한빛사논문
Yu-Ri Lee1,20, Kamal Khan2,3,4,5,20, Kim Armfield-Uhas6,20, Sujata Srikanth7,20, Nicola A. Thompson8, Mercedes Pardo9, Lu Yu9, Joy W. Norris7, Yunhui Peng10, Karen W. Gripp11, Kirk A. Aleck12, Chumei Li13, Ed Spence14, Tae-Ik Choi1, Soo Jeong Kwon15, Hee-Moon Park15, Daseuli Yu16, Won Do Heo16, Marie R. Mooney2,3, Shahid M. Baig4, Ingrid M. Wentzensen17, Aida Telegrafi17, Kirsty McWalter17, Trevor Moreland7, Chelsea Roadhouse13, Keri Ramsey18, Michael J. Lyons7, Cindy Skinner7, Emil Alexov10, Nicholas Katsanis2,3,19, Roger E. Stevenson7, Jyoti S. Choudhary9, David J. Adams8, Cheol-Hee Kim 1,21,*, Erica E. Davis2,3,19,21,* & Charles E. Schwartz7,21,*
1Department of Biology, Chungnam National University, Daejeon, Korea.
2Center for Human Disease Modeling, Duke University Medical Center, Durham, NC, USA.
3Advanced Center for Translational and Genetic Medicine (ACT-GeM), Stanley Manne Children’s Research Institute, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA.
4Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan.
5Pakistan Institute of Engineering and Applied Sciences (PIEAS), Islamabad, Pakistan.
6Children’s Healthcare of Atlanta, Atlanta, GA, USA.
7Greenwood Genetic Center, Greenwood, SC, USA.
8Wellcome Sanger Institute, Hinxton, Cambridge, UK.
9Chester Beatty Laboratories, Institute of Cancer Research, London, UK.
10Department of Physics, Clemson University, Clemson, SC, USA.
11Division of Medical Genetics, A. I. duPont Hospital for Children, Wilmington, DE, USA.
12Genetics and Metabolism, Phoenix Children’s Medical Group, Phoenix, AZ, USA.
13Clinical Genetics Program, McMaster University Medical Center, Hamilton, ON, Canada.
14Division of Pediatric Genetics and Metabolism, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
15Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon, Korea.
16Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
17GeneDx Inc, Gaithersburg, MD, USA.
18Center for Rare Childhood Disorders, TGen, Phoenix, AZ, USA.
19Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
20These authors contributed equally: Yu-Ri Lee, Kamal Khan, Kim Armfield-Uhas, Sujata Srikanth.
21These authors jointly supervised: Cheol-Hee Kim, Erica E. Davis, Charles E. Schwartz
*Corresponding author
Abstract
Intellectual disability (ID) is a heterogeneous clinical entity and includes an excess of males who harbor variants on the X-chromosome (XLID). We report rare FAM50A missense variants in the original Armfield XLID syndrome family localized in Xq28 and four additional unrelated males with overlapping features. Our fam50a knockout (KO) zebrafish model exhibits abnormal neurogenesis and craniofacial patterning, and in vivo complementation assays indicate that the patient-derived variants are hypomorphic. RNA sequencing analysis from fam50a KO zebrafish show dysregulation of the transcriptome, with augmented spliceosome mRNAs and depletion of transcripts involved in neurodevelopment. Zebrafish RNA-seq datasets show a preponderance of 3′ alternative splicing events in fam50a KO, suggesting a role in the spliceosome C complex. These data are supported with transcriptomic signatures from cell lines derived from affected individuals and FAM50A protein-protein interaction data. In sum, Armfield XLID syndrome is a spliceosomopathy associated with aberrant mRNA processing during development.
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TOP52020년 후보
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