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t(4;5)(q21;q33) PRKG2/PDGFRB

Written2009-11Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

(Note : for Links provided by Atlas : click)

Identity

ICD-Topo C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS
ICD-Morpho 9966/3 Myeloid and lymphoid neoplasms with PDGFRB rearrangement
ICD-Morpho 9975/3 Chronic myelogenous leukaemia, BCR-ABL1 positive; Myeloproliferative neoplasm, unclassifiable; Myelodysplastic/myeloproliferative neoplasm, unclassifiable
Atlas_Id 1510

Clinics and Pathology

Disease Atypical myeloproliferative disease (a-MPD) and systemic mast cell disease (SMCD)
Epidemiology 3 cases to date, a 45-year-old female patient with a-MPD with basophilia and eosinophilia (Walz et al., 2007), a 61-year-old male patient with systemic mast cell disease (SMCD) and an associated chronic basophilic leukemia (Lahortiga et al., 2008), and a 45-year-old male patient with a SMCD with eosinophilia (Gallagher et al., 2008).
Prognosis This translocation seems to respond well to imatinib therapy: the chromosomal anomaly disappered with imatinib in the first patient; in the second case, the patient remained in clinical and cytogenetic remission 3 years after imatinib was initiated; the third patient was alive and well after about 4 years of therapy with imatinib.

Genes involved and Proteins

Note The patient with SMCD and an associated chronic basophilic leukemia was negative for KIT mutations (Lahortiga et al., 2008).
Gene Name PRKG2
Location 4q21
Protein 762 amino acids; comprises a coiled-coil domain (leucine zipper, amino acids 23-85), cGMP binding sites (168-285 and 286-417) and a serine-threonine kinase domain (453-711); involved in signaling pathway. Belongs to the family of cyclic GMP-dependent protein kinase. PRKG2 phosphorylates CFTR. PRKG2 is an ion transport regulator (Vaandrager et al., 2005). PRKG2 regulates SOX9-mediated transcription of collagen 2 through phosphorylation (Chikuda et al., 2004). It was found that PRKG2 has an anti-proliferative effect via suppression of SOX9 expression, inhibition of Akt phosphorylation, and G1 arrest in glioma cell lines (Swartling et al., 2009).
Gene Name PDGFRB
Location 5q33
Protein Comprises an extracellular part with 5 Ig-like C2 type domains, a transmembrane domain, and an intracellular part with a tyrosine kinase domain (made of two tyrosine kinase subdomains) for transduction of the signal. Receptor tyrosine kinase; receptor for PDGFB and PDGFD (Bergsten et al., 2001); forms homodimers, or heterodimer with PDGFRA; upon dimerization, subsequent activation by autophosphorylation of the tyrosine kinase intracellular domains occurs.

Result of the chromosomal anomaly

Hybrid gene
Description 5' PRKG2 - 3' PDGFRB. In-frame fusion between exon 2 of PRKG2, a 5 bp insert derived from intron 2 of PRKG2, and a truncated version (last 33 bp) of exon 12 of PDGFRB in one case (Lahortiga et al., 2008), and In-frame fusion between exon 5 of PRKG2, a 17 bp insert derived from PRKG2 intron 5, and a 41 bp truncated version exon 12 of PDGFRB in another case (Walz et al., 2007).
  
Fusion Protein
Oncogenesis The coiled-coil domain from PRKG2 would favour dimerization, with subsequent constitutive activation of the PDGFRB tyrosine kinase domain.
  

To be noted

Additional cases are needed to delineate the epidemiology of this rare entity:
you are welcome to submit a paper to our new Case Report section.

Bibliography

PDGF-D is a specific, protease-activated ligand for the PDGF beta-receptor.
Bergsten E, Uutela M, Li X, Pietras K, Ostman A, Heldin CH, Alitalo K, Eriksson U.
Nat Cell Biol. 2001 May;3(5):512-6.
PMID 11331881
 
Cyclic GMP-dependent protein kinase II is a molecular switch from proliferation to hypertrophic differentiation of chondrocytes.
Chikuda H, Kugimiya F, Hoshi K, Ikeda T, Ogasawara T, Shimoaka T, Kawano H, Kamekura S, Tsuchida A, Yokoi N, Nakamura K, Komeda K, Chung UI, Kawaguchi H.
Genes Dev. 2004 Oct 1;18(19):2418-29.
PMID 15466490
 
Fusion of PRKG2 and SPTBN1 to the platelet-derived growth factor receptor beta gene (PDGFRB) in imatinib-responsive atypical myeloproliferative disorders.
Gallagher G, Horsman DE, Tsang P, Forrest DL.
Cancer Genet Cytogenet. 2008 Feb;181(1):46-51.
PMID 18262053
 
Activity of imatinib in systemic mastocytosis with chronic basophilic leukemia and a PRKG2-PDGFRB fusion.
Lahortiga I, Akin C, Cools J, Wilson TM, Mentens N, Arthur DC, Maric I, Noel P, Kocabas C, Marynen P, Lessin LS, Wlodarska I, Robyn J, Metcalfe DD.
Haematologica. 2008 Jan;93(1):49-56.
PMID 18166785
 
Cyclic GMP-dependent protein kinase II inhibits cell proliferation, Sox9 expression and Akt phosphorylation in human glioma cell lines.
Swartling FJ, Ferletta M, Kastemar M, Weiss WA, Westermark B.
Oncogene. 2009 Sep 3;28(35):3121-31. Epub 2009 Jun 22.
PMID 19543319
 
Molecular properties and biological functions of cGMP-dependent protein kinase II.
Vaandrager AB, Hogema BM, de Jonge HR.
Front Biosci. 2005 Sep 1;10:2150-64.
PMID 15970484
 
Characterization of three new imatinib-responsive fusion genes in chronic myeloproliferative disorders generated by disruption of the platelet-derived growth factor receptor beta gene.
Walz C, Metzgeroth G, Haferlach C, Schmitt-Graeff A, Fabarius A, Hagen V, Prümmer O, Rauh S, Hehlmann R, Hochhaus A, Cross NC, Reiter A.
Haematologica. 2007 Feb;92(2):163-9.
PMID 17296564
 

Citation

This paper should be referenced as such :
Huret, JL
t(4;5)(q21;q33)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(9):889-890.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Anomalies/t0405q21q33ID1510.html


Translocations implicated (Data extracted from papers in the Atlas)

 t(4;5)(q21;q33) PRKG2/PDGFRB

External links

PRKG2 (4q21.21) PDGFRB (5q32)

PRKG2 (4q21.21) PDGFRB (5q32)

PRKG2 (4q21.21) PDGFRB (5q32)

Mitelman databaset(4;5)(q21;q33) [Case List]    t(4;5)(q21;q33) [Association List] Mitelman database (CGAP - NCBI)
arrayMapTopo ( C42) Morph ( 9966/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMapTopo ( C42) Morph ( 9975/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
 
Mitelman databasePRKG2/PDGFRB [MCList]  PRKG2 (4q21.21) PDGFRB (5q32)
Mitelman databasePRKG2/PDGFRB [MCList]  PRKG2 (4q21.21) PDGFRB (5q32)
TICdbPRKG2/PDGFRB  PRKG2 (4q21.21) PDGFRB (5q32)
 
Disease databaset(4;5)(q21;q33) PRKG2/PDGFRB
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
All articlesautomatic search in PubMed


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