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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; Ugurlu Çi Men, 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; Yilmaz, 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.
Afiliación
  • Wong HH; Institute of Molecular and Cell Biology, A(∗)STAR, Biopolis, Singapore 138673, Singapore.
  • Seet SH; Institute of Molecular and Cell Biology, A(∗)STAR, Biopolis, Singapore 138673, Singapore.
  • Maier M; Laboratory of Human Genetics & Therapeutics, Genome Institute of Singapore, A(∗)STAR, Biopolis, Singapore 138672, Singapore.
  • Gurel A; Department of Medical Genetics, Faculty of Medicine, Hacettepe University, Ankara 06230, Turkey.
  • Traspas RM; Laboratory of Human Genetics & Therapeutics, Genome Institute of Singapore, A(∗)STAR, Biopolis, Singapore 138672, Singapore.
  • Lee C; Institute of Molecular and Cell Biology, A(∗)STAR, Biopolis, Singapore 138673, Singapore; Cardiovascular and Metabolic Diseases, Duke-NUS Medical School, Singapore 169857, Singapore.
  • Zhang S; Department of Medical Genetics, Faculty of Medicine, Hacettepe University, Ankara 06230, Turkey.
  • Talim B; Pediatric Pathology Unit, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara 06230, Turkey.
  • Loh AYT; Institute of Molecular and Cell Biology, A(∗)STAR, Biopolis, Singapore 138673, Singapore.
  • Chia CY; Laboratory of Human Genetics & Therapeutics, Genome Institute of Singapore, A(∗)STAR, Biopolis, Singapore 138672, Singapore.
  • Teoh TS; Laboratory of Human Genetics & Therapeutics, Genome Institute of Singapore, A(∗)STAR, Biopolis, Singapore 138672, Singapore.
  • Sng D; Laboratory of Human Genetics & Therapeutics, Genome Institute of Singapore, A(∗)STAR, Biopolis, Singapore 138672, Singapore.
  • Rensvold J; Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Morgridge Institute for Research, Madison, WI 53715, USA.
  • Unal S; Pediatric Hematology Unit, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara 06230, Turkey; Research Center of Fanconi Anemia and Other Inherited Bone Marrow Failure Syndromes, Hacettepe University, Ankara 06230, Turkey.
  • Shishkova E; National Center for Quantitative Biology of Complex Systems, Madison, WI 53562, USA; Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI 53562, USA.
  • Cepni E; Institute of Health Sciences, Koç University, 34010 Istanbul, Turkey.
  • Nathan FM; Yale-NUS College, 12 College Avenue West, Singapore 138610, Singapore.
  • Sirota FL; Bioinformatics Institute, A(∗)STAR, Biopolis, Singapore 138671, Singapore.
  • Liang C; Department of Medical Genetics, Faculty of Medicine, Hacettepe University, Ankara 06230, Turkey.
  • Yarali N; Ankara Child Health and Diseases Hematology Oncology Training and Research Hospital, Ankara 06110, Turkey.
  • Simsek-Kiper PO; Pediatric Genetics Unit, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara 06230, Turkey.
  • Mitani T; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • Ceylaner S; Intergen Genetic Diagnosis Center, Ankara 06680, Turkey.
  • Arman-Bilir O; Ankara Child Health and Diseases Hematology Oncology Training and Research Hospital, Ankara 06110, Turkey.
  • Mbarek H; Qatar Genome Program, Qatar Foundation Research, Development and Innovation, Qatar Foundation, Doha, Qatar.
  • Gumruk F; Pediatric Hematology Unit, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara 06230, Turkey; Research Center of Fanconi Anemia and Other Inherited Bone Marrow Failure Syndromes, Hacettepe University, Ankara 06230, Turkey.
  • Efthymiou S; Molecular and Clinical Sciences Institute, St. George's University of London, Cranmer Terrace, London SW17 0RE, UK.
  • Ugurlu Çi Men D; Medical Genetics Department, Koç University School of Medicine, 34010 Istanbul, Turkey.
  • Georgiadou D; Laboratory of Human Genetics & Therapeutics, Genome Institute of Singapore, A(∗)STAR, Biopolis, Singapore 138672, Singapore.
  • Sotiropoulou K; Institute of Molecular and Cell Biology, A(∗)STAR, Biopolis, Singapore 138673, Singapore.
  • Houlden H; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK.
  • Paul F; Institute of Molecular and Cell Biology, A(∗)STAR, Biopolis, Singapore 138673, Singapore.
  • Pehlivan D; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
  • Lainé C; Paris University, Imagine Institute, Paris 75015, France; Laboratory of Human Genetics of Infectious Disease, Necker Branch, INSERM U1163, Paris, France.
  • Chai G; Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
  • Ali NA; Laboratory of Human Genetics & Therapeutics, Genome Institute of Singapore, A(∗)STAR, Biopolis, Singapore 138672, Singapore.
  • Choo SC; Laboratory of Human Genetics & Therapeutics, Genome Institute of Singapore, A(∗)STAR, Biopolis, Singapore 138672, Singapore.
  • Keng SS; Institute of Molecular and Cell Biology, A(∗)STAR, Biopolis, Singapore 138673, Singapore.
  • Boisson B; Paris University, Imagine Institute, Paris 75015, France; Laboratory of Human Genetics of Infectious Disease, Necker Branch, INSERM U1163, Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA.
  • Yilmaz E; Medical Genetics Department, Koç University School of Medicine, 34010 Istanbul, Turkey.
  • Xue S; Institute of Molecular and Cell Biology, A(∗)STAR, Biopolis, Singapore 138673, Singapore; Department of Biological Sciences, National University of Singapore, Singapore 117558, Singapore.
  • Coon JJ; Morgridge Institute for Research, Madison, WI 53715, USA; National Center for Quantitative Biology of Complex Systems, Madison, WI 53562, USA; Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI 53562, USA; Department of Chemistry, University of Wisconsin-Madison, Madi
  • Ly TTN; Institute of Molecular and Cell Biology, A(∗)STAR, Biopolis, Singapore 138673, Singapore; Department of Biological Sciences, National University of Singapore, Singapore 117558, Singapore.
  • Gilani N; Farabi Medical Laboratory, Erbil, Iraq.
  • Hasbini D; Chief Division Pediatric Neurology, Department of Pediatrics, Rafic Hariri University Hospital, Beirut, Lebanon.
  • Kayserili H; Medical Genetics Department, Koç University School of Medicine, 34010 Istanbul, Turkey.
  • Zaki MS; Clinical Genetics Department, National Research Centre, Cairo 12622, Egypt.
  • Isfort RJ; Corporate Research, The Procter and Gamble Company, Cincinnati, OH 45040, USA.
  • Ordonez N; Genomic Research, CENTOGENE GmbH, 18055 Rostock, Germany.
  • Tripolszki K; Genomic Research, CENTOGENE GmbH, 18055 Rostock, Germany.
Am J Hum Genet ; 108(7): 1301-1317, 2021 07 01.
Article en En | MEDLINE | ID: mdl-34038740
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedades Mitocondriales / Encefalitis Tipo de estudio: Risk_factors_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: Am J Hum Genet Año: 2021 Tipo del documento: Article País de afiliación: Singapur Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedades Mitocondriales / Encefalitis Tipo de estudio: Risk_factors_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: Am J Hum Genet Año: 2021 Tipo del documento: Article País de afiliación: Singapur Pais de publicación: Estados Unidos