c-mpl mutations are the cause of congenital amegakaryocytic thrombocytopenia

Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare disease presen ting with isolated thrombocytopenia in infancy and developing into a pancyt openia in later childhood, Thrombopoietin (TPO) is the main regulator of th rombocytopoiesis and has also been demonstrated to be an important factor i n early hematopoiesis, We analyzed 9 patients with CAMT for defects in TPO production and reactivity, We found high levels of TPO in the sera of all p atients, However, platelets and hematopoietic progenitor cells of patients with CAMT did not show any reactivity to TPO, as measured by testing TPO-sy nergism to adenosine diphosphate in platelet activation or by megakaryocyte colony assays, Plow cytometric analysis revealed absent surface expression of the TPO receptor c-Mpl in 3 of 3 patients. Sequence analysis of the c-m pl gene revealed point mutations in 8 of 8 patients: We found frameshift or nonsense mutations that are predicted to result in a complete loss of c-Mp l function in 5 patients, Heterozygous or homozygous missense mutations pre dicted to lead to amino acid exchanges in the extracellular domain of the r eceptor were found in 3 other patients. The type of mutations correlated wi th the clinical course of the disease. We propose a defective c-Mpl express ion due to c-mpl mutations as the cause for thrombocytopenia and progressio n into pancytopenia seen in patients with CAMT. (C) 2001 by The American So ciety of Hematology.