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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.

ABSTRACT: 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.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.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.

SUBMITTER: Di Gregorio E

PROVIDER: S-EPMC4133931 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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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.

Di Gregorio Eleonora E Bianchi Federico T FT Bianchi Federico T FT Schiavi Alfonso A Chiotto Alessandra M A AM Rolando Marco M Verdun di Cantogno Ludovica L Grosso Enrico E Cavalieri Simona S Calcia Alessandro A Lacerenza Daniela D Zuffardi Orsetta O Retta Saverio Francesco SF Stevanin Giovanni G Marelli Cecilia C Durr Alexandra A Forlani Sylvie S Chelly Jamel J Montarolo Francesca F Tempia Filippo F Beggs Hilary E HE Reed Robin R Squadrone Stefania S Abete Maria C MC Brussino Alessandro A Ventura Natascia N Di Cunto Ferdinando F Brusco Alfredo A

Journal of medical genetics 20130607 8

<h4>Background and aim</h4>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.<h4>Methods and results</h4>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 chromosom ...[more]

PMID: 23749989

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Project description:BACKGROUND:Balanced reciprocal chromosomal translocations (RCTs) are the ones of the most common structural aberrations in the population, with an incidence of 1:625. RCT carriers usually do not demonstrate changes in phenotype, except when the translocation results in gene interruption. However, these people are at risk of production of unbalanced gametes during meiosis, as a result of various forms of chromosome segregation. This may cause infertility, non-implantation of the embryo, shorter embryo or foetus survival, as well as congenital defects and developmental disorders in children after birth. The increasing popularity of cytogenetic molecular techniques, such as microarray-based CGH (aCGH), contributed to the improved detection of chromosomal abnormalities in patients with intellectual disability, however, these modern techniques do not allow the identification of the balanced in potential carriers. Therefore, classical chromosome analysis with GTG technique still plays an important role in the identification of balanced rearrangements in every case of procreation failure. CASE PRESENTATION:In this article, a family with multiple occurrences of 17p13.3 duplication syndrome in the offspring and multiple miscarriages resulting from carrying of the balanced reciprocal translocation t(7;17)(p22;p13.2) by proband father is presented. The aCGH diagnostics allowed the identification of an unbalanced fragment responsible for the occurrence of clinical signs in the female patient, while karyotyping and FISH using specific probes allowed the localization of the additional material in the patient chromosomes, and identified the type of this translocation in the carriers. CONCLUSIONS:Identification of a balanced structural aberration in one of the partners allows direct diagnostics for the exclusion or confirmation of genetic imbalance in the foetus via traditional invasive prenatal diagnostics. It is also possible to use an alternative method, Preimplantation Genetic Diagnosis (PGD) after in vitro fertilization, which prevents initiating pregnancy if genetic imbalance is detected in the embryo.

Dataset Information

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.

Publications

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.

Similar Datasets

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