title: 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.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medical Sciences, University of Torino, Turin, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Di Gregorio
authors.forename: Federico T
authors.initials: FT
authors.lastname: Bianchi
authors.forename: Alfonso
authors.initials: A
authors.lastname: Schiavi
authors.forename: Alessandra M A
authors.initials: AM
authors.lastname: Chiotto
authors.forename: Marco
authors.initials: M
authors.lastname: Rolando
authors.forename: Ludovica
authors.initials: L
authors.lastname: Verdun di Cantogno
authors.forename: Enrico
authors.initials: E
authors.lastname: Grosso
authors.forename: Simona
authors.initials: S
authors.lastname: Cavalieri
authors.forename: Alessandro
authors.initials: A
authors.lastname: Calcia
authors.forename: Daniela
authors.initials: D
authors.lastname: Lacerenza
authors.forename: Orsetta
authors.initials: O
authors.lastname: Zuffardi
authors.forename: Saverio Francesco
authors.initials: SF
authors.lastname: Retta
authors.forename: Giovanni
authors.initials: G
authors.lastname: Stevanin
authors.forename: Cecilia
authors.initials: C
authors.lastname: Marelli
authors.forename: Alexandra
authors.initials: A
authors.lastname: Durr
authors.forename: Sylvie
authors.initials: S
authors.lastname: Forlani
authors.forename: Jamel
authors.initials: J
authors.lastname: Chelly
authors.forename: Francesca
authors.initials: F
authors.lastname: Montarolo
authors.forename: Filippo
authors.initials: F
authors.lastname: Tempia
authors.forename: Hilary E
authors.initials: HE
authors.lastname: Beggs
authors.forename: Robin
authors.initials: R
authors.lastname: Reed
authors.forename: Stefania
authors.initials: S
authors.lastname: Squadrone
authors.forename: Maria C
authors.initials: MC
authors.lastname: Abete
authors.forename: Alessandro
authors.initials: A
authors.lastname: Brussino
authors.forename: Natascia
authors.initials: N
authors.lastname: Ventura
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Di Cunto
authors.forename: Alfredo
authors.initials: A
authors.lastname: Brusco
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics; D002461:Cell Line, Transformed; D002531:Cerebellum / Q000002:abnormalities*; D002648:Child; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D002658:Developmental Disabilities / Q000150:complications / Q000235:genetics; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000235:genetics*; D050939:Gene Fusion; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009421:Nervous System Malformations / Q000150:complications / Q000235:genetics*; D011596:Psychomotor Disorders / Q000150:complications / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics*; D051381:Rats; D014178:Translocation, Genetic
chemical_list: D016601:RNA-Binding Proteins; C579432:Thoc2 protein, human; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human
keywords: Chromosomal; Genetics; Molecular genetics; Movement disorders (other than Parkinsons); Neurology