An inherited duplication at the gene p21 Protein-Activated Kinase 7 (PAK7) is a risk factor for psychosis

Identifying rare, highly penetrant risk mutations may be an important step in dissecting the molecular etiology of schizophrenia. We conducted a gene-based analysis of large (>100kb), rare copy number variants (CNVs) in the Wellcome Trust Case Control Consortium 2 (WTCCC2) schizophrenia sample of 1,564 cases and 1,748 controls all from Ireland, and further extended the analysis to include an additional 5,196 UK controls. We found association with duplications at chr20p12.2 (P=0.007) and evidence of replication in large independent European schizophrenia (P=0.052) and UK bipolar disorder case-control cohorts (P=0.047). A combined analysis of Irish/UK subjects including additional psychosis cases (schizophrenia and bipolar disorder) identified 22 carriers in 11,707 cases and 10 carriers in 21,204 controls (meta-analysis CMH P value=2x10(-4) (odds ratio (OR)=11.3, 95% CI=3.7, ∞)). Nineteen of the 22 cases and 8 of the 10 controls carried duplications starting at 9.68Mb with similar breakpoints across samples. By haplotype analysis and sequencing we identified a tandem ∼149kb duplication overlapping the gene p21 Protein-Activated Kinase 7 (PAK7, also called PAK5) which was in linkage disequilibrium with local haplotypes (P=2.5x10(-21)), indicative of a single ancestral duplication event. We confirmed the breakpoints in 8/8 carriers tested and found co-segregation of the duplication with illness in two additional family members of one of the affected probands. We demonstrate that PAK7 is developmentally co-expressed with another known psychosis risk gene (DISC1) suggesting a potential molecular mechanism involving aberrant synapse development and plasticity.

Polycythaemia-inducing mutations in the erythropoietin receptor (EPOR):mechanism and function as elucidated by epidermal growth factor receptor-EPOR chimeras

Primary familial and congenital polycythaemia (PFCP) is a disease characterized by increased red blood cell mass, and can be associated with mutations in the intracellular region of the erythropoietin (EPO) receptor (EPOR). Here we explore the mechanisms by which EPOR mutations induce PFCP, using an experimental system based on chimeric receptors between epidermal growth factor receptor (EGFR) and EPOR. The design of the chimeras enabled EPOR signalling to be triggered by EGF binding. Using this system we analysed three novel EPOR mutations discovered in PFCP patients: a deletion mutation (Del1377-1411), a nonsense mutation (C1370A) and a missense mutation (G1445A). Three different chimeras, bearing these mutations in the cytosolic, EPOR region were generated; Hence, the differences in the chimera-related effects are specifically attributed to the mutations. The results show that the different mutations affect various aspects related to the signalling and metabolism of the chimeric receptors. These include slower degradation rate, higher levels of glycan-mature chimeric receptors, increased sensitivity to low levels of EGF (replacing EPO in this system) and extended signalling cascades. This study provides a novel experimental system to study polycythaemia-inducing mutations in the EPOR, and sheds new light on underlying mechanisms of EPOR over-activation in PFCP patients.

Clinical correlates of serum pigment epithelium-derived factor in type 2 diabetes patients

Aim: To determine if serum pigment epithelium-derived factor (PEDF) levels in Type 2 diabetes are related to vascular risk factors and renal function. Methods: PEDF was quantified by ELISA in a cross-sectional study of 857 male Veterans Affairs Diabetes Trial (VADT) subjects, and associations with cardiovascular risk factors and renal function were determined. In a subset (n = 246) in whom serum was obtained early in the VADT (2.0 ± 0.3 years post-randomization), PEDF was related to longitudinal changes in renal function over 3.1 years. Results: Cross-sectional study: In multivariate regression models, PEDF was positively associated with serum triglycerides, waist-to-hip ratio, serum creatinine, use of ACE inhibitors or angiotensin receptor blockers, and use of lipid-lowering agents; it was negatively associated with HDL-C (all p < 0.05). Longitudinal study: PEDF was not associated with changes in renal function over 3.1 years (p > 0.09). Conclusions: Serum PEDF in Type 2 diabetic men was cross-sectionally associated with dyslipidemia, body habitus, use of common drugs for blood pressure and dyslipidemia, and indices of renal function; however, PEDF was not associated with renal decline over 3.1 years.