👤 Hector Donoro Blazquez

Zinc fingers and homeoboxes (ZHX) proteins are heterodimeric transcriptional factors largely expressed at the cell membrane in podocytes in vivo. We found ZHX2-based heterodimers in podocytes, with ZHX2-ZHX1 predominantly at the cell membrane of the podocyte cell body, and ZHX2-ZHX3 at the slit diaphragm. In addition to changes in overall ZHX2 expression, there was increased podocyte nuclear ZHX3 and ZHX2 in patients with focal segmental glomerulosclerosis, and increased podocyte nuclear ZHX1 in patients with minimal change disease. Zhx2 deficient mice had increased podocyte ZHX1 and ZHX3 expression. Zhx2 deficient mice and podocyte specific Zhx2 overexpressing transgenic rats develop worse experimental focal segmental glomerulosclerosis than controls, with increased nuclear ZHX3 and ZHX2, respectively. By contrast, podocyte specific Zhx2 overexpressing transgenic rats develop lesser proteinuria during experimental minimal change disease due to peripheral sequestration of ZHX1 by ZHX2. Using co-immunoprecipitation, the interaction of ZHX2 with aminopeptidase A in the podocyte body cell membrane, and EPHRIN B1 in the slit diaphragm were noted to be central to upstream events in animal models of minimal change disease and focal segmental glomerulosclerosis, respectively. Mice deficient in Enpep, the gene for aminopeptidase A, and Efnb1, the gene for ephrin B1 developed worse albuminuria in glomerular disease models. Targeting aminopeptidase A in Zhx2 deficient mice with monoclonal antibodies induced albuminuria and upregulation of the minimal change disease mediator angiopoietin-like 4 through nuclear entry of ZHX1. Thus, podocyte ZHX2 imbalance is a critical factor in human glomerular disease, with minimal change disease disparities mediated mostly through ZHX1, and focal segmental glomerulosclerosis deviations through ZHX3 and ZHX2. Show less

The Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases. To perform the largest PD genome-wide association study restricted to a single country. We performed a GWAS for both risk of PD and age at onset in 7,849 Spanish individuals. Further analyses included population-specific risk haplotype assessments, polygenic risk scoring through machine learning, Mendelian randomization of expression, and methylation data to gain insight into disease-associated loci, heritability estimates, genetic correlations, and burden analyses. We identified a novel population-specific genome-wide association study signal at PARK2 associated with age at onset, which was likely dependent on the c.155delA mutation. We replicated four genome-wide independent signals associated with PD risk, including SNCA, LRRK2, KANSL1/MAPT, and HLA-DQB1. A significant trend for smaller risk haplotypes at known loci was found compared to similar studies of non-Spanish origin. Seventeen PD-related genes showed functional consequence by two-sample Mendelian randomization in expression and methylation data sets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls. Our data demonstrate the utility of the Spanish risk haplotype substructure for future fine-mapping efforts, showing how leveraging unique and diverse population histories can benefit genetic studies of complex diseases. The present study points to PARK2 as a major hallmark of PD etiology in Spain. © 2019 International Parkinson and Movement Disorder Society. Show less