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A de novo X;8 translocation creates a PTK2-THOC2 gene fusion with THOC2 expression knockdown in a patient with psychomotor retardation and congenital cerebellar hypoplasia
  1. Eleonora Di Gregorio1,2,
  2. Federico T Bianchi3,
  3. Alfonso Schiavi4,5,
  4. Alessandra M A Chiotto3,
  5. Marco Rolando6,
  6. Ludovica Verdun di Cantogno7,
  7. Enrico Grosso2,
  8. Simona Cavalieri2,
  9. Alessandro Calcia1,
  10. Daniela Lacerenza1,
  11. Orsetta Zuffardi8,9,
  12. Saverio Francesco Retta10,
  13. Giovanni Stevanin11,12,
  14. Cecilia Marelli11,12,
  15. Alexandra Durr11,12,
  16. Sylvie Forlani11,
  17. Jamel Chelly13,
  18. Francesca Montarolo14,
  19. Filippo Tempia14,
  20. Hilary E Beggs15,
  21. Robin Reed16,
  22. Stefania Squadrone17,
  23. Maria C Abete17,
  24. Alessandro Brussino1,
  25. Natascia Ventura4,5,
  26. Ferdinando Di Cunto3,
  27. Alfredo Brusco1,2
  1. 1Department of Medical Sciences, University of Torino, Turin, Italy
  2. 2S.C.d.U. Medical Genetics, Città della Salute e della Scienza, Torino, Italy
  3. 3Department of Molecular Biotechnology and Health Sciences, University of Torino, Molecular Biotechnology Centre, Torino, Italy
  4. 4Department of Biomedicine and Prevention, University of Roma ‘Tor Vergata’, Rome, Italy
  5. 5Institute of Clinical Chemistry and Laboratory Medicine of the Heinrich Heine University, and the IUF—Leibniz Research Institute for Environmental Medicine, Duesseldorf, Germany
  6. 6S.C. Neuropsichiatria Infantile, Pinerolo, Italy
  7. 7S.C.d.U. Anatomia Patologica, Città della Salute e della Scienza, Torino, Italy
  8. 8Department of Molecular Medicine, University of Pavia, Pavia, Italy
  9. 9IRCCS ‘National Neurological Institute C. Mondino’ Foundation, Pavia, Italy
  10. 10Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy
  11. 11Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (INSERM/UPMC Univ. Paris 6, UMR_S975; CNRS 7225, EPHE), Pitié-Salpêtrière Hospital, Paris, France
  12. 12APHP, Fédération de génétique, Pitié-Salpêtrière Hospital, Paris, France
  13. 13Université Paris Descartes, Institut Cochin, Hôpital Cochin, Paris, France
  14. 14University of Torino, Neuroscience Institute Cavalieri Ottolenghi (NICO), Torino, Italy
  15. 15Department of Ophthalmology, University of California San Francisco, San Francisco, California, USA
  16. 16Department of Cell Biology, Harvard Medical School, Boston, USA
  17. 17Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle d'Aosta, CReAA- National Reference Centre for Surveillance and Monitoring of Animal Feed, Lab. Contaminanti Ambientali, Torino, Italy
  1. Correspondence to Alfredo Brusco, Department of Medical Sciences, University of Torino, via Santena, 19, Torino 10126, Italy; alfredo.brusco{at}{at}


Background and aim We identified a balanced de novo translocation involving chromosomes Xq25 and 8q24 in an eight year-old girl with a non-progressive form of congenital ataxia, cognitive impairment and cerebellar hypoplasia.

Methods and Results Breakpoint definition showed that the promoter of the Protein Tyrosine Kinase 2 (PTK2, also known as Focal Adhesion Kinase, FAK) gene on chromosome 8q24.3 is translocated 2 kb upstream of the THO complex subunit 2 (THOC2) gene on chromosome Xq25. PTK2 is a well-known non-receptor tyrosine kinase whereas THOC2 encodes a component of the evolutionarily conserved multiprotein THO complex, involved in mRNA export from nucleus. The translocation generated a sterile fusion transcript under the control of the PTK2 promoter, affecting expression of both PTK2 and THOC2 genes. PTK2 is involved in cell adhesion and, in neurons, plays a role in axonal guidance, and neurite growth and attraction. However, PTK2 haploinsufficiency alone is unlikely to be associated with human disease. Therefore, we studied the role of THOC2 in the CNS using three models: 1) THOC2 ortholog knockout in C.elegans which produced functional defects in specific sensory neurons; 2) Thoc2 knockdown in primary rat hippocampal neurons which increased neurite extension; 3) Thoc2 knockdown in neuronal stem cells (LC1) which increased their in vitro growth rate without modifying apoptosis levels.

Conclusion We suggest that THOC2 can play specific roles in neuronal cells and, possibly in combination with PTK2 reduction, may affect normal neural network formation, leading to cognitive impairment and cerebellar congenital hypoplasia.

  • Chromosomal
  • Genetics
  • Molecular genetics
  • Movement disorders (other than Parkinsons)
  • Neurology

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