دورية أكاديمية
أعرض في EDS

Biallelic variants in KARS1 are associated with neurodevelopmental disorders and hearing loss recapitulated by the knockout zebrafish.

التفاصيل البيبلوغرافية
العنوان: Biallelic variants in KARS1 are associated with neurodevelopmental disorders and hearing loss recapitulated by the knockout zebrafish.
المؤلفون: Lin SJ; Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA., Vona B; Department of Otolaryngology-Head & Neck Surgery, Tübingen Hearing Research Centre, Eberhard Karls University of Tübingen, Tübingen, Germany.; Institute of Human Genetics, Julius Maximilians University Würzburg, Würzburg, Germany., Barbalho PG; Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA., Kaiyrzhanov R; Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London, London, UK., Maroofian R; Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London, London, UK., Petree C; Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA., Severino M; Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy., Stanley V; Department of Neurosciences, Rady Children's Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA., Varshney P; Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA., Bahena P; Institute of Human Genetics, Julius Maximilians University Würzburg, Würzburg, Germany., Alzahrani F; Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Alhashem A; Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia., Pagnamenta AT; NIHR Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK., Aubertin G; Division of Medical Genetics, Department of Pathology and Lab Medicine, Island Health, Victoria General Hospital, Victoria, BC, Canada., Estrada-Veras JI; Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.; Pediatric Subspecialty Genetics Walter Reed National Military Medical Center, Bethesda, MD, USA.; Murtha Cancer Center / Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA., Hernández HAD; Department of Gastrointestinal Endoscopy, National Institute of Medical Sciences and Nutrition Salvador Zubirán, Mexico City, Mexico., Mazaheri N; Department of Genetics, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran.; Narges Medical Genetics and Prenatal Diagnostics Laboratory, East Mihan Ave., Kianpars, Iran., Oza A; Otolaryngology and Communication Enhancement, Boston Children's Hospital, and Dept. of Otolaryngology, Harvard medical School, Boston, USA., Thies J; Department of Biochemical Genetics, Seattle Children's Hospital, Seattle, WA, USA., Renaud DL; Departments of Neurology and Pediatrics, Mayo Clinic College of Medicine and Science, Rochester, MN, USA., Dugad S; Bioinformatics Centre, S. P. Pune University, Pune, India., McEvoy J; Department of Neurosciences, Rady Children's Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA., Sultan T; Department of Pediatric Neurology, Children's Hospital and Institute of Child Health, Lahore, Pakistan., Pais LS; Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA., Tabarki B; Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia., Villalobos-Ramirez D; Department of Bioinformatics, Biocenter, University of Würzburg, Würzburg, Germany., Rad A; Department of Otolaryngology-Head & Neck Surgery, Tübingen Hearing Research Centre, Eberhard Karls University of Tübingen, Tübingen, Germany., Galehdari H; Department of Gastrointestinal Endoscopy, National Institute of Medical Sciences and Nutrition Salvador Zubirán, Mexico City, Mexico., Ashrafzadeh F; Department of Pediatric Diseases, Mashhad University of Medical Sciences, Mashhad, Iran., Sahebzamani A; Pediatric and Genetic Counselling Center, Kerman Welfare Organization, Kerman, Iran., Saeidi K; Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran., Torti E; GeneDx, 207 Perry Parkway Gaithersburg, Gaithersburg, MD, USA., Elloumi HZ; GeneDx, 207 Perry Parkway Gaithersburg, Gaithersburg, MD, USA., Mora S; GeneDx, 207 Perry Parkway Gaithersburg, Gaithersburg, MD, USA., Palculict TB; GeneDx, 207 Perry Parkway Gaithersburg, Gaithersburg, MD, USA., Yang H; GeneDx, 207 Perry Parkway Gaithersburg, Gaithersburg, MD, USA., Wren JD; Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA., Ben Fowler; Imaging core facility, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA., Joshi M; Bioinformatics Centre, S. P. Pune University, Pune, India., Behra M; Department of Neurobiology, University of Puerto Rico, San Juan, PR, USA., Burgess SM; Translational & Functional Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA., Nath SK; Arthritis & Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA., Hanna MG; Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London, London, UK., Kenna M; Otolaryngology and Communication Enhancement, Boston Children's Hospital, and Dept. of Otolaryngology, Harvard medical School, Boston, USA., Merritt JL 2nd; Department of Pediatrics, Biochemical Genetics, University of Washington, Seattle, WA, USA., Houlden H; Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London, London, UK., Karimiani EG; Molecular and Clinical Sciences Institute, St. George's, University of London, Cranmer Terrace London, London, UK.; Innovative Medical Research Center, Mashhad Branch, Islamic Azdad University, Mashhad, Iran., Zaki MS; Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt., Haaf T; Institute of Human Genetics, Julius Maximilians University Würzburg, Würzburg, Germany., Alkuraya FS; Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.; Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia., Gleeson JG; Department of Neurosciences, Rady Children's Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA., Varshney GK; Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA. gaurav-varshney@omrf.org.
مؤلفون مشاركون: Genomics England Research Consortium
المصدر: Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2021 Oct; Vol. 23 (10), pp. 1933-1943. Date of Electronic Publication: 2021 Jun 25.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Elsevier Country of Publication: United States NLM ID: 9815831 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1530-0366 (Electronic) Linking ISSN: 10983600 NLM ISO Abbreviation: Genet Med Subsets: MEDLINE
أسماء مطبوعة: Publication: 2022- : [New York] : Elsevier
Original Publication: Baltimore, MD : Lippincott, Williams & Wilkins, c1998-
مواضيع طبية MeSH: Hearing Loss*/genetics , Neurodevelopmental Disorders*/genetics, Lysine-tRNA Ligase/*genetics, Alleles ; Animals ; Disease Models, Animal ; Humans ; Phenotype ; Zebrafish/genetics
مستخلص: Purpose: Pathogenic variants in Lysyl-tRNA synthetase 1 (KARS1) have increasingly been recognized as a cause of early-onset complex neurological phenotypes. To advance the timely diagnosis of KARS1-related disorders, we sought to delineate its phenotype and generate a disease model to understand its function in vivo.
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.
(© 2021. The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.)
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معلومات مُعتمدة: UM1 HG008900 United States HG NHGRI NIH HHS; MC_EX_MR/M009203/1 United Kingdom MRC_ Medical Research Council; R01 HG009141 United States HG NHGRI NIH HHS; R01 NS048453 United States NS NINDS NIH HHS; U54 HG006504 United States HG NHGRI NIH HHS; R01 NS052455 United States NS NINDS NIH HHS; MR/M009203/1 United Kingdom MRC_ Medical Research Council; P20 GM103636 United States GM NIGMS NIH HHS; MC_PC_14089 United Kingdom MRC_ Medical Research Council
فهرسة مساهمة: Investigator: JC Ambrose; P Arumugam; M Bleda; F Boardman-Pretty; CR Boustred; H Brittain; MJ Caulfield; GC Chan; T Fowler; A Giess; A Hamblin; S Henderson; TJP Hubbard; R Jackson; LJ Jones; D Kasperaviciute; M Kayikci; A Kousathanas; L Lahnstein; SEA Leigh; IUS Leong; FJ Lopez; F Maleady-Crowe; L Moutsianas; M Mueller; N Murugaesu; AC Need; P O'Donovan; CA Odhams; C Patch; D Perez-Gil; MB Pereira; J Pullinger; T Rahim; A Rendon; T Rogers; K Savage; K Sawant; RH Scott; A Siddiq; A Sieghart; SC Smith; A Sosinsky; A Stuckey; M Tanguy; ERA Thomas; SR Thompson; A Tucci; E Walsh; MJ Welland; E Williams; K Witkowska; SM Wood
المشرفين على المادة: EC 6.1.1.6 (Lysine-tRNA Ligase)
تواريخ الأحداث: Date Created: 20210626 Date Completed: 20211025 Latest Revision: 20230315
رمز التحديث: 20240829
مُعرف محوري في PubMed: PMC8956360
DOI: 10.1038/s41436-021-01239-1
PMID: 34172899
قاعدة البيانات: MEDLINE
الوصف
تدمد:1530-0366
DOI:10.1038/s41436-021-01239-1