Hypomagnesemia in Hypoparathyroidism, Sensorineural Deafness, and Renal Dysplasia Syndrome Caused by Pathogenic Variants of GATA3.

BACKGROUND

Heterozygous pathogenic variants in the transcription factor GATA binding protein 3 (GATA3) cause hypoparathyroidism, sensorineural deafness and renal dysplasia (HDR) syndrome, also known as Barakat syndrome. Although not typically associated with the disease, hypomagnesemia has been reported. We aimed to determine its prevalence in HDR syndrome and explore how GATA3 impacts magnesium balance.

METHODS

Retrospective clinical and laboratory data from 66 patients with GATA3 variants were collected via European Rare Kidney Diseases Reference Network (ERKNet) and European Reference Network Rare Endocrine Disorders (Endo-ERN). GATA3 chromatin immunoprecipitation (ChIP) sequencing was performed in a mouse distal convoluted tubule cell line and validated using dual promoter luciferase assays in human embryonic kidney 293 (HEK293) cells.

RESULTS

The cohort was 47% female, median age was 16 years (0-74) and 56% had the full HDR triad. Overall, 25% had hypomagnesemia (Z-score: <-2). Magnesium levels did not correlate with parathyroid hormone (PTH), estimated glomerular filtration rate, genotype, or other phenotypic traits. ChIP-sequencing revealed GATA3 binding to promoters of the magnesium channel Trpm6 and Slc12a3 (encoding the thiazide-sensitive sodium-chloride cotransporter [NCC]). Luciferase assays showed GATA3 increased TRPM6 promoter activity 23-fold and SLC12A3 by 10-fold. Pathogenic GATA3 variants failed to activate these promoters.

CONCLUSION

Hypomagnesemia is an underrecognized feature of HDR syndrome. Our findings suggest that pathogenic variants of GATA3 impair transcriptional regulation of genes involved in renal magnesium reabsorption. We propose that serum magnesium measurements should be included in the standard clinical workup of patients diagnosed with HDR syndrome.