Biallelic variants in KARS1 are associated with neurodevelopmental disorders and hearing loss recapitulated by the knockout zebrafish.
Обработка статьи · этапы, ошибки и управление
Ошибки и ограничения
История · было → стало
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Lin Sheng-Jia, Vona Barbara, Barbalho Patricia G, Kaiyrzhanov Rauan, Maroofian Reza, Petree Cassidy, Severino Mariasavina, Stanley Valentina, Varshney Pratishtha, Bahena Paulina, Alzahrani Fatema, Alhashem Amal, Pagnamenta Alistair T, Aubertin Gudrun, Estrada-Veras Juvianee I, Hernández Héctor Adrián Díaz, Mazaheri Neda, Oza Andrea, Thies Jenny, Renaud Deborah L, Dugad Sanmati, McEvoy Jennifer, Sultan Tipu, Pais Lynn S, Tabarki Brahim, Villalobos-Ramirez Daniel, Rad Aboulfazl, Genomics England Research Consortium, Galehdari Hamid, Ashrafzadeh Farah, Sahebzamani Afsaneh, Saeidi Kolsoum, Torti Erin, Elloumi Houda Z, Mora Sara, Palculict Timothy B, Yang Hui, Wren Jonathan D, Ben Fowler, Joshi Manali, Behra Martine, Burgess Shawn M, Nath Swapan K, Hanna Michael G, Kenna Margaret, Merritt J Lawrence, Houlden Henry, Karimiani Ehsan Ghayoor, Zaki Maha S, Haaf Thomas, Alkuraya Fowzan S, Gleeson Joseph G, Varshney Gaurav K
Аннотация
METHODS: Through international collaboration, we identified 22 affected individuals from 16 unrelated families harboring biallelic likely pathogenic or pathogenic in KARS1 variants. Sequencing approaches ranged from disease-specific panels to genome sequencing. We generated loss-of-function alleles in zebrafish.
RESULTS: We identify ten new and four known biallelic missense variants in KARS1 presenting with a moderate-to-severe developmental delay, progressive neurological and neurosensory abnormalities, and variable white matter involvement. We describe novel KARS1-associated signs such as autism, hyperactive behavior, pontine hypoplasia, and cerebellar atrophy with prevalent vermian involvement. Loss of kars1 leads to upregulation of p53, tissue-specific apoptosis, and downregulation of neurodevelopmental related genes, recapitulating key tissue-specific disease phenotypes of patients. Inhibition of p53 rescued several defects of kars1-/- knockouts.
CONCLUSION: Our work delineates the clinical spectrum associated with KARS1 defects and provides a novel animal model for KARS1-related human diseases revealing p53 signaling components as potential therapeutic targets.