American journal of human genetics · 2021

Loss of C2orf69 defines a fatal autoinflammatory syndrome in humans and zebrafish that evokes a glycogen-storage-associated mitochondriopathy.

СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди

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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 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, 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

Аннотация

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.

Предметные рубрики MeSH

Animals Biological Evolution CRISPR-Cas Systems Cell Line Encephalitis Female Genes, Recessive Glycogen Humans Inflammation Male Membrane Proteins Mitochondrial Diseases Pedigree Seizures Zebrafish

Loss of C2orf69 defines a fatal autoinflammatory syndrome in humans and zebrafish that evokes a glycogen-storage-associated mitochondriopathy.

Ошибки и ограничения

Аннотация

Предметные рубрики MeSH