Mutations in PCBD1 Cause Hypomagnesemia and Renal Magnesium Wasting
Mutations in PCBD1 Cause Hypomagnesemia and Renal Magnesium Wasting
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DOI：
10.1681/asn.2013040337
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发表时间：
2014-03-01
影响因子：
13.6
通讯作者：
Bindels, Rene J. M.
中科院分区：
文献类型：
--
作者：
Ferre, Silvia;de Baaij, Jeroen H. F.;Bindels, Rene J. M.
PCBD1基因突变可导致短暂性新生儿高苯丙氨酸血症和尿素（HPABH 4D）。迄今为止，HPABH 4D一直被认为是一种短暂的良性新生儿综合征，成年后无并发症。在我们的研究中，3例PCBD1基因纯合突变的成年患者，2例患者被诊断为低镁血症和肾性镁丢失，2例患者发展为糖尿病，其特征为青年成熟型糖尿病（MODY），无论血清镁水平如何。我们的研究结果表明，这些临床发现与PCBD1作为转录因子HNF 1B的二聚辅因子的功能有关。HNF1B基因突变已被证明可导致肾畸形、低镁血症和MODY。基因表达研究结合免疫组织化学分析表明，Pcbd 1在远曲小管（DCT），其中Pcbd 1转录水平上调低镁含饮食中表达。在人肾细胞系中的过表达表明，野生型PCBD1结合HNF1B共刺激FXYD2启动子，其活性有助于DCT中的Mg 2+重吸收。在HPABH 4D患者先前报告的7个PCBD 1突变中，5个突变引起蛋白水解不稳定，导致FXYD 2启动子活性降低。此外，PCBD1的胞质定位增加时，共表达HNF 1B突变体。总体而言，我们的研究结果确定PCBD1作为HNF 1B介导的转录的共激活因子，这是在DCT中微调FXYD2转录所必需的，并表明HPABH 4D患者应监测以前未被识别的晚期并发症，如低镁血症和MODY糖尿病。
Mutations in PCBD1 are causative for transient neonatal hyperphenylalaninemia and primapterinuria (HPABH4D). Until now, HPABH4D has been regarded as a transient and benign neonatal syndrome without complications in adulthood. In our study of three adult patients with homozygous mutations in the PCBD1 gene, two patients were diagnosed with hypomagnesemia and renal Mg2+ loss, and two patients developed diabetes with characteristics of maturity onset diabetes of the young (MODY), regardless of serum Mg2+ levels. Our results suggest that these clinical findings are related to the function of PCBD1 as a dimerization cofactor for the transcription factor HNF1B. Mutations in the HNF1B gene have been shown to cause renal malformations, hypomagnesemia, and MODY. Gene expression studies combined with immunohistochemical analysis in the kidney showed that Pcbd1 is expressed in the distal convoluted tubule (DCT), where Pcbd1 transcript levels are upregulated by a low Mg2+-containing diet. Overexpression in a human kidney cell line showed that wild-type PCBD1 binds HNF1B to costimulate the FXYD2 promoter, the activity of which is instrumental in Mg2+ reabsorption in the DCT. Of seven PCBD1 mutations previously reported in HPABH4D patients, five mutations caused proteolytic instability, leading to reduced FXYD2 promoter activity. Furthermore, cytosolic localization of PCBD1 increased when coexpressed with HNF1B mutants. Overall, our findings establish PCBD1 as a coactivator of the HNF1B-mediated transcription necessary for fine tuning FXYD2 transcription in the DCT and suggest that patients with HPABH4D should be monitored for previously unrecognized late complications, such as hypomagnesemia and MODY diabetes.