Abstract 837

The TAR syndrome is a rare, autosomal recessive disorder associated with thrombocytopenia and skeletal defects, most often bilateral absent radii. The genetic lesion(s) responsible for the syndrome is unknown. In addition to low blood platelet counts, TAR patients have low or absent megakaryocytes in their bone marrow and normal to elevated levels of thrombopoietin. These findings suggest a molecular abnormality in the thrombopoietin receptor (c-mpl) or in the megakaryocyte-specific signal transduction pathway. To address this question we performed complete DNA sequencing on c-mpl cDNA clones from two patients with TAR syndrome. In one patient, an A to C polymorphism was found at base 1520 resulting in an alanine to valine substitution. We have sequenced the c-mpl CDNA from 50 patients and normal individuals and have not detected this polymorphism previously. The patient's mother, who is phenotypically normal, also exhibited the polymorphism. The c-mpl gene in the second TAR patient was normal. In addition, we also detected three alternative splice variants of c-mpl in the TAR patients and in normal individuals. Therefore, in patients with TAR syndrome that we have studied the primary structure of the c-mpl gene appears to be normal.

National Institute of Heart and Lung