinical characteristics and cellular phenotype of a patient with severe neurological dysfunction, possessing a homozygous DNM1L variant c.305C>T (p.T115M) in the GTPase domain. For comparative analysis, we also describe a previously identified heterozygous variant demonstrating a rapidly fatal neurocognitive phenotype (c.261dup/c.385:386del, p.W88M*9/E129K*6). Using patient-generated fibroblasts, we demonstrated both DNM1L variants undergo adverse alterations to mitochondrial structure and function, including impaired mitochondrial fission, reduced membrane potential, and lower oxidative capacity including an increased cellular level of reactive oxygen species (ROS) and dsDNA breaks. Mutation of DNM1L was also associated with impaired responses to oxidative stress, as treatment with hydrogen peroxide dramatically increased cellular ROS, with minimal exacerbation of already impaired mitochondrial function. Taken together, our observations indicate that homozygous p.T115M variant of DNM1L produces a neurological and neurodevelopmental phenotype, consistent with impaired mitochondrial architecture and function, through a diminished ability to oligomerize, which was most prevalent under oxidative stress.
فهرسة مساهمة: Keywords: DNM1L; DRP-1; Mitochondrial fission; Oxidative function
المشرفين على المادة: 0 (Microtubule-Associated Proteins)
0 (Mitochondrial Proteins)
0 (Reactive Oxygen Species)
EC 3.6.1.- (GTP Phosphohydrolases)
EC 3.6.5.5 (DNM1L protein, human)
EC 3.6.5.5 (Dynamins)
تواريخ الأحداث: Date Created: 20171108 Date Completed: 20180723 Latest Revision: 20201209
رمز التحديث: 20221213
DOI: 10.1007/s10528-017-9829-2
PMID: 29110115
قاعدة البيانات: MEDLINE
الوصف
تدمد:1573-4927
DOI:10.1007/s10528-017-9829-2