Aberrant mitochondrial function in patient-derived neural cells from CDKL5 deficiency disorder and Rett syndrome

Smita Jagtap, Jessica M. Thanos, Ting Fu, Jennifer Wang, Jasmin Lalonde, Thomas O. Dial, Ariel Feiglin, Jeffrey Chen, Isaac Kohane, Jeannie T. Lee, Steven D. Sheridan, Roy H. Perlis

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


The X-linked neurodevelopmental diseases CDKL5 deficiency disorder (CDD) and Rett syndrome (RTT) are associated with intellectual disability, infantile spasms and seizures. Although mitochondrial dysfunction has been suggested in RTT, less is understood about mitochondrial function in CDD. A comparison of bioenergetics and mitochondrial function between isogenic wild-type and mutant neural progenitor cell (NPC) lines revealed increased oxygen consumption in CDD mutant lines, which is associated with altered mitochondrial function and structure. Transcriptomic analysis revealed differential expression of genes related to mitochondrial and REDOX function in NPCs expressing the mutant CDKL5. Furthermore, a similar increase in oxygen consumption specific to RTT patient-derived isogenic mutant NPCs was observed, though the pattern of mitochondrial functional alterations was distinct from CDKL5 mutant-expressing NPCs. We propose that aberrant neural bioenergetics is a common feature between CDD and RTT disorders. The observed changes in oxidative stress and mitochondrial function may facilitate the development of therapeutic agents for CDD and related disorders.

Original languageEnglish
Pages (from-to)3625-3636
Number of pages12
JournalHuman Molecular Genetics
Issue number21
StatePublished - 1 Nov 2019
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2019 Published by Oxford University Press 2019. This work is written by (a) US Government employee(s) and is in the public domain in the US.


Authors thank Mriganka Sur (Department of Brain and Cognitive Sciences, MIT) for providing RTT isogenic iPSCs, Jayla Ruliera (Center for Genomic Medicine, MGH) for technical assistance with deriving patient fibroblast cultures for iPSC reprogramming and Diane Capen (Center for Systems Biology, MGH) for technical assistance in TEM sample preparation and imaging. This work was supported by a National Institute of Mental Health/National Human Genome Research Institute Center for Excellence in Genomic Science award [grant number P50 MH106933 to I.K. and R.H.P.] with preliminary support from the LouLou Foundation [R.H.P. and J.T.L.]. Conflict of Interest statement. Dr. Perlis has served on advisory boards or provided consulting to Genomind, Psy Therapeutics, RIDVentures and Takeda. He receives salary support from JAMA Network-Open for service as associate editor. He holds equity in Psy Therapeutics and Outermost Therapeutics. He reports research support from the National Institute of Mental Health, National Heart, Lung and Blood Institute, National Center for Complementary and Integrative Health and National Human Genomics Research Institute. The other authors have declared that no conflicts of interest exist.

FundersFunder number
LouLou Foundation
National Institute of Mental HealthP50MH106933
National Heart, Lung, and Blood Institute
National Human Genome Research Institute
National Center for Complementary and Integrative Health


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