Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Hematology, Peripheral Vascular Disease, Cardiovascular System & Cardiology, 1102 Cardiorespiratory Medicine and Haematology, 1103 Clinical Sciences, Cardiovascular System & Hematology, 3201 Cardiovascular medicine and haematology, 3202 Clinical sciences

Abstract:

Aquaglyceroporin 7 (AQP7) belongs to the aquaglyceroporin family transporting glycerol in addition to water. It is mainly expressed in adipocytes and renal proximal tubule cells. AQP7 deficient mice develop obesity and insulin resistance on a high-fat diet and show glyceroluria with normal plasma glycerol values. AQPs have also been shown to play a role in secretion by regulating vesicle volume. We here describe 3 unrelated patients with psychomotor retardation. An extensive metabolic screening showed pronounced hyperglyceroluria (400 to 998 mmol glycerol/mol creatinine in cases, as compared to 11 ± 10 mmol glycerol/mol creatinine in controls) with normal plasma glycerol levels. Mutation analysis of AQP7 revealed a homozygous missense mutation in all three patients (G264V). The mutation is located in the highly conserved GxxGxxG motif of the 6th transmembrane helix of nearly all AQPs. Disturbance of this motif has a functional impact, as shown by Kondo et al (Eur J Biochem 2002), describing this mutation in a man with impaired glycerol release from fat tissue during endurance exercise tests. We also detected a subclinical platelet secretion defect in our patients as highlighted by absent ADP induced ATP secretion and secondary aggregation wave after epinephrine stimulation. Electron microscopy revealed round platelets with centrally located granules. We detected AQP7 expression in human platelets by RT-PCR and immunoblot analysis without differences between patients and controls. After stimulation of platelets with strong agonists (A23187/TRAP6), we found AQP7 in the platelet releasate. Immunofluorescent staining showed a colocalisation of AQP7 with platelet dense granules. Further studies are ongoing to identify AQP7 binding proteins. In conclusion, the association of glyceroluria and a platelet secretion defect is novel and our studies imply the involvement of a new category of proteins, the AQPs, in platelet dense granule secretion.