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.
J Med Genet. 2013-06-07; 50(8): 543-551
DOI: 10.1136/jmedgenet-2013-101542
Read on PubMed
1. J Med Genet. 2013 Aug;50(8):543-51. doi: 10.1136/jmedgenet-2013-101542. Epub 2013
Jun 7.
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.
Di Gregorio E(1), Bianchi FT, Schiavi A, Chiotto AM, Rolando M, Verdun di
Cantogno L, Grosso E, Cavalieri S, Calcia A, Lacerenza D, Zuffardi O, Retta SF,
Stevanin G, Marelli C, Durr A, Forlani S, Chelly J, Montarolo F, Tempia F, Beggs
HE, Reed R, Squadrone S, Abete MC, Brussino A, Ventura N, Di Cunto F, Brusco A.
Author information:
(1)Department of Medical Sciences, University of Torino, Turin, Italy.
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.
DOI: 10.1136/jmedgenet-2013-101542
PMCID: PMC4133931
PMID: 23749989 [Indexed for MEDLINE]