Elucidation of the distal convoluted tubule transcriptome identifies Pcbd1 as new causative gene for hereditary hypomagnesemia (860.4)

Abstract

The distal convoluted tubule (DCT) is instrumental in fine‐tuning of the renal Mg2+ handling. Here, we aim to discover new Mg2+‐related genes in DCT. Transgenic mice expressing eGFP under a DCT‐specific parvalbumin promoter were subjected to Mg2+‐deficient or Mg2+‐enriched diets. Subsequently, the Complex Object Parametric Analyzer and Sorter (COPAS) allowed for the first time isolation of eGFP‐positive DCT cells. RNA extracts thereof were analyzed by DNA microarrays to identify Mg2+ regulatory genes and 46 genes showed differential expression. Several known magnesiotropic genes, such as Trpm6 and Parvalbumin, were upregulated under low dietary Mg2+. Moreover, new genes were identified that are potentially involved in renal Mg2+ handling. Among others, Pcbd1 was identified to be higher expressed in low Mg2+ conditions. Pcbd1 encodes a transcriptional co‐activator of Hnf1b, which was previously implicated in renal Mg2+ handling and maturity onset diabetes of the young (MODY). Interestingly, when examining three independent patients with Pcbd1 mutations, two individuals were diagnosed with hypomagnesemia and renal Mg2+ loss. Moreover, two patients also developed diabetes with characteristics of MODY regardless of the serum Mg2+ levels. By elucidating the Mg2+‐sensitive DCT transcriptome new candidate genes in renal Mg2+ handling have been identified.