2. Academic Validation
  3. Mutations in FAM50A suggest that Armfield XLID syndrome is a spliceosomopathy

Mutations in FAM50A suggest that Armfield XLID syndrome is a spliceosomopathy

  • Nat Commun. 2020 Jul 23;11(1):3698. doi: 10.1038/s41467-020-17452-6.
Yu-Ri Lee # 1,  Kamal Khan # 2 3 4 5,  Kim Armfield-Uhas # 6,  Sujata Srikanth # 7,  Nicola A Thompson 8,  Mercedes Pardo 9,  Lu Yu 9,  Joy W Norris 7,  Yunhui Peng 10,  Karen W Gripp 11,  Kirk A Aleck 12,  Chumei Li 13,  Ed Spence 14,  Tae-Ik Choi 1,  Soo Jeong Kwon 15,  Hee-Moon Park 15,  Daseuli Yu 16,  Won Do Heo 16,  Marie R Mooney 2 3,  Shahid M Baig 4,  Ingrid M Wentzensen 17,  Aida Telegrafi 17,  Kirsty McWalter 17,  Trevor Moreland 7,  Chelsea Roadhouse 13,  Keri Ramsey 18,  Michael J Lyons 7,  Cindy Skinner 7,  Emil Alexov 10,  Nicholas Katsanis 2 3 19,  Roger E Stevenson 7,  Jyoti S Choudhary 9,  David J Adams 8,  Cheol-Hee Kim 20,  Erica E Davis 21 22 23,  Charles E Schwartz 24
Affiliations

Affiliations

  • 1 Department of Biology, Chungnam National University, Daejeon, Korea.
  • 2 Center for Human Disease Modeling, Duke University Medical Center, Durham, NC, USA.
  • 3 Advanced 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.
  • 4 Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan.
  • 5 Pakistan Institute of Engineering and Applied Sciences (PIEAS), Islamabad, Pakistan.
  • 6 Children's Healthcare of Atlanta, Atlanta, GA, USA.
  • 7 Greenwood Genetic Center, Greenwood, SC, USA.
  • 8 Wellcome Sanger Institute, Hinxton, Cambridge, UK.
  • 9 Chester Beatty Laboratories, Institute of Cancer Research, London, UK.
  • 10 Department of Physics, Clemson University, Clemson, SC, USA.
  • 11 Division of Medical Genetics, A. I. duPont Hospital for Children, Wilmington, DE, USA.
  • 12 Genetics and Metabolism, Phoenix Children's Medical Group, Phoenix, AZ, USA.
  • 13 Clinical Genetics Program, McMaster University Medical Center, Hamilton, ON, Canada.
  • 14 Division of Pediatric Genetics and Metabolism, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
  • 15 Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon, Korea.
  • 16 Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
  • 17 GeneDx Inc, Gaithersburg, MD, USA.
  • 18 Center for Rare Childhood Disorders, TGen, Phoenix, AZ, USA.
  • 19 Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  • 20 Department of Biology, Chungnam National University, Daejeon, Korea. zebrakim@cnu.ac.kr.
  • 21 Center for Human Disease Modeling, Duke University Medical Center, Durham, NC, USA. eridavis@luriechildrens.org.
  • 22 Advanced 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. eridavis@luriechildrens.org.
  • 23 Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. eridavis@luriechildrens.org.
  • 24 Greenwood Genetic Center, Greenwood, SC, USA. ceschwartz@ggc.org.
  • # Contributed equally.
PMID: 32703943 DOI: 10.1038/s41467-020-17452-6
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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