Ade novoX;8 translocation creates aPTK2-THOC2gene fusion withTHOC2expression 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.

THOC2 Mutations Implicate mRNA-Export Pathway in X-Linked Intellectual Disability

“…THOC2 is in high abundance in the developing and mature human [10][11][12] and adult mouse brains. 6 We observed THOC2 in primary mouse hippocampal and cortical neurons and human cerebral cortex and hippocampus ( Figure S3). THOC2 function is critical for many living organisms as indicated by studies in yeast, roundworms, fruit flies, and vertebrates.…”

“…6,13-17 THOC2 depletion has been shown to (1) interfere with mRNA export, chromosome alignment, mitotic progression, and genomic stability in humans 13,15 and (2) stimulate neurite outgrowth in primary rat hippocampal neurons. 6 Depletion of other TREX subunits also interferes with mRNA export, resulting in nuclear retention of mRNAs. 15,16,18 Mouse Thoc2, along with Thoc5, is required for epithelial stem cell self-renewal and differentiation.…”

“…This conclusion is also supported by the recent publication of an individual with cognitive impairment and who carries a de novo chromosome translocation that includes PTK2-THOC2 fusion genes. 6 Human THOC2 encodes a 1,593-aa, 183-kDa nuclear protein with 98% amino acid identity to mouse THOC2. THOC2 forms part of the THO sub-complex (THOC1-3 and THOC5-7), which is an essential component of the large TREX complex (THO, UAP56, Aly, CIP29, PDIP3, ZC11A, and Chtop).…”

Mechanisms of Origin, Phenotypic Effects and Diagnostic Implications of Complex Chromosome Rearrangements

“…In a patient with schizophrenia, the CCR apparently activated an alternative transcription mode, since the authors found 3 fusion transcripts [Eykelenboom et al, 2012]. While in 8 cases a fusion transcript was successfully demonstrated, other causes of the patient's phenotypes, such as haploinsufficiency of truncated genes, altered expression of unrelated genes, or additional CNVs, still have to be considered [Nothwang et al, 2001;Yue et al, 2005;Mansouri et al, 2006;Borsani et al, 2008;Backx et al, 2011;Eykelenboom et al, 2012;Kloosterman et al, 2012;Di Gregorio et Malli et al, 2014]. In 2 cases, regions of homology have been identified at the fusion points, such that for the other 8 cases NHEJ seems to be the most likely mechanism of fusion.…”

Gene Fusion due to Chromosome Misconnection May Seriously Affect Your Health

“…Analyzing the data in this resource, Mitelman et al [2007] discovered that genome rearrangements in all forms of cancer had resulted in the formation of 358 gene fusions, which affected 337 genes. In the human germline, gene fusions were also found, albeit as extremely rare events resulting from copy number variations and complex chromosome rearrangements [Nothwang et al 2001;Yue et al, 2005;Mansouri et al, 2006;Borsani et al, 2008;Backx et al, 2011;Eykelenboom et al, 2012;Holt et al, 2012;Di Gregorio et al, 2013;Malli et al, 2014;Rippey et al, 2013;van Heesch et al, 2014;Bertelsen et al, 2015]. Hence, one could argue that gene fusions, resulting from chromosome rearrangements and occurring in both somatic cells and in the germline, would be such a type of abnormal chromosome constitution as hypothesized by Boveri [1914].…”