Hypomagnesemia in Hypoparathyroidism-Sensorineural Deafness-Renal Syndrome Caused by Pathogenic Variants in GATA3

Background: Mutations in GATA binding protein 3 (GATA3) cause HDR syndrome, a rare disorder marked by Hypoparathyroidism, sensorineural Deafness and Renal dysplasia. Recently, we identified several cases in which hypomagnesemia was the primary symptom, suggesting a regulatory role of GATA3 in renal magnesium reabsorption. Therefore, we aim to establish the prevalence of hypomagnesemia and to characterize how GATA3 is involved in renal magnesium handling. Methods: Retrospective clinical and laboratory data corresponding to the first and last possible hospital visit of 72 patients with mutations in GATA3 were provided by members of the European Rare Kidney Diseases Reference Network (ERKNet) or European Reference Network Rare Endocrine Conditions (Endo-ERN). Chromatin immunoprecipitation (ChIP) was performed on a distal convoluted tubule cell line (mpkDCT4a) to map GATA3-DNA interactions. Results: Our patient cohort consisted for 45% of females, the mean age was 26 with a standard deviation of 22, and 56% of patients carried the HDR triad. Importantly, we showed that ±25% of patients had a serum magnesium level below the provided lower reference limit. The serum magnesium concentration did not correlate with parathyroid hormone level or kidney (dys)function, as determined by eGFR. Serum magnesium level was also independent of genotype and other phenotypic traits. Moreover, we observed a left-skewed distribution of serum magnesium levels, indicating an overall lowered magnesium balance in patients with GATA3 pathogenic variants. By ChIP-sequencing, we identified that GATA3 binds to the promoter regions (< 4 kb upstream of transcription start site) of the apical magnesium channels TRPM6/7 and the thiazide-sensitive sodium-chloride cotransporter NCC, encoded by SLC12A3. Additionally, the GATA3 binding sites upstream of TRPM6/7 coincided with the promoter-associated histone mark H3K27me3 in mpkDCT4a. Conclusion: We demonstrate that 25% of patients diagnosed with a GATA3 pathogenic variant also present with magnesium deficiency, a previously undefined phenotype of HDR syndrome. GATA3 might be involved in renal magnesium handling through transcriptional regulation of TRPM6/7 and NCC in the distal convoluted tubule. Funding: Government Support – Non-U.S.