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

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Biallelic variants in KARS1 are associated with neurodevelopmental disorders and hearing loss recapitulated by the knockout zebrafish
Genetics in Medicine ( IF 8.8 ) Pub Date : 2021-06-25 , DOI: 10.1038/s41436-021-01239-1
Sheng-Jia Lin ₁ , Barbara Vona _{2,

3} , Patricia G Barbalho ₁ , Rauan Kaiyrzhanov ₄ , Reza Maroofian ₄ , Cassidy Petree ₁ , Mariasavina Severino ₅ , Valentina Stanley ₆ , Pratishtha Varshney ₁ , Paulina Bahena ₃ , Fatema Alzahrani ₇ , Amal Alhashem ₈ , Alistair T Pagnamenta ₉ , Gudrun Aubertin ₁₀ , Juvianee I Estrada-Veras _{11,

12,

13} , Héctor Adrián Díaz Hernández ₁₄ , Neda Mazaheri _{15,

16} , Andrea Oza ₁₇ , Jenny Thies ₁₈ , Deborah L Renaud ₁₉ , Sanmati Dugad ₂₀ , Jennifer McEvoy ₆ , Tipu Sultan ₂₁ , Lynn S Pais ₂₂ , Brahim Tabarki ₈ , Daniel Villalobos-Ramirez ₂₃ , Aboulfazl Rad ₂ , , Hamid Galehdari ₁₄ , Farah Ashrafzadeh ₂₄ , Afsaneh Sahebzamani ₂₅ , Kolsoum Saeidi ₂₆ , Erin Torti ₂₇ , Houda Z Elloumi ₂₇ , Sara Mora ₂₇ , Timothy B Palculict ₂₇ , Hui Yang ₂₇ , Jonathan D Wren ₁ , Ben Fowler ₂₈ , Manali Joshi ₂₀ , Martine Behra ₂₉ , Shawn M Burgess ₃₀ , Swapan K Nath ₃₁ , Michael G Hanna ₄ , Margaret Kenna ₁₇ , J Lawrence Merritt ₃₂ , Henry Houlden ₄ , Ehsan Ghayoor Karimiani _{33,

34} , Maha S Zaki ₃₅ , Thomas Haaf ₃ , Fowzan S Alkuraya _{7,

8} , Joseph G Gleeson ₆ , Gaurav K Varshney ₁

Affiliation

Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
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.
Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London, London, UK.
Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
Department of Neurosciences, Rady Children's Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA.
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
NIHR Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
Division of Medical Genetics, Department of Pathology and Lab Medicine, Island Health, Victoria General Hospital, Victoria, BC, Canada.
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.
Department of Gastrointestinal Endoscopy, National Institute of Medical Sciences and Nutrition Salvador Zubirán, Mexico City, Mexico.
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.
Otolaryngology and Communication Enhancement, Boston Children's Hospital, and Dept. of Otolaryngology, Harvard medical School, Boston, USA.
Department of Biochemical Genetics, Seattle Children's Hospital, Seattle, WA, USA.
Departments of Neurology and Pediatrics, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.
Bioinformatics Centre, S. P. Pune University, Pune, India.
Department of Pediatric Neurology, Children's Hospital and Institute of Child Health, Lahore, Pakistan.
Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
Department of Bioinformatics, Biocenter, University of Würzburg, Würzburg, Germany.
Department of Pediatric Diseases, Mashhad University of Medical Sciences, Mashhad, Iran.
Pediatric and Genetic Counselling Center, Kerman Welfare Organization, Kerman, Iran.
Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.
GeneDx, 207 Perry Parkway Gaithersburg, Gaithersburg, MD, USA.
Imaging core facility, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
Department of Neurobiology, University of Puerto Rico, San Juan, PR, USA.
Translational & Functional Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA.
Arthritis & Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
Department of Pediatrics, Biochemical Genetics, University of Washington, Seattle, WA, USA.
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.
Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.

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.

中文翻译：

KARS1 中的双等位基因变异与敲除斑马鱼重现的神经发育障碍和听力损失有关

目的

Lysyl-tRNA 合成酶 1 (KARS1) 的致病变异越来越多地被认为是早发性复杂神经表型的原因。为了推进 KARS1 相关疾病的及时诊断，我们试图描绘其表型并生成疾病模型以了解其体内功能。

方法

通过国际合作，我们从 16 个不相关的家族中鉴定出 22 名受影响的个体，他们在 KARS1 变异中携带双等位基因可能致病或致病。测序方法的范围从疾病特异性面板到基因组测序。我们在斑马鱼中生成了功能缺失等位基因。

结果

我们在KARS1中发现了 10 个新的和 4 个已知的双等位基因错义变异，这些变异具有中度至重度的发育迟缓、进行性神经和神经感觉异常以及可变的白质受累。我们描述了新的 KARS1 相关体征，例如自闭症、多动行为、脑桥发育不全和小脑萎缩，其中普遍存在蚓部受累。kars1的缺失导致 p53 的上调、组织特异性细胞凋亡和神经发育相关基因的下调，重现患者的关键组织特异性疾病表型。p53 的抑制挽救了kars1 ^−/−敲除的几个缺陷。