title: Loss of the JAK2 intramolecular auto-inhibition mechanism is predicted by structural modelling of a novel exon 12 insertion mutation in a case of idiopathic erythrocytosis.
abstract: We report a novel gain-of-function JAK2 exon 12 insertion mutation in a patient with idiopathic erythrocytosis and low serum erythropoietin level. To date, only rare cases of such mutations have been reported in the JAK2 exon 12. Using computer-based structural modelling we propose that this mutation causes the loss of the JAK2 auto-inhibition step, leading to the constitutive activation of JAK2 tyrosine kinase-dependent activity. Our model-based hypothesis provides a useful approach for the investigation of the phenotype-genotype relationship in myeloproliferative disorders involving JAK2.
authors.affiliation: Department of Cellular Therapy and Haematology, San Bortolo Hospital, Vicenza, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Albiero
authors.forename: Domenico
authors.initials: D
authors.lastname: Madeo
authors.forename: Marco
authors.initials: M
authors.lastname: Ruggeri
authors.forename: Martina
authors.initials: M
authors.lastname: Bernardi
authors.forename: Alejandro
authors.initials: A
authors.lastname: Giorgetti
authors.forename: Francesco
authors.initials: F
authors.lastname: Rodeghiero
mesh_terms: D001483:Base Sequence; D005091:Exons / Q000235:genetics; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics* / Q000502:physiology; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D011086:Polycythemia / Q000235:genetics*; D011087:Polycythemia Vera / Q000235:genetics; D017434:Protein Structure, Tertiary
chemical_list: C507924:JAK2 protein, human; D053614:Janus Kinase 2