title: Implications of mutations in hematopoietic growth factor receptor genes in congenital cytopenias.
abstract: Mutations in the genes of hematopoietic growth factor receptors as a cause of congenital cytopenia, such as congenital amegakaryocytic thrombocytopenia (CAMT) or severe congenital neutropenia (CN), are discussed. There are striking differences in the relevance of receptor mutations in these diseases. CAMT is a rare disease characterized by severe hypomegakaryocytic thrombocytopenia during the first years of life that develops into pancytopenia in later childhood. In patients with CAMT, we found inherited mutations in c-mpl, the gene coding for the thrombopoietin receptor, in 8 out of 8 cases. The type of mutation seems to correlate with the clinical course seen in the patients. Functional studies demonstrated defective thrombopoietin (TPO) reactivity in hematopoietic progenitor cells and platelets in CAMT patients. CN is a group of hematopoietic disorders characterized by profound, absolute neutropenia due to a maturation arrest of myeloid progenitor cells. About 10% of all patients develop secondary MDS/leukemia. The malignant progression is associated with acquired nonsense mutations within the G-CSF receptor gene that lead to the truncation of the carboxy-terminal cytoplasmic domain of the receptor protein involved in maturation of myeloid progenitor cells. This seems to be one important step in leukemogenesis in CN patients. CAMT is caused by inherited mutations in c-mpl, the gene for the thrombopoietin receptor, which lead to reduced or absent reactivity to TPO. In contrast, mutations in the G-CSF receptor in CN are acquired and are most probably connected with progression of the neutropenia into MDS/leukemia as a result of a loss of differentiation signaling.
authors.affiliation: Pediatric Hematology and Oncology, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Germeshausen
authors.forename: M
authors.initials: M
authors.lastname: Ballmaier
authors.forename: K
authors.initials: K
authors.lastname: Welte
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D018450:Disease Progression; D016179:Granulocyte Colony-Stimulating Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D006801:Humans; D007951:Leukemia, Myeloid / Q000209:etiology; D008533:Megakaryocytes / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D020125:Mutation, Missense; D009190:Myelodysplastic Syndromes / Q000209:etiology / Q000473:pathology; D009363:Neoplasm Proteins; D009503:Neutropenia / Q000151:congenital / Q000235:genetics*; D010198:Pancytopenia / Q000209:etiology / Q000235:genetics; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics*; D018121:Receptors, Cytokine; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000172:deficiency / Q000235:genetics*; D053628:Receptors, Thrombopoietin; D015398:Signal Transduction / Q000235:genetics; D013577:Syndrome; D013921:Thrombocytopenia / Q000151:congenital / Q000235:genetics* / Q000473:pathology; D013926:Thrombopoietin / Q000502:physiology
chemical_list: D018389:Codon, Nonsense; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D018121:Receptors, Cytokine; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D053628:Receptors, Thrombopoietin; D016179:Granulocyte Colony-Stimulating Factor; C082218:MPL protein, human; D013926:Thrombopoietin