2 NEW EPO RECEPTOR MUTATIONS - TRUNCATED EPO RECEPTORS ARE MOST FREQUENTLY ASSOCIATED WITH PRIMARY FAMILIAL AND CONGENITAL POLYCYTHEMIAS

Primary polycythemias are caused by an acquired or inborn mutation aff ecting hematopoietic/erythroid progenitors that results in an abnormal response to hematopoietic cytokines. Primary familial and congenital polycythemia (PFCP; also known as familial erythrocytosis) is characte rized by elevated red blood cell mass, low serum erythropoietin (EPO) level, normal oxygen affinity of hemoglobin, and typically autosomal d ominant inheritance. In this study we screened for mutations in the cy toplasmic domain of the EPO receptor (EPOR; exons 7 and 8 of the EPOR gene) in 27 unrelated subjects with primary or unidentified polycythem ia. Two new EPOR mutations were found, which lead to truncation of the EPOR similarly to previously described mutations in PFCP subjects, Th e first is a 7-bp deletion (del5385-5991) found in a Caucasian family from Ohio. The second mutation (5967insT) was found in a Caucasian fam ily from the Czech Republic. In both cases the EPO dose responses of t he erythroid progenitors of the affected subjects were examined to con firm the diagnosis of PFCP. In one of these families, the in vitro beh avior of erythroid progenitors in serum-containing cultures without th e addition of EPO mimicked the behavior of polycythemia vera progenito rs; however, we show that antibodies against either EPO or the EPOR di stinguish the in vitro growth abnormality of polycythemia vera erythro id progenitors from that seen in this particular PFCP family, We concl ude that PFCP is a disorder that appears to be associated in some fami lies with EPOR mutations. So far, most of the described EPOR mutations (6 out of 8) associated with PFCP result in an absence of the C-termi nal negative regulatory domain of the receptor, (C) 1997 by The Americ an Society of Hematology.