title: Molecular study of congenital erythrocytosis in 70 unrelated patients revealed a potential causal mutation in less than half of the cases (Where is/are the missing gene(s)?).
abstract: BACKGROUND
  Congenital erythrocytosis can be classified as primary, when the defect is intrinsic to the RBC progenitors and independent of the serum erythropoietin (Epo) concentration, or secondary, when the erythrocytosis is the result of an upregulation of Epo production. Primary erythrocytosis is associated with mutations in the EPOR gene, secondary CE can de due to mutations that stabilize the hemoglobin in the oxygenated form or to mutations in the genes that control the transcriptional activation of the EPO gene - VHL, EGLN1, EPAS1. Chuvash polycythemia, caused by mutations in VHL gene, shares features of both primary and secondary erythrocytosis, with increased Epo production but also hypersensitivity of progenitors to Epo.
  
  
  METHODS
  With the main objective of describing the etiology and molecular basis of CE, we have studied 70 consecutive unrelated patients presenting with idiopathic erythrocytosis from our hematology clinic or referred from other centers. According to a study algorithm, we have sequenced all the genes described as associated with CE.
  
  
  CONCLUSIONS
  Erythrocytosis molecular etiology was identify in 25 (36%) of the 70 subjects. High-affinity Hb variants were the most common cause, present in 20% of the cases. New mutations were identified in the JAK2, EPOR, VHL, and EGLN1 genes.
  
  
  CONCLUSIONS
  High-affinity hemoglobin variants are a very rare cause of secondary CE, but it seems likely that their incidence may be underestimated. Our experience shows that in erythrocytosis with a dominant inheritance and normal or inappropriate high Epo levels, the HBB and HBA genes should be the first to be studied. In spite of the seven genes known to be involved in CE, the majority of the cases have unknown etiology.
authors.affiliation: Serviço de Hematologia, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
authors.forename: Celeste
authors.initials: C
authors.lastname: Bento
authors.forename: Helena
authors.initials: H
authors.lastname: Almeida
authors.forename: Tabita M
authors.initials: TM
authors.lastname: Maia
authors.forename: Luís
authors.initials: L
authors.lastname: Relvas
authors.forename: Ana C
authors.initials: AC
authors.lastname: Oliveira
authors.forename: Cédric
authors.initials: C
authors.lastname: Rossi
authors.forename: François
authors.initials: F
authors.lastname: Girodon
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernandez-Lago
authors.forename: Ascension
authors.initials: A
authors.lastname: Aguado-Diaz
authors.forename: Cristina
authors.initials: C
authors.lastname: Fraga
authors.forename: Ricardo M
authors.initials: RM
authors.lastname: Costa
authors.forename: Ana L
authors.initials: AL
authors.lastname: Araújo
authors.forename: João
authors.initials: J
authors.lastname: Silva
authors.forename: Helena
authors.initials: H
authors.lastname: Vitória
authors.forename: Natalina
authors.initials: N
authors.lastname: Miguel
authors.forename: Maria Pedro
authors.initials: MP
authors.lastname: Silveira
authors.forename: Guillermo
authors.initials: G
authors.lastname: Martin-Nuñez
authors.forename: Maria Letícia
authors.initials: ML
authors.lastname: Ribeiro
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D003598:Cytoskeletal Proteins; D004252:DNA Mutational Analysis; D005260:Female; D006455:Hemoglobins, Abnormal / Q000235:genetics*; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000235:genetics*; D053614:Janus Kinase 2 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008967:Molecular Biology; D018832:Molecular Chaperones; D009154:Mutation; D010100:Oxygen / Q000378:metabolism; D011086:Polycythemia / Q000151:congenital / Q000175:diagnosis / Q000235:genetics*; D017467:Receptors, Erythropoietin / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D006455:Hemoglobins, Abnormal; D018832:Molecular Chaperones; D017467:Receptors, Erythropoietin; C108825:VBP1 protein, human; C490190:EGLN1 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D010100:Oxygen
keywords: congenital erythrocytosis; diagnosis; molecular etiology