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Pulmonary Hypertension and Polycythemia – novel mutations

Pulmonary Hypertension and Polycythemia – novel mutations. Stuart Adams. Pulmonary hypertension. Narrowing of primary arterioles within the lung Heart becomes enlarged from pumping blood against resistance Chest pain, weakness, shortness of breath, and fatigue.

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Pulmonary Hypertension and Polycythemia – novel mutations

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  1. Pulmonary Hypertension and Polycythemia – novel mutations Stuart Adams

  2. Pulmonary hypertension • Narrowing of primary arterioles within the lung • Heart becomes enlarged from pumping blood against resistance • Chest pain, weakness, shortness of breath, and fatigue. • Treatment to control symptoms but disease progresses to congestive heart failure

  3. Polycythemia

  4. Case Study • 2 month old boy presented with pulmonary hypertension (associated hypoxia) and polycythemia. • Full blood counts showed high haemoglobin 25g/dL (normal range 10-13.5). • Also had very high erythropoietinlevels 4120 mIU/ml (normal range 2.5-10.5). • No evidence of EPO secreting malignancy. • No high affinity haemoglobin or EPO receptor mutation. • Referred to Consultant Haematologist at GOSH

  5. Case Study • Regular venesection to maintain haemoglobin levels but this has pushed his EPO levels higher. • Was not expected to live beyond 2-3 years of age. • Now 6 years old with a stable respiratory function. • Lung transplant being considered. • Mutation in the oxygen sensing pathway?

  6. Polycythemia

  7. Oxygen Regulation – Epo system • Kidney senses decreased tissue oxygenation and produces Epo • Epo – hormone stimulates production of red blood cells, VEGF and other proteins. • Too much Epo leads to polycythemia. • Epo production regulated by hypoxia-inducible factor (3 isoforms; HIF1α, HIF2α and HIF3α). • If HIF is hydroxylated it is degraded by VHL protein.

  8. Oxygen Regulation – Epo system • Under hypoxic conditions, hydroxylation is inhibited - HIF upregulated – more EPO produced. • HIF hydroxylated on two specific prolyl residues. • HIF targeted for hydroxylation by von Hippel-Lindau (VHL) tumour-suppressor protein and prolyl hydroxylase domain protein 2 (PHD2).

  9. Target genes • Chuvash polycythemia (VHL gene): - homozygous 598C>T • HIF1 mutations (Percy et al. 2003) - exons 9, 12 and 15 (contain hydroxylation sites) • HIF2 mutations (Percy et al. 2008) - exons 9, 12 and 15 (contain hydroxylation sites) • PHD2 mutations (Al-Sheikh et al. 2007) - any exon

  10. Results No mutation • Chuvash polycythaemia • HIF1 • HIF2 • PHD2 No mutation No mutation No mutation

  11. Results • Sequenced remaining exons and found compound heterozygous point mutations in exon 2 and 3 of VHL gene. Exon 3 hetero c.548C>T S183L TCG>TTG Exon 2 hetero c.376G>A D125N GAT>AAT

  12. Current investigations • Sequenced both parents’ VHL gene and found contributing single mutation from each. • Obtained VHL null cell-line and made both wild type and patient-derived constructs for transduction. • Planning luciferase assay to observe effect of patients mutation on HIF activity

  13. Clinical implications • Patient and parents informed of findings. • Patient now unlikely to receive lung transplant. • Other patients who presented with similar symptoms being analysed retrospectively (only two families).

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