PMID- 31868880
OWN - NLM
STAT- MEDLINE
DCOM- 20201019
LR  - 20221207
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Linking)
VI  - 29
IP  - 2
DP  - 2020 Jan 15
TI  - Impaired turnover of hyperfused mitochondria in severe axonal neuropathy due to a 
      novel DRP1 mutation.
PG  - 177-188
LID - 10.1093/hmg/ddz211 [doi]
AB  - Mitochondria undergo continuous cycles of fusion and fission in response to 
      physiopathological stimuli. The key player in mitochondrial fission is 
      dynamin-related protein 1 (DRP1), a cytosolic protein encoded by dynamin 1-like 
      (DNM1L) gene, which relocalizes to the outer mitochondrial membrane, where it 
      assembles, oligomerizes and drives mitochondrial division upon 
      guanosine-5'-triphosphate (GTP) hydrolysis. Few DRP1 mutations have been 
      described so far, with patients showing complex and variable phenotype ranging 
      from early death to encephalopathy and/or optic atrophy. The disease is the 
      consequence of defective mitochondrial fission due to faulty DRP1 function. 
      However, the underlying molecular mechanisms and the functional consequences at 
      mitochondrial and cellular level remain elusive. Here we report on a 5-year-old 
      girl presenting psychomotor developmental delay, global hypotonia and severe 
      ataxia due to axonal sensory neuropathy harboring a novel de novo heterozygous 
      missense mutation in the GTPase domain of DRP1 (NM_012062.3:c.436G>A, 
      NP_036192.2: p.D146N variant in DNM1L). Patient's fibroblasts show 
      hyperfused/balloon-like giant mitochondria, highlighting the importance of D146 
      residue for DRP1 function. This dramatic mitochondrial rearrangement phenocopies 
      what observed overexpressing DRP1-K38A, a well-known experimental dominant 
      negative version of DRP1. In addition, we demonstrated that p.D146N mutation has 
      great impact on peroxisomal shape and function. The p.D146N mutation compromises 
      the GTPase activity without perturbing DRP1 recruitment or assembly, causing 
      decreased mitochondrial and peroxisomal turnover. In conclusion, our findings 
      highlight the importance of sensory neuropathy in the clinical spectrum of DRP1 
      variants and, for the first time, the impact of DRP1 mutations on mitochondrial 
      turnover and peroxisomal functionality.
CI  - (c) The Author(s) 2019. Published by Oxford University Press. All rights reserved. 
      For Permissions, please email: journals.permissions@oup.com.
FAU - Longo, Fabiana
AU  - Longo F
AD  - Neurogenomics Unit, Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan, 
      Italy.
FAU - Benedetti, Sara
AU  - Benedetti S
AD  - Laboratory of Clinical Molecular Biology and Cytogenetics, IRCCS Ospedale San 
      Raffaele, Milan, Italy.
FAU - Zambon, Alberto A
AU  - Zambon AA
AD  - Department of Neurology, IRCCS Ospedale San Raffaele, Milan, Italy.
FAU - Sora, Maria Grazia Natali
AU  - Sora MGN
AD  - Department of Neurology, IRCCS Ospedale San Raffaele, Milan, Italy.
FAU - Di Resta, Chiara
AU  - Di Resta C
AD  - Universita Vita-Salute San Raffaele, Milan, Italy.
AD  - Genomic Unit for the Diagnosis of Human Pathologies, Division of Genetics and 
      Cellular Biology IRCCS Ospedale San Raffaele, Milan, Italy.
FAU - De Ritis, Daniele
AU  - De Ritis D
AD  - Neurogenomics Unit, Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan, 
      Italy.
FAU - Quattrini, Angelo
AU  - Quattrini A
AD  - Department of Neurology, IRCCS Ospedale San Raffaele, Milan, Italy.
AD  - Inspe and Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan, Italy.
FAU - Maltecca, Francesca
AU  - Maltecca F
AD  - Neurogenomics Unit, Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan, 
      Italy.
AD  - Universita Vita-Salute San Raffaele, Milan, Italy.
FAU - Ferrari, Maurizio
AU  - Ferrari M
AD  - Laboratory of Clinical Molecular Biology and Cytogenetics, IRCCS Ospedale San 
      Raffaele, Milan, Italy.
AD  - Universita Vita-Salute San Raffaele, Milan, Italy.
AD  - Genomic Unit for the Diagnosis of Human Pathologies, Division of Genetics and 
      Cellular Biology IRCCS Ospedale San Raffaele, Milan, Italy.
FAU - Previtali, Stefano Carlo
AU  - Previtali SC
AD  - Department of Neurology, IRCCS Ospedale San Raffaele, Milan, Italy.
AD  - Inspe and Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan, Italy.
LA  - eng
PT  - Case Reports
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (Reactive Oxygen Species)
RN  - EC 3.6.5.5 (DNM1L protein, human)
RN  - EC 3.6.5.5 (Dynamins)
SB  - IM
MH  - Autophagy/genetics
MH  - Child, Preschool
MH  - Dynamins/*genetics/metabolism
MH  - Female
MH  - Fibroblasts/cytology/metabolism/*ultrastructure
MH  - Heterozygote
MH  - Humans
MH  - Mitochondria/*genetics/metabolism/pathology/*ultrastructure
MH  - Mitochondrial Dynamics/*genetics
MH  - Mutation
MH  - Pedigree
MH  - Peripheral Nervous System Diseases/enzymology/*genetics/metabolism/pathology
MH  - Peroxisomes/metabolism
MH  - Reactive Oxygen Species/metabolism
MH  - Exome Sequencing
EDAT- 2019/12/24 06:00
MHDA- 2020/10/21 06:00
CRDT- 2019/12/24 06:00
PHST- 2019/03/26 00:00 [received]
PHST- 2019/08/09 00:00 [revised]
PHST- 2019/08/28 00:00 [accepted]
PHST- 2019/12/24 06:00 [pubmed]
PHST- 2020/10/21 06:00 [medline]
PHST- 2019/12/24 06:00 [entrez]
AID - 5559950 [pii]
AID - 10.1093/hmg/ddz211 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2020 Jan 15;29(2):177-188. doi: 10.1093/hmg/ddz211.