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Familial erythrocytosis associated with a short deletion in the
erythropoietin receptor gene
MO Arcasoy, BA Degar, KW Harris and BG Forget
Department of Medicine, Yale University School of Medicine, New Haven, CT
06520-8021, USA.
Familial erythrocytosis (familial polycythemia) inherited as an autosomal
dominant trait has recently been reported to be associated with mutations
in the gene encoding the erythropoietin receptor (EpoR) in a small number
of families. We studied a new kindred with dominantly inherited familial
erythrocytosis associated with heterozygosity for a deletion of seven
nucleotides between positions 5985 and 5991 in exon 8 of the EpoR gene,
resulting in an EpoR peptide that is truncated by 59 amino acids at its
C-terminus. A 7-bp direct repeat is present in the normal EpoR gene at the
site of this mutation, consistent with the slipped mispairing model for the
generation of short deletions during DNA replication. Hypersensitivity to
Epo of erythroid progenitors from an affected individual was observed in in
vitro methylcellulose cultures, as indicated by more numerous and larger
colonies compared with those of a control subject. To study mutant EpoR
function, the cDNA encoding the mutant EpoR was synthesized by reverse
transcription- polymerase chain reaction of peripheral blood RNA from the
proband and stably tranfected into murine interleukin-3-dependent 32D
cells. Epo dose-response assays showed that cells expressing the mutant
EpoR displayed fivefold to 10-fold increased sensitivity to Epo compared
with cells expressing similar numbers of the wild-type EpoR.
Volume 89,
Issue 12,
pp. 4628-4635,
06/15/1997
Copyright © 1997 by The American Society of Hematology
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