Loss of C2orf69 defines a fatal auto-inflammatory mitochondriopathy in Humans and Zebrafish
Author:
Wong Hui Hui, Seet Sze Hwee, Maier MichaelORCID, Traspas Ricardo MorenoORCID, Lee CherylORCID, Shan Zhang, Loh Abigail Y. T.ORCID, Chia Crystal Y.ORCID, Teoh Tze ShinORCID, Sng DanielleORCID, Cepni EceORCID, Nathan Fatima M., Sirota Fernanda L., Chao Liang, Tadahiro Mitani, Mbarek HamdiORCID, Georgiadou DanaiORCID, Sotiropoulou Kortessa, Paul FranziskaORCID, Pehlivan DavutORCID, Lainé Candice, Chai GuoliangORCID, Ali Nur Ain, Choo Siew Chin, Boisson BertrandORCID, Xue ShifengORCID, Kayserili HulyaORCID, Zaki MahaORCID, Isfort Robert J., Bauer PeterORCID, Rezaei NimaORCID, Seyedpour SiminORCID, Khotaei Ghamar Taj, Bascom Charles C., Chaabouni Myriam, AlSubhi Afaf, Eyaid Wafaa, Işıkay Sedat, Gleeson Joseph G., Lupski James R.ORCID, Casanova Jean-LaurentORCID, Maurer-Stroh SebastianORCID, Bertoli-Avella AidaORCID, Mathuru Ajay S.ORCID, Ho LenaORCID, Bard FredericORCID, Reversade BrunoORCID
Abstract
AbstractHuman C2orf69 is an evolutionary-conserved gene whose function is unknown. Here, we report 9 children from 5 unrelated families with a fatal syndrome consisting of severe auto-inflammation, progredient leukoencephalopathy with recurrent seizures that segregate homozygous loss-of-function C2orf69 variants. C2ORF69 orthologues, which can be found in most eukaryotic genomes including that of unicellular phytoplanktons, bear homology to esterase enzymes. We find that human C2ORF69 is loosely bound to the mitochondrion and its depletion affects mitochondrial membrane potential in human fibroblasts and neurons. Moreover, we show that CRISPR/Cas9-inactivation of zebrafish C2orf69 results in lethality by 8 months of age due to spontaneous epileptic seizures which is accompanied by persistent brain inflammation. Collectively, our results delineate a novel auto-inflammatory Mendelian disorder of C2orf69 deficiency that disrupts the development/homeostasis of the immune and central nervous systems as demonstrated in patients and in a zebrafish model of the disease.One Sentence SummaryC2orf69 is a putative enzyme whose inactivation in humans and zebrafish causes a hitherto unknown auto-inflammatory syndrome.
Publisher
Cold Spring Harbor Laboratory
Reference38 articles.
1. The Protein-Coding Human Genome: Annotating High-Hanging Fruits;Bioessays,2019 2. Poverennaya, E. , Kiseleva, O. , Romanova, A. , and Pyatnitskiy, M. (2020). Predicting Functions of Uncharacterized Human Proteins: From Canonical to Proteoforms. Genes 11,. 3. Quality control of the mitochondrial proteome;Nat. Rev. Mol. Cell Biol,2021 4. Mitochondrial diseases;Nat Rev Dis Primers,2016 5. Mitochondria: In Sickness and in Health
|
|