Loss of C2orf69 Defines a Fatal Autoinflammatory Syndrome in Humans and Zebrafish That Evokes a Glycogen-Storage-Associated Mitochondriopathy

Loss of C2orf69 Defines a Fatal Autoinflammatory Syndrome in Humans and Zebrafish That Evokes a Glycogen-Storage-Associated Mitochondriopathy Publisher Pubmed

Wong HH¹ ; Seet SH¹ ; Maier M² ; Gurel A³ ; Traspas RM² ; Lee C^{1, 4} ; Zhang S³ ; Talim B⁵ ; Loh AYT¹ ; Chia CY² ; Teoh TS² ; Sng D² ; Rensvold J^{6, 7} ; Unal S^{8, 9} Show All Authors

Wong HH¹
Seet SH¹
Maier M²
Gurel A³
Traspas RM²
Lee C^{1, 4}
Zhang S³
Talim B⁵
Loh AYT¹
Chia CY²
Teoh TS²
Sng D²
Rensvold J^{6, 7}
Unal S^{8, 9}
Shishkova E^{10, 11}
Cepni E¹²
Nathan FM¹³
Sirota FL¹⁴
Liang C³
Yarali N¹⁵
Simsekkiper PO¹⁶
Mitani T¹⁷
Ceylaner S¹⁸
Armanbilir O¹⁵
Mbarek H¹⁹
Gumruk F^{8, 9}
Efthymiou S²⁰
Ugurlu Cimen D²¹
Georgiadou D²
Sotiropoulou K¹
Houlden H²²
Paul F¹
Pehlivan D^{17, 23, 24}
Laine C^{25, 26}
Chai G^{27, 28}
Ali NA²
Choo SC²
Keng SS¹
Boisson B^{25, 26, 29}
Yilmaz E²¹
Xue S^{1, 30}
Coon JJ^{7, 10, 11, 31}
Ly TTN^{1, 30}
Gilani N³²
Hasbini D³³
Kayserili H²¹
Zaki MS³⁴
Isfort RJ³⁵
Ordonez N³⁶
Tripolszki K³⁶
Bauer P³⁶
Rezaei N^{37, 38}
Seyedpour S⁴⁰
Khotaei GT³⁹
Bascom CC³⁵
Maroofian R²⁰
Chaabouni M⁴⁰
Alsubhi A^{41, 42}
Eyaid W^{41, 42}
Isikay S⁴³
Gleeson JG^{27, 28}
Lupski JR^{17, 23, 24, 44}
Casanova JL^{25, 26, 29, 45, 46}
Pagliarini DJ^{6, 7, 10, 47, 48, 49}
Akarsu NA³
Maurerstroh S¹⁴
Cetinkaya A³
Bertoliavella A³⁶
Mathuru AS^{1, 13, 50}
Ho L^{1, 4}
Bard FA¹
Reversade B^{1, 2, 21, 51}

Show Affiliations

1. Institute of Molecular and Cell Biology, STAR, Biopolis, Singapore, 138673, Singapore
2. Laboratory of Human Genetics & Therapeutics, Genome Institute of Singapore, STAR, Biopolis, Singapore, 138672, Singapore
3. Department of Medical Genetics, Faculty of Medicine, Hacettepe University, Ankara, 06230, Turkey
4. Cardiovascular and Metabolic Diseases, Duke-NUS Medical School, Singapore, 169857, Singapore
5. Pediatric Pathology Unit, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, 06230, Turkey
6. Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, 63110, MO, United States
7. Morgridge Institute for Research, Madison, 53715, WI, United States
8. Pediatric Hematology Unit, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, 06230, Turkey
9. Research Center of Fanconi Anemia and Other Inherited Bone Marrow Failure Syndromes, Hacettepe University, Ankara, 06230, Turkey
10. National Center for Quantitative Biology of Complex Systems, Madison, 53562, WI, United States
11. Department of Biomolecular Chemistry, University of Wisconsinâ€“Madison, Madison, 53562, WI, United States
12. Institute of Health Sciences, Koc University, Istanbul, 34010, Turkey
13. Yale-NUS College, 12 College Avenue West, Singapore, 138610, Singapore
14. Bioinformatics Institute, STAR, Biopolis, Singapore, 138671, Singapore
15. Ankara Child Health and Diseases Hematology Oncology Training and Research Hospital, Ankara, 06110, Turkey
16. Pediatric Genetics Unit, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, 06230, Turkey
17. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, 77030, TX, United States
18. Intergen Genetic Diagnosis Center, Ankara, 06680, Turkey
19. Qatar Genome Program, Qatar Foundation Research, Development and Innovation, Qatar Foundation, Doha, Qatar
20. Molecular and Clinical Sciences Institute, St. George's University of London, Cranmer Terrace, London, SW17 0RE, UK, United Kingdom
21. Medical Genetics Department, Koc University School of Medicine, Istanbul, 34010, Turkey
22. Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, UK, United Kingdom
23. Department of Pediatrics, Baylor College of Medicine, Houston, 77030, TX, United States
24. Texas Children's Hospital, Houston, 77030, TX, United States
25. Paris University, Imagine Institute, Paris, 75015, France
26. Laboratory of Human Genetics of Infectious Disease, INSERM U1163, Necker Branch, Paris, France
27. Rady Children's Institute for Genomic Medicine, San Diego, 92123, CA, United States
28. Department of Neurosciences, University of California, San Diego, La Jolla, 92093, CA, United States
29. St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, Rockefeller Branch, New York, 10065, NY, United States
30. Department of Biological Sciences, National University of Singapore, Singapore, 117558, Singapore
31. Department of Chemistry, University of Wisconsinâ€“Madison, Madison, 53562, WI, United States
32. Farabi Medical Laboratory, Erbil, Iraq
33. Chief Division Pediatric Neurology, Department of Pediatrics, Rafic Hariri University Hospital, Beirut, Lebanon
34. Clinical Genetics Department, National Research Centre, Cairo, 12622, Egypt
35. Corporate Research, The Procter and Gamble Company, Cincinnati, 45040, OH, United States
36. Genomic Research, CENTOGENE GmbH, Rostock, 18055, Germany
37. Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, 14194, Iran
38. Network of Immunity in Infection, Malignancy and Autoimmunity, Universal Scientific Education and Research Network, Tehran, 14197, Iran
39. Department of Pediatric Infectious Diseases, Children's Medical Center, Tehran University of Medical Sciences, Tehran, 14194, Iran
40. Laboratoire d'analyses specialise en Genetique, Tunis, 1082, Tunisia
41. Division of Genetics, Department of Pediatrics, King Abdullah Specialized Children Hospital, King Abdulaziz Medical City, MNGHA, Riyadh, 14611, Saudi Arabia
42. King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, MNGHA, Riyadh, 11481, Saudi Arabia
43. Department of Pediatrics, Division of Neurology, University of Gaziantep, School of Medicine, Gaziantep, 27310, Turkey
44. Human Genome Sequencing Center, Baylor College of Medicine, Houston, 77030, TX, United States
45. Pediatric Immunology-Hematology Unit, Assistance Publique-Hopitaux de Paris, Necker Hospital for Sick Children, Paris, 75015, France
46. Howard Hughes Medical Institute, New York, 10065, NY, United States
47. Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, 63110, MO, United States
48. Department of Genetics, Washington University School of Medicine, St. Louis, 63110, MO, United States
49. Department of Biochemistry, University of Wisconsinâ€“Madison, Madison, 53706, WI, United States
50. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117593, Singapore
51. Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore

Source: American Journal of Human Genetics Published:2021

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. © 2021 American Society of Human Genetics

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Ghorbangol Ashabi (1)

Style	Citing Format
MLA	Wong HH, et al.. "Loss of C2orf69 Defines a Fatal Autoinflammatory Syndrome in Humans and Zebrafish That Evokes a Glycogen-Storage-Associated Mitochondriopathy." American Journal of Human Genetics, vol. 108, no. 7, 2021, pp. 1301-1317.
APA	Wong HH, Seet SH, Maier M, Gurel A, Traspas RM, Lee C, Zhang S, Talim B, Loh AYT, Chia CY, Teoh TS, Sng D, Rensvold J, Unal S, Shishkova E, Cepni E, Nathan FM, Sirota FL, Liang C, ... Reversade B (2021). Loss of C2orf69 Defines a Fatal Autoinflammatory Syndrome in Humans and Zebrafish That Evokes a Glycogen-Storage-Associated Mitochondriopathy. American Journal of Human Genetics, 108(7), 1301-1317.
Chicago	Wong HH, Seet SH, Maier M, Gurel A, Traspas RM, Lee C, Zhang S, et al.. "Loss of C2orf69 Defines a Fatal Autoinflammatory Syndrome in Humans and Zebrafish That Evokes a Glycogen-Storage-Associated Mitochondriopathy." American Journal of Human Genetics 108, no. 7 (2021): 1301-1317.
Harvard	Wong HH et al. (2021) 'Loss of C2orf69 Defines a Fatal Autoinflammatory Syndrome in Humans and Zebrafish That Evokes a Glycogen-Storage-Associated Mitochondriopathy', American Journal of Human Genetics, 108(7), pp. 1301-1317.
Vancouver	Wong HH, Seet SH, Maier M, Gurel A, Traspas RM, Lee C, et al.. Loss of C2orf69 Defines a Fatal Autoinflammatory Syndrome in Humans and Zebrafish That Evokes a Glycogen-Storage-Associated Mitochondriopathy. American Journal of Human Genetics. 2021;108(7):1301-1317.
BibTex	@article{ author = {Wong HH and Seet SH and Maier M and Gurel A and Traspas RM and Lee C and Zhang S and Talim B and Loh AYT and Chia CY and Teoh TS and Sng D and Rensvold J and Unal S and Shishkova E and Cepni E and Nathan FM and Sirota FL and Liang C and Yarali N and Simsekkiper PO and Mitani T and Ceylaner S and Armanbilir O and Mbarek H and Gumruk F and Efthymiou S and Ugurlu Cimen D and Georgiadou D and Sotiropoulou K and Houlden H and Paul F and Pehlivan D and Laine C and Chai G and Ali NA and Choo SC and Keng SS and Boisson B and Yilmaz E and Xue S and Coon JJ and Ly TTN and Gilani N and Hasbini D and Kayserili H and Zaki MS and Isfort RJ and Ordonez N and Tripolszki K and Bauer P and Rezaei N and Seyedpour S and Khotaei GT and Bascom CC and Maroofian R and Chaabouni M and Alsubhi A and Eyaid W and Isikay S and Gleeson JG and Lupski JR and Casanova JL and Pagliarini DJ and Akarsu NA and Maurerstroh S and Cetinkaya A and Bertoliavella A and Mathuru AS and Ho L and Bard FA and Reversade B}, title = {Loss of C2orf69 Defines a Fatal Autoinflammatory Syndrome in Humans and Zebrafish That Evokes a Glycogen-Storage-Associated Mitochondriopathy}, journal = {American Journal of Human Genetics}, volume = {108}, number = {7}, pages = {1301-1317}, year = {2021} }
RIS	TY - JOUR AU - Wong HH AU - Seet SH AU - Maier M AU - Gurel A AU - Traspas RM AU - Lee C AU - Zhang S AU - Talim B AU - Loh AYT AU - Chia CY AU - Teoh TS AU - Sng D AU - Rensvold J AU - Unal S AU - Shishkova E AU - Cepni E AU - Nathan FM AU - Sirota FL AU - Liang C AU - Yarali N AU - Simsekkiper PO AU - Mitani T AU - Ceylaner S AU - Armanbilir O AU - Mbarek H AU - Gumruk F AU - Efthymiou S AU - Ugurlu Cimen D AU - Georgiadou D AU - Sotiropoulou K AU - Houlden H AU - Paul F AU - Pehlivan D AU - Laine C AU - Chai G AU - Ali NA AU - Choo SC AU - Keng SS AU - Boisson B AU - Yilmaz E AU - Xue S AU - Coon JJ AU - Ly TTN AU - Gilani N AU - Hasbini D AU - Kayserili H AU - Zaki MS AU - Isfort RJ AU - Ordonez N AU - Tripolszki K AU - Bauer P AU - Rezaei N AU - Seyedpour S AU - Khotaei GT AU - Bascom CC AU - Maroofian R AU - Chaabouni M AU - Alsubhi A AU - Eyaid W AU - Isikay S AU - Gleeson JG AU - Lupski JR AU - Casanova JL AU - Pagliarini DJ AU - Akarsu NA AU - Maurerstroh S AU - Cetinkaya A AU - Bertoliavella A AU - Mathuru AS AU - Ho L AU - Bard FA AU - Reversade B TI - Loss of C2orf69 Defines a Fatal Autoinflammatory Syndrome in Humans and Zebrafish That Evokes a Glycogen-Storage-Associated Mitochondriopathy JO - American Journal of Human Genetics VL - 108 IS - 7 SP - 1301 EP - 1317 PY - 2021 ER -

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