Mutations in the erythropoietin receptor gene, EPOR, have been found in some families with primary familial and congenital polycythemia (PFCP). Most of these mutations result in truncation of the polypeptide and loss of part of the cy-toplasmic negative regulatory domain, although missense mutations in the same region have also been reported. The finding of EPOR mutations in some cases of PFCP stimulated
Fig. 9.8 Possible defects in signal transduction in MPD
Progenitor cells from patients are hypersensitive to a number of cytokines (A and B), such as EPO, which act through specific receptor molecules (C and D). There may be a defect in a common receptor component (E), a common signaling intermediate (F) or a common effector molecule (G) such as a transcription factor. Reproduced from Hinshelwood etal. (1997) with permission from Elsevier Science.
an intensive search for acquired mutations of the EPOR gene in PV. However, no acquired mutations in the EPOR gene were identified in patients with PV or other MPDs. Interestingly, not all families with PFCP have EPOR mutations, suggesting the existence of other target genes, in which mutations can give rise to polycythemia. An autosomal recessive inherited polycythemia endemic in the Russian region of Chuvashia results from mutation of the VHL gene (von Hippel-Lindau) on chromosome 3p25. The normal role of the VHL protein is to degrade HIF-1a (hypoxia inducible factor 1 a subunit) by ubiquitination. The decreased association of VHL with HIF-1a in Chuvash polycythemia leads to an increased level of HIF-1a, the upregulation of downstream target genes, including EPO, and increased erythropoiesis.
Rare examples of familial thrombocythemia exist. In a number of such families, a mutation in the 5' UTR of the TPO (thrombopoietin) gene has been detected. The consequence of this mutation is to increase the expression level of TPO, leading to increased megakaryopoiesis. Other families show no linkage to either the TPO or the C-MPL (TPO receptor) locus, implying the existence of other genetic loci which contribute to familial thrombocythemia. No acquired mutations in the TPO gene have been found in patients with acquired ET. In addition, no acquired mutations in the C-MPL gene have been detected in ET or PV.
Despite the lack of C-MPL mutations in MPD, there is some evidence that C-MPL is defective in a proportion of MPD patients. Platelets derived from some PV patients show reduced
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