Abstract
Human C2orf69 is an evolutionarily conserved gene whose function is unknown. Here, we report eight unrelated families from which 20 children presented with a fatal syndrome consisting of severe autoinflammation and progredient leukoencephalopathy with recurrent seizures; 12 of these subjects, whose DNA was available, segregated homozygous loss-of-function C2orf69 variants. C2ORF69 bears homology to esterase enzymes, and orthologs can be found in most eukaryotic genomes, including that of unicellular phytoplankton. We found that endogenous C2ORF69 (1) is loosely bound to mitochondria, (2) affects mitochondrial membrane potential and oxidative respiration in cultured neurons, and (3) controls the levels of the glycogen branching enzyme 1 (GBE1) consistent with a glycogen-storage-associated mitochondriopathy. We show that CRISPR-Cas9-mediated inactivation of zebrafish C2orf69 results in lethality by 8 months of age due to spontaneous epileptic seizures, which is preceded by persistent brain inflammation. Collectively, our results delineate an autoinflammatory Mendelian disorder of C2orf69 deficiency that disrupts the development/homeostasis of the immune and central nervous systems.
| Original language | English |
|---|---|
| Pages (from-to) | 1301-1317 |
| Number of pages | 17 |
| Journal | American journal of human genetics |
| Volume | 108 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jul 1 2021 |
Keywords
- C2ORF69, mitochondriopathy, inflammation, GBE1, encephalopathy, zebrafish, Elbracht-Işikay syndrome, lipase, glycogen, Mendelian genetics
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Loss of C2orf69 defines a fatal autoinflammatory syndrome in humans and zebrafish that evokes a glycogen-storage-associated mitochondriopathy. / Wong, Hui Hui; Seet, Sze Hwee; Maier, Michael; Gurel, Ayse; Traspas, Ricardo Moreno; Lee, Cheryl; Zhang, Shan; Talim, Beril; Loh, Abigail Y.T.; Chia, Crystal Y.; Teoh, Tze Shin; Sng, Danielle; Rensvold, Jarred; Unal, Sule; Shishkova, Evgenia; Cepni, Ece; Nathan, Fatima M.; Sirota, Fernanda L.; Liang, Chao; Yarali, Nese; Simsek-Kiper, Pelin O.; Mitani, Tadahiro; Ceylaner, Serdar; Arman-Bilir, Ozlem; Mbarek, Hamdi; Gumruk, Fatma; Efthymiou, Stephanie; Uğurlu Çi̇men, Deniz; Georgiadou, Danai; Sotiropoulou, Kortessa; Houlden, Henry; Paul, Franziska; Pehlivan, Davut; Lainé, Candice; Chai, Guoliang; Ali, Nur Ain; Choo, Siew Chin; Keng, Soh Sok; Boisson, Bertrand; Yılmaz, Elanur; Xue, Shifeng; Coon, Joshua J.; Ly, Thanh Thao Nguyen; Gilani, Naser; Hasbini, Dana; Kayserili, Hulya; Zaki, Maha S.; Isfort, Robert J.; Ordonez, Natalia; Tripolszki, Kornelia; Bauer, Peter; Rezaei, Nima; Seyedpour, Simin; Khotaei, Ghamar Taj; Bascom, Charles C.; Maroofian, Reza; Chaabouni, Myriam; Alsubhi, Afaf; Eyaid, Wafaa; Işıkay, Sedat; Gleeson, Joseph G.; Lupski, James R.; Casanova, Jean Laurent; Pagliarini, David J.; Akarsu, Nurten A.; Maurer-Stroh, Sebastian; Cetinkaya, Arda; Bertoli-Avella, Aida; Mathuru, Ajay S.; Ho, Lena; Bard, Frederic A.; Reversade, Bruno.
In: American journal of human genetics, Vol. 108, No. 7, 01.07.2021, p. 1301-1317.Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Loss of C2orf69 defines a fatal autoinflammatory syndrome in humans and zebrafish that evokes a glycogen-storage-associated mitochondriopathy
AU - Wong, Hui Hui
AU - Seet, Sze Hwee
AU - Maier, Michael
AU - Gurel, Ayse
AU - Traspas, Ricardo Moreno
AU - Lee, Cheryl
AU - Zhang, Shan
AU - Talim, Beril
AU - Loh, Abigail Y.T.
AU - Chia, Crystal Y.
AU - Teoh, Tze Shin
AU - Sng, Danielle
AU - Rensvold, Jarred
AU - Unal, Sule
AU - Shishkova, Evgenia
AU - Cepni, Ece
AU - Nathan, Fatima M.
AU - Sirota, Fernanda L.
AU - Liang, Chao
AU - Yarali, Nese
AU - Simsek-Kiper, Pelin O.
AU - Mitani, Tadahiro
AU - Ceylaner, Serdar
AU - Arman-Bilir, Ozlem
AU - Mbarek, Hamdi
AU - Gumruk, Fatma
AU - Efthymiou, Stephanie
AU - Uğurlu Çi̇men, Deniz
AU - Georgiadou, Danai
AU - Sotiropoulou, Kortessa
AU - Houlden, Henry
AU - Paul, Franziska
AU - Pehlivan, Davut
AU - Lainé, Candice
AU - Chai, Guoliang
AU - Ali, Nur Ain
AU - Choo, Siew Chin
AU - Keng, Soh Sok
AU - Boisson, Bertrand
AU - Yılmaz, Elanur
AU - Xue, Shifeng
AU - Coon, Joshua J.
AU - Ly, Thanh Thao Nguyen
AU - Gilani, Naser
AU - Hasbini, Dana
AU - Kayserili, Hulya
AU - Zaki, Maha S.
AU - Isfort, Robert J.
AU - Ordonez, Natalia
AU - Tripolszki, Kornelia
AU - Bauer, Peter
AU - Rezaei, Nima
AU - Seyedpour, Simin
AU - Khotaei, Ghamar Taj
AU - Bascom, Charles C.
AU - Maroofian, Reza
AU - Chaabouni, Myriam
AU - Alsubhi, Afaf
AU - Eyaid, Wafaa
AU - Işıkay, Sedat
AU - Gleeson, Joseph G.
AU - Lupski, James R.
AU - Casanova, Jean Laurent
AU - Pagliarini, David J.
AU - Akarsu, Nurten A.
AU - Maurer-Stroh, Sebastian
AU - Cetinkaya, Arda
AU - Bertoli-Avella, Aida
AU - Mathuru, Ajay S.
AU - Ho, Lena
AU - Bard, Frederic A.
AU - Reversade, Bruno
N1 - Funding Information: We thank all the families for partaking in this study and the referring clinicians for their generous help. We are grateful to all members of the Reversade, Ho, and Bard laboratories for swift support. We thank Z. Ekim Taskiran for facilitating WES studies in the Hacettepe University Exome Facility and Can Kosukcu for obtaining WES data. We thank Mohd Agus and the IMCB aquatics facility for zebrafish husbandry. H.H.W. and S.H.S. are supported by a grant from Procter and Gamble . J.L.C. is supported by the Howard Hughes Medical Institute (HHMI), the Rockefeller University , the St. Giles Foundation , Institut National de la Santé et de la Recherche Médicale ( INSERM ), and the “Université de Paris.” S.U. is supported by E-Rare grants for EuroDBA Project (TUBITAK, #315S192 ). S.Z. is supported by a Khoo Teck Puat postdoctoral fellowship. A.C. is supported by the EU’s Horizon 2020 research and innovation program under the EJP RD COFUND-EJP no. 825575 (TUBİTAK, #319S062 ). D.J.P. is supported by NIH awards R35 GM131795 and P41 GM108538 , a UW2020 award, and funds from the BJC Investigator Program . J.J.C. is supported by NIH awards, P41 GM108538, and a UW2020 award. S.X. is supported by NMRC/OFYIRG/062/2017 . A.S.M. and F.M.N. are supported by the Ministry of Education, Singapore and Yale-NUS College ( IG19-BG106 and SUG ). L.H. is supported by fellowships NRF-NRFF2017-05 and HHMI-IRSP55008732 . T.M. is supported by The Uehara Memorial Foundation . D.P. is supported by International Rett Syndrome Foundation ( #3701-1 ). J.R.L. is supported by the National Human Genome Research Institute , the National Heart, Lung, and Blood Institute , The Baylor-Hopkins Center for Mendelian Genomics ( #HG006542 ), and the National Institutes of Neurological Disease and Stroke ( R35NS105078 ) and Muscular Dystrophy Association ( #512848 ). B.R. is an investigator of the National Research Foundation (Singapore) and is supported by a use-inspired basic research grant from the Agency for Science & Technology and Research (A ∗ STAR) in Singapore. Funding Information: We thank all the families for partaking in this study and the referring clinicians for their generous help. We are grateful to all members of the Reversade, Ho, and Bard laboratories for swift support. We thank Z. Ekim Taskiran for facilitating WES studies in the Hacettepe University Exome Facility and Can Kosukcu for obtaining WES data. We thank Mohd Agus and the IMCB aquatics facility for zebrafish husbandry. H.H.W. and S.H.S. are supported by a grant from Procter and Gamble. J.L.C. is supported by the Howard Hughes Medical Institute (HHMI), the Rockefeller University, the St. Giles Foundation, Institut National de la Santé et de la Recherche Médicale (INSERM), and the “Université de Paris.” S.U. is supported by E-Rare grants for EuroDBA Project (TUBITAK, #315S192). S.Z. is supported by a Khoo Teck Puat postdoctoral fellowship. A.C. is supported by the EU's Horizon 2020 research and innovation program under the EJP RD COFUND-EJP no. 825575 (TUBİTAK, #319S062). D.J.P. is supported by NIH awards R35 GM131795 and P41 GM108538, a UW2020 award, and funds from the BJC Investigator Program. J.J.C. is supported by NIH awards, P41 GM108538, and a UW2020 award. S.X. is supported by NMRC/OFYIRG/062/2017. A.S.M. and F.M.N. are supported by the Ministry of Education, Singapore and Yale-NUS College (IG19-BG106 and SUG). L.H. is supported by fellowships NRF-NRFF2017-05 and HHMI-IRSP55008732. T.M. is supported by The Uehara Memorial Foundation. D.P. is supported by International Rett Syndrome Foundation (#3701-1). J.R.L. is supported by the National Human Genome Research Institute, the National Heart, Lung, and Blood Institute, The Baylor-Hopkins Center for Mendelian Genomics (#HG006542), and the National Institutes of Neurological Disease and Stroke (R35NS105078) and Muscular Dystrophy Association (#512848). B.R. is an investigator of the National Research Foundation (Singapore) and is supported by a use-inspired basic research grant from the Agency for Science & Technology and Research (A∗STAR) in Singapore. Publisher Copyright: © 2021 American Society of Human Genetics
PY - 2021/7/1
Y1 - 2021/7/1
N2 - Human C2orf69 is an evolutionarily conserved gene whose function is unknown. Here, we report eight unrelated families from which 20 children presented with a fatal syndrome consisting of severe autoinflammation and progredient leukoencephalopathy with recurrent seizures; 12 of these subjects, whose DNA was available, segregated homozygous loss-of-function C2orf69 variants. C2ORF69 bears homology to esterase enzymes, and orthologs can be found in most eukaryotic genomes, including that of unicellular phytoplankton. We found that endogenous C2ORF69 (1) is loosely bound to mitochondria, (2) affects mitochondrial membrane potential and oxidative respiration in cultured neurons, and (3) controls the levels of the glycogen branching enzyme 1 (GBE1) consistent with a glycogen-storage-associated mitochondriopathy. We show that CRISPR-Cas9-mediated inactivation of zebrafish C2orf69 results in lethality by 8 months of age due to spontaneous epileptic seizures, which is preceded by persistent brain inflammation. Collectively, our results delineate an autoinflammatory Mendelian disorder of C2orf69 deficiency that disrupts the development/homeostasis of the immune and central nervous systems.
AB - Human C2orf69 is an evolutionarily conserved gene whose function is unknown. Here, we report eight unrelated families from which 20 children presented with a fatal syndrome consisting of severe autoinflammation and progredient leukoencephalopathy with recurrent seizures; 12 of these subjects, whose DNA was available, segregated homozygous loss-of-function C2orf69 variants. C2ORF69 bears homology to esterase enzymes, and orthologs can be found in most eukaryotic genomes, including that of unicellular phytoplankton. We found that endogenous C2ORF69 (1) is loosely bound to mitochondria, (2) affects mitochondrial membrane potential and oxidative respiration in cultured neurons, and (3) controls the levels of the glycogen branching enzyme 1 (GBE1) consistent with a glycogen-storage-associated mitochondriopathy. We show that CRISPR-Cas9-mediated inactivation of zebrafish C2orf69 results in lethality by 8 months of age due to spontaneous epileptic seizures, which is preceded by persistent brain inflammation. Collectively, our results delineate an autoinflammatory Mendelian disorder of C2orf69 deficiency that disrupts the development/homeostasis of the immune and central nervous systems.
KW - C2ORF69, mitochondriopathy, inflammation, GBE1, encephalopathy, zebrafish, Elbracht-Işikay syndrome, lipase, glycogen, Mendelian genetics
UR - http://www.scopus.com/inward/record.url?scp=85108947728&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2021.05.003
DO - 10.1016/j.ajhg.2021.05.003
M3 - Article
C2 - 34038740
AN - SCOPUS:85108947728
VL - 108
SP - 1301
EP - 1317
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 7
ER -