A Mild PUM1 Mutation Is Associated with Adult-Onset Ataxia, whereas Haploinsufficiency Causes Developmental Delay and Seizures

  • Cell. 2018 Feb 22;172(5):924-936.e11. doi: 10.1016/j.cell.2018.02.006.
Vincenzo A Gennarino  1 ,  Elizabeth E Palmer  2 ,  Laura M McDonell  3 ,  Li Wang  4 ,  Carolyn J Adamski  5 ,  Amanda Koire  6 ,  Lauren See  7 ,  Chun-An Chen  4 ,  Christian P Schaaf  4 ,  Jill A Rosenfeld  7 ,  Jessica A Panzer  8 ,  Ute Moog  9 ,  Shuang Hao  10 ,  Ann Bye  11 ,  Edwin P Kirk  12 ,  Pawel Stankiewicz  13 ,  Amy M Breman  13 ,  Arran McBride  3 ,  Tejaswi Kandula  11 ,  Holly A Dubbs  14 ,  Rebecca Macintosh  15 ,  Michael Cardamone  11 ,  Ying Zhu  16 ,  Kevin Ying  17 ,  Kerith-Rae Dias  17 ,  Megan T Cho  18 ,  Lindsay B Henderson  18 ,  Berivan Baskin  18 ,  Paula Morris  17 ,  Jiang Tao  19 ,  Mark J Cowley  19 ,  Marcel E Dinger  19 ,  Tony Roscioli  20 ,  Oana Caluseriu  21 ,  Oksana Suchowersky  22 ,  Rani K Sachdev  11 ,  Olivier Lichtarge  7 ,  Jianrong Tang  10 ,  Kym M Boycott  3 ,  J Lloyd Holder Jr  10 ,  Huda Y Zoghbi  23
Affiliations
  • 1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA. Electronic address: [email protected].
  • 2. Sydney Children's Hospital, Randwick, NSW 2031, Australia; School of Women's and Children's Health, UNSW Medicine, The University of New South Wales, NSW 2031, Australia; Genetics of Learning Disability Service, Waratah, NSW 2298, Australia.
  • 3. Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
  • 4. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA.
  • 5. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA.
  • 6. Program in Quantitative and Computational Biosciences, Baylor College of Medicine, Houston, TX 77030, USA.
  • 7. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 8. Department of Pediatrics, Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 9. Institute of Human Genetics, Heidelberg University, Im Neuenheimer Feld 440, 69120 Heidelberg, Germany.
  • 10. Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 11. Sydney Children's Hospital, Randwick, NSW 2031, Australia; School of Women's and Children's Health, UNSW Medicine, The University of New South Wales, NSW 2031, Australia.
  • 12. Sydney Children's Hospital, Randwick, NSW 2031, Australia; School of Women's and Children's Health, UNSW Medicine, The University of New South Wales, NSW 2031, Australia; Genetics Laboratory, NSW Health Pathology East Randwick, Sydney, NSW, Australia.
  • 13. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics Laboratories, Baylor College of Medicine, Houston, TX 77030, USA.
  • 14. Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 15. Sydney Children's Hospital, Randwick, NSW 2031, Australia.
  • 16. Genetics Laboratory, NSW Health Pathology East Randwick, Sydney, NSW, Australia.
  • 17. Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia.
  • 18. GeneDx, 207 Perry Pkwy Gaithersburg, MD 20877, USA.
  • 19. Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; St. Vincent's Clinical School, University of New South Wales, Sydney, NSW 2010, Australia.
  • 20. Sydney Children's Hospital, Randwick, NSW 2031, Australia; Genetics Laboratory, NSW Health Pathology East Randwick, Sydney, NSW, Australia; Neuroscience Research Australia and Prince of Wales Clinical School, University of New South Wales, Randwick, NSW 2031, Australia.
  • 21. Department of Medical Genetics, University of Alberta, AB T6G 2H7, Canada.
  • 22. Department of Medical Genetics, University of Alberta, AB T6G 2H7, Canada; Departments of Medicine (Neurology) and Pediatrics, University of Alberta, AB, Canada.
  • 23. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: [email protected].
PMID: 29474920 DOI: 10.1016/j.cell.2018.02.006
Abstract

Certain mutations can cause proteins to accumulate in neurons, leading to neurodegeneration. We recently showed, however, that upregulation of a wild-type protein, Ataxin1, caused by haploinsufficiency of its repressor, the RNA-binding protein Pumilio1 (PUM1), also causes neurodegeneration in mice. We therefore searched for human patients with PUM1 mutations. We identified eleven individuals with either PUM1 deletions or de novo missense variants who suffer a developmental syndrome (Pumilio1-associated developmental disability, ataxia, and seizure; PADDAS). We also identified a milder missense mutation in a family with adult-onset ataxia with incomplete penetrance (Pumilio1-related cerebellar ataxia, PRCA). Studies in patient-derived cells revealed that the missense mutations reduced PUM1 protein levels by ∼25% in the adult-onset cases and by ∼50% in the infantile-onset cases; levels of known PUM1 targets increased accordingly. Changes in protein levels thus track with phenotypic severity, and identifying posttranscriptional modulators of protein expression should identify new candidate disease genes.

Keywords
Ataxin-1; PADDAS; PRCA; Pumilio1; RNA-binding proteins; ataxia; chromosome 1p35.2; copy number variants; developmental delay; intellectual disability; seizures.