The first inherited retinal disease registry in Iran: Research protocol and results of a pilot study

Background: To describe the protocol for developing a national inherited retinal disease (IRD) registry in Iran and present its initial report. Methods: This community-based participatory research was approved by the Ministry of Health and Medical Education of Iran in 2016. To provide the minimum data set (MDS), several focus group meetings were held. The final MDS was handed over to an engineering team to develop a web-based software. In the pilot phase, the software was set up in two referral centers in Iran. Final IRD diagnosis was made based on clinical manifestations and genetic findings. Ultimately, patient registration was done based on all clinical and non-clinical manifestations. Results: Initially, a total of 151 data elements were approved with Delphi technique. The registry software went live at www.IRDReg.org based on DHIS2 open source license agreement since February 2016. So far, a total of 1001 patients have been registered with a mean age of 32.41±15.60 years (range, 3 months to 74 years). The majority of the registered patients had retinitis pigmentosa (42, 95 CI: 38.9 to 45). Genetic testing was done for approximately 20 of the registered individuals. Conclusion: Our study shows successful web-based software design and data collection as a proof of concept for the first IRD registry in Iran. Multicenter integration of the IRD registry in medical centers throughout the country is well underway as planned. These data will assist researchers to rapidly access information about the distribution and genetic patterns of this disease. © 2020 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons. org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Arginine Vasopressin regulates the renal Na-Cl and Na-K-Cl Cotransporters through With-No-Lysine Kinase 4 and Inhibitor 1 Phosphorylation

Vasopressin regulates water homeostasis via the V2 receptor in the kidney at least in part through protein kinase A (PKA) activation. Vasopressin, through an unknown pathway, upregulates the activity and phosphorylation of the Na+-Cl- cotransporter (NCC) and Na+-K+-2Cl- cotransporter 2 (NKCC2) by Ste20-related Proline/Alanine rich Kinase (SPAK) and Oxidative Stress Responsive kinase 1 (OSR1), which are regulated by the With No Lysine (K) kinase (WNK) family. Phosphorylation of WNK4 at PKA consensus motifs may be involved. Inhibitor 1 (I1), a Protein Phosphatase 1 (PP1) inhibitor, may also play a role. In HEK293 cells, we assessed the phosphorylation of WNK4, SPAK, NCC, or NKCC2 in response to forskolin or desmopressin. WNK4 and cotransporter phosphorylation was studied in desmopressin-infused WNK4$^{-/-}$ mice and in tubule suspensions. In HEK293 cells, only wild-type WNK4, but not WNK1, WNK3, or a WNK4 mutant lacking PKA phosphorylation motifs could upregulate SPAK or cotransporter phosphorylation in response to forskolin or desmopressin. I1 transfection maximized SPAK phosphorylation in response to forskolin in the presence of WNK4, but not of mutant WNK4 lacking PP1 regulation. We observed direct PP1 regulation of NKCC2 dephosphorylation, but not of NCC or SPAK in the absence of WNK4. WNK4$^{-/-}$ mice with desmopressin treatment did not increase SPAK/OSR1, NCC, or NKCC2 phosphorylation. In stimulated tubule suspensions from WNK4$^{-/-}$ mice, upregulation of pNKCC2 was reduced, whereas upregulation of pSPAK was absent. These findings suggest that WNK4 is a central node in which kinase and phosphatase signaling converge to connect cAMP signaling to the SPAK/OSR1-NCC/NKCC2 pathway