EPOR – Primary familial polycythemia due to EPO receptor mutation

Primary familial and congenital polycythemia (PFCP) is an autosomal dominant erythrocytosis characterized by increased red blood cell mass and hypersensitivity of erythroid progenitors to erythropoietin. Heterozygous variants in the erythropoietin receptor gene (EPOR) remove C-terminal negative regulatory domains, leading to gain-of-function signaling. Early case series identified truncating exon 8 mutations in PFCP families by co-segregation and functional assays of erythroid progenitors and cell lines ([PMID:7795221]; [PMID:9292543]).

Genetic evidence from two large cohorts demonstrates that EPOR variants account for ~15% of PFCP cases. In 27 unrelated subjects with primary polycythemia, two novel C-terminal truncating mutations were reported ([PMID:9292543]). In an independent study of 43 unrelated PFCP probands, five exon VIII truncating or nonsense variants were identified, including c.1300C>T (p.Gln434Ter), each segregating with disease in affected relatives ([PMID:11559951]). Combined, over 70 probands across multiple families harbor heterozygous EPOR variants.

Segregation studies confirm autosomal dominant inheritance: pedigrees spanning up to four generations show co-segregation of truncating EPOR alleles with hypersensitive erythroid progenitor phenotypes. However, linkage to EPOR was excluded in some PFCP families, such as a C6148T non-segregating variant in three generations ([PMID:9394420]) and by genomewide analysis mapping an alternative locus at 7q22.1-7q22.2 ([PMID:14636647]).

The variant spectrum in PFCP is dominated by frameshift and nonsense changes in exon 8. Representative examples include c.1288dup (p.Asp430Ter) and c.1300C>T (p.Gln434Ter) leading to loss of the distal intracellular domain. Recurrent founder alleles have not been reported, and missense EPOR variants are rare.

Functional assays demonstrate that truncating EPOR mutants confer erythropoietin hypersensitivity: burst-forming units-erythroid from patients proliferate at low EPO concentrations, and Ba/F3 cells expressing EPOR 5974insG exhibit increased EPO-dependent proliferation compared to wild type ([PMID:7795221]). A humanized mouse model with a truncated EPOR allele recapitulates the polycythemia phenotype, confirming in vivo gain-of-function ([PMID:11158582]).

Mechanistically, removal of C-terminal negative regulatory tyrosines enhances receptor dimerization, JAK2/STAT5 activation, and stability at the cell surface. Novel frameshift tails, such as p.Gln434Profs*11, further increase receptor pre-activation and signaling, revealing a sequence-dependent mechanism for EPO hypersensitivity ([PMID:29269524]).

Despite definitive evidence linking EPOR truncations to PFCP, the low prevalence (~12%) in large cohorts indicates genetic heterogeneity. Other erythropoiesis regulators remain to be discovered. Genetic testing of EPOR exon 8 is clinically useful for diagnosis, management, and family counseling.

Key Take-home: Truncating heterozygous EPOR variants are a definitive cause of autosomal dominant PFCP and should be included in diagnostic genetic panels.

References

• Blood • 1995 • Primary familial polycythemia: a frameshift mutation in the erythropoietin receptor gene and increased sensitivity of erythroid progenitors to erythropoietin. PMID:7795221
• Blood • 1997 • Two new EPO receptor mutations: truncated EPO receptors are most frequently associated with primary familial and congenital polycythemias. PMID:9292543
• American journal of hematology • 2001 • Genetic heterogeneity of primary familial and congenital polycythemia. PMID:11559951
• Proceedings of the National Academy of Sciences of the United States of America • 2001 • Mouse model of congenital polycythemia: Homologous replacement of murine gene by mutant human erythropoietin receptor gene. PMID:11158582
• Haematologica • 2018 • New pathogenic mechanisms induced by germline erythropoietin receptor mutations in primary erythrocytosis. PMID:29269524
• Proceedings of the Association of American Physicians • 1997 • The erythropoietin receptor gene is not linked with the polycythemia phenotype in a family with autosomal dominant primary polycythemia. PMID:9394420
• Blood cells, molecules & diseases • 2003 • Possible primary familial and congenital polycythemia locus at 7q22.1-7q22.2. PMID:14636647

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