NB4S, a Member of the TBC1 Domain Family of Genes, is Truncated as a Result of a Constitutional t(1;10)(p22;q21) Chromosome Translocation in a Patient with Stage 4S Neuroblastoma

Abstract

Molecular cloning of the breakpoints of a t(1;10)(p22q21) constitutional translocation breakpoint in a patient with stage 4S neuroblastoma has identified two genes which are fused in-frame to generate a novel gene. The 1p22 gene, which we have called NB4S , encodes a 7.5 kb transcript with an 810 amino acid open reading frame and is expressed in a wide variety of tissues. NB4S has >88% homology with the mouse EVI -5 gene within the coding region and shows strong homology over a 200 amino acid region with TBC1 box motif genes involved in cell growth and differentiation. The C-teminal end of the protein contains a number of coiled coil domains, indicating a possible protein-protein binding function. The chromosome 10 breakpoint interrupts a novel transcript (TRNG10) which could only be detected in tumor cells. This transcript has no exon/intron structure or significant open reading frame, suggesting that it is a structural RNA which is transcribed but not translated. The chromosome rearrangement creates a fusion gene product which combines the TBC1 motif of NB4S with a polyadenylation signal from TRNG10 , potentially generating a truncated protein with oncogenic properties.

WAVE3, an actin-polymerization gene, is truncated and inactivated as a result of a constitutional t(1;13)(q21;q12) chromosome translocation in a patient with ganglioneuroblastoma

“…Interestingly, the three tumors which showed absence of WAVE3 expression were also derived from low grade tumors. It is unlikely that the rearrangement generates a chimeric gene, as shown in another Nb patient described by Roberts et al (1998b), since no gene could be found on chromosome 1. Consequently, the translocation appears to be an inactivating event.…”

“…Since only 1 -2% of the genome codes for genes it is unlikely that this is a random event that involves a coding region by chance. In fact, all of the constitutional chromosome translocation breakpoints we have described to date (Mitchell and Cowell, 1989;Roberts et al, 1998b) as well as tumor-specific translocations (Still and Cowell, 1998;Chernova et al, 1998Chernova et al, , 2001, have involved breakpoints within the coding regions of genes, often on both sides of the breakpoints. From the molecular evidence it seems likely that WAVE3 is inactivated as a result of this translocation but, since it is not normally expressed in hematopoietic cells, we cannot verify this using the only tissue we have available from patient DG, which is a lymphoblastoid cell line.…”

A transcription map of the minimally deleted region from 13q14 in B-cell chronic lymphocytic leukemia as defined by large scale sequencing of the 650 kb critical region

“…Individual BACs were purchased from Research Genetics and tested against the original primers for authenticity. BAC DNA was prepared for restriction enzyme analysis and end-sequencing, as described by Roberts et al (1998) and end-sequencing was achieved directly from the linearized BAC using T7 and SP6 vector primers.…”

The EVI5 TBC domain provides the GTPase-activating protein motif for RAB11

“…There are, however, over 50 human proteins with predicted TBC domains, and over 70 human Rab proteins, of which only two TBC domain-containing proteins have so far been shown to demonstrably have Rab/GAP activity. The human EVI5 protein, which was identified at the breakpoint in a constitutional chromosome translocation in a patient with stage 4S neuroblastoma (Roberts et al, 1998), contains a TBC domain near its N terminus. EVI5 has been identified in the centrosome in interphase cells (Faitar et al, 2005) and in the midbody during the terminal stages of cytokinesis.…”