Early Development of Hyperparathyroidism Due to Loss of PTH Transcriptional Repression in Patients With HNF1β Mutations?

Context: Heterozygous mutations or deletions of the transcription factor hepatocyte nuclear factor 1 beta (HNF1 beta) result in a heterogeneous syndrome characterized by renal cysts and diabetes, together with a variety of other extrarenal and renal manifestations. Interestingly, in several patients with HNF1 beta abnormalities, we observed early hyperparathyroidism and PTH levels that we judged inappropriately high compared with the degree of renal function decline. Objective: Based on the above clinical observations, we tested the hypothesis of a direct role of HNF1 beta in the transcriptional regulation of the human PTH gene in the parathyroid gland. Design, Setting, and Patients: Immunostaining of human parathyroid sections, RT-PCR, chromatin immunoprecipitation (ChIP), and luciferase reporter assays in human embryonic kidney cells (HEK293) were performed. We eventually report clinical data from all 11 HNF1 beta patients known at our institute, 9 with heterozygous HNF1 beta whole-gene deletions and 2 with heterozygous HNF1 beta mutations. Results: PTH levels were high in 8 patients. In 2 of these patients, the hyperparathyroidism was clearly appropriate for the level of kidney function, whereas PTH might be discrepant in the others. We demonstrated HNF1 beta expression in PTH-positive cells of human parathyroid gland. Chromatin immunoprecipitation analysis showed that HNF1 beta directly binds responsive elements within the human PTH promoter. Cotransfection of a PTH promoter-luciferase construct with a wild-type HNF1 beta construct resulted in a maximal reduction of 30% of PTH promoter activity. Importantly, HNF1 beta mutants lacked this inhibitory property. Serial deletions in the PTH promoter construct revealed that the inhibitory effect of HNF1 beta resides between -200 and -70 bp from the transcription initiation site. Conclusions: Our data demonstrate that HNF1 beta is a novel repressor of human PTH gene transcription, which could contribute to the development of hyperparathyroidism in patients with HNF1 beta mutations or deletions.