Showing papers by "Claire N. Harrison published in 2006"

A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis

Abstract: The number of red blood cells is normally tightly regulated by a classic homeostatic mechanism based on oxygen sensing in the kidney. Decreased oxygen delivery resulting from anemia induces the production of erythropoietin, which increases red cell production and hence oxygen delivery. Investigations of erythropoietin regulation identified the transcription factor hypoxia-inducible factor (HIF). HIF is now recognized as being a key regulator of genes that function in a comprehensive range of processes besides erythropoiesis, including energy metabolism and angiogenesis. HIF itself is regulated through the α-subunit, which is hydroxylated in the presence of oxygen by a family of three prolyl hydroxylase domain proteins (PHDs)/HIF prolyl hydroxylases/egg-laying-defective nine enzymes. Hydroxylation allows capture by the von Hippel–Lindau tumor suppressor gene product, ubiquitination, and destruction by the proteasome. Here we describe an inherited mutation in a mammalian PHD enzyme. We show that this mutation in PHD2 results in a marked decrease in enzyme activity and is associated with familial erythrocytosis, identifying a previously unrecognized cause of this condition. Our findings indicate that PHD2 is critical for normal regulation of HIF in humans.

The presence of the JAK2 V617F mutation is associated with a higher haemoglobin and increased risk of thrombosis in essential thrombocythaemia

Abstract: Recently, several groups have identified a single point mutation in the JAK2 gene in the Philadelphia-negative myeloproliferative disorders, including polycythaemia vera (PV), essential thrombocythaemia (ET) and myelofibrosis with myeloid metaplasia (MMM) (Baxter et al, 2005; James et al, 2005; Jones et al, 2005; Kralovics et al, 2005; Levine et al, 2005). A G fi T transversion results in the substitution of valine by phenylalanine at codon 617 (V617F) within the pseudokinase autoinhibitory centre with overall constitutive activation of the tyrosine kinase. The presence of this mutation has been detected in high frequency in patients with PV (65–97%), ET (23–57%) and MMM (35–57%) and suggests that it may have a fundamental role in the pathogenesis of these disorders. Most studies have shown no differences in the clinical phenotype of patients with or without the JAK2 mutation. However, a longer disease duration was associated with the ‘homozygous’ status (Levine et al, 2005) and the mutation correlated with an older age, greater requirement for cytoreductive therapy, and higher frequency of thrombotic, haemorrhagic and fibrotic complications (Kralovics et al, 2005) in myeloproliferative disorders. Only one group have investigated ET patients independently, and they demonstrated a higher haemoglobin and haematocrit in ET patients with the mutation (Antonioli et al, 2005). To address these clinical findings further, we investigated 60 patients with ET for the presence of the JAK2 mutation and possible phenotypic associations. Patient notes were examined for their diagnostic blood counts and thrombotic histories. Thrombotic complications included major thromboses as well as microvascular disturbances. The clinical characteristics for the patients are shown in Table I. We used the previously published allele-specific polymerase chain reaction (PCR) method (Baxter et al, 2005) on whole blood DNA to detect qualitatively the presence or absence of the JAK2 V617F mutation and designed a second allele-specific PCR to confirm the findings independently. Statistical analysis was performed with the Statistical Package for the Social Sciences (SPSS Inc., Chicago, IL, USA) software, version 11.5, using Wilcoxon’s rank sum for continuous variables, Fisher’s exact test for nominal variables and binary logistic regression for multivariate