Decreased platelet expression of myosin regulatory light chain polypeptide (MYL9) and other genes with platelet dysfunction and CBFA2/RUNX1 mutation: insights from platelet expression profiling.

Abstract

We have reported on a patient with thrombocytopenia, impaired platelet aggregation, secretion, phosphorylation of pleckstrin and myosin light chain (MLC), and GPIIb-IIIa activation, associated with a heterozygous mutation in transcription factor CBFA2 (core binding factor A2, RUNX1 or AML1). To obtain insights into the abnormal platelet mechanisms and CBFA2-regulated genes, we performed platelet expression profiling in four control subjects and the patient using the Affymetrix U133 GeneChips. In the patient, 298 probe sets were significantly downregulated at least 2-fold. MLC regulatory polypeptide (MYL9 gene) was decreased approximately 77-fold; this is an important finding because agonist-stimulated MLC phosphorylation is decreased in patient platelets. Genes downregulated > or = 5-fold include those involving calcium binding proteins (CABP5), ion transport (sodium/potassium/Ca exchanger, SLC24A3), cytoskeletal/microtubule proteins (erythrocyte membrane protein band 4.1-like 3, EPB41L3; tropomyosin 1, TPM1; tubulin, alpha 1, TUBA1), signaling proteins (RAB GTPase activating protein 1-like, RABGAP1L; beta3-endonexin, ITGB3 BP) and chemokines (platelet factor 4 variant 1, PF4V1; chemokine CXCL5, CXCL5). These and other downregulated genes are relevant to the patient's platelet defects in function and production. These studies provide the first proof of concept that platelet expression profiling can be applied to obtain insights into the molecular basis of inherited platelet defects.

• Authors: L Sun, J R Gorospe, E P Hoffman, A K Rao
• Journal: Journal of thrombosis and haemostasis : JTH (J Thromb Haemost) Vol. 5 Issue 1 Pg. 146-54 (Jan 2007) ISSN: 1538-7933 [Print] England
• PMID: 17059412 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Validation Study)

Chemical References

• Core Binding Factor Alpha 2 Subunit
• Myosin Light Chains
• RNA, Messenger
• RUNX1 protein, human

Topics

• Adult
• Blood Platelets (metabolism)
• Cluster Analysis
• Core Binding Factor Alpha 2 Subunit (genetics)
• Down-Regulation
• Gene Expression Profiling
• Humans
• Immunoblotting
• Male
• Mutation
• Myosin Light Chains (metabolism)
• Oligonucleotide Array Sequence Analysis
• Platelet Activation
• RNA, Messenger (metabolism)
• Reproducibility of Results
• Reverse Transcriptase Polymerase Chain Reaction
• Thrombocytopenia (genetics, metabolism, physiopathology)