Kidney international reports · 2026
Hypomagnesemia in Hypoparathyroidism, Sensorineural Deafness, and Renal Dysplasia Syndrome Caused by Pathogenic Variants of GATA3.
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Kahlman Eveline J E M, van der Zanden Nicole, Zaťková Ela, Bos Caro, Bacchetta Justine, Belge Hendrica, Bootsma-Robroeks Charlotte M H H T, Brandi Maria Luisa, Cambier Jean-François, Colliou Éloïse, Demoulin Nathalie, Figueres Lucile, Heidet Laurence, Mantovani Giovanna, Marlais Matko, Sayer John A, Schlingmann Karl P, European Rare Kidney Diseases Reference Network (ERKNet) and European Reference Network rare endocrine conditions (Endo-ERN) collaborators, Monnens Leo A, Hoenderop Joost G J, Nijenhuis Tom, de Baaij Jeroen H F
Аннотация
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.
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.