| First Author | Chan ER | Year | 2009 |
| Journal | Exp Hematol | Volume | 37 |
| Issue | 2 | Pages | 276-84 |
| PubMed ID | 19059699 | Mgi Jnum | J:146577 |
| Mgi Id | MGI:3837927 | Doi | 10.1016/j.exphem.2008.10.005 |
| Citation | Chan ER, et al. (2009) An ENU-induced recessive mutation in Mpl leads to thrombocytopenia with overdominance. Exp Hematol 37(2):276-84 |
| abstractText | OBJECTIVE: The aim of this study was to identify and characterize the causative mutation in the thrombocytopenic mouse strain HLB219 that was generated at the Jackson Laboratory as part of a large-scale N-ethyl-N-nitrosourea mutagenesis screen. MATERIALS AND METHODS: The HLB219 mutation was identified by interval mapping of F2 mice generated from intercross breeding of HLB219 to both BALB/cByJ (BALB) and 129/SvImJ (129/Sv). Mpl was identified as a candidate gene and sequenced. The mutation was characterized in vivo in mouse hematopoietic stem/progenitor cell assays and in cell culture by expression in Ba/F3 cells. RESULTS: A novel mutation in the thrombopoietin (TPO) receptor Mpl in HLB219 mice caused a Cys-->Arg substitution at codon 40 in the extracellular region of the receptor. Mice homozygous for the Mpl(hlb219) mutation had an 80% decrease in the number of platelets in comparison to the wild-type C57BL/6J strain, low numbers of bone marrow megakaryocytes, high TPO levels, and decreased competitive repopulating ability, consistent with a loss-of-function mutation in the receptor. Mice heterozygous for Mpl(hlb219) however, showed an overdominance effect with a significant increase in platelet number. Functional analysis in vitro demonstrated that Ba/F3 cells expressing the mutant MPL(hlb219) protein failed to activate extracellular signal-regulated kinase and signal transducers and activators of transcription 5, but proliferated in the absence of TPO and required constitutive phosphorylation of RAC-alpha serine/threonine protein kinase (AKT) for cytokine-independent growth. CONCLUSION: Thrombocytopenia in HLB219 mice is caused by a recessive mutation in Mpl that abrogates mitogen-activated protein kinase-extracellular signal regulated kinase and janus kinase-signal transducers and activators of transcription signaling. |
